STEM Today

Special Edition on Long Duration Spaceflight

STEM TODAY June 2016, No.9

STEM TODAY June 2016 , No. 9

CONTENTS Cognitive Neuroscience in Space

Effects of long足duration space flight on target acquisition

Gaze Control and Vestibular足Cervical足Ocular Responses After Prolonged Exposure to Microgravity

Cortical Reorganization in an Astronaut's brain after long足duration spaceflight

Individual Predictors of Sensorimotor Adaptability

Effects of Sex and Gender on Adaptation to Space: Neurosensory Systems

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

Cover Page Mars’ Spring Storms Early spring typically brings dust storms to northern polar regions of Mars. As the north polar cap begins to thaw, the temperature difference between the cold frost region and recently thawed surface results in swirling winds. The choppy dust clouds of at least three dust storms are visible in this mosaic of images taken by the Mars Global Surveyor spacecraft in 2002. Currently, the Phoenix Mars Lander is exploring the Red Planet’s northern region

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Image Credit: NASA/JPL/Malin Space Science Systems Background Hubble Rocks with a Heavy-Metal Home This 10.5-billion-year-old globular cluster, NGC 6496, is home to heavy-metal stars of a celestial kind! The stars comprising this spectacular spherical cluster are enriched with much higher proportions of metals - elements heavier than hydrogen and helium are curiously known as metals in astronomy - than stars found in similar clusters.

A handful of these high-metallicity stars are also variable stars, meaning that their brightness fluctuates over time. NGC 6496 hosts a selection of long-period variables - giant pulsating stars whose brightness can take up to, and even over, a thousand days to change - and short-period eclipsing binaries, which dim when eclipsed by a stellar companion.

The nature of the variability of these stars can reveal important information about their mass, radius, luminosity, temperature, composition, and evolution, providing astronomers with measurements that would be difficult or even impossible to obtain through other methods.

NGC 6496 was discovered in 1826 by Scottish astronomer James Dunlop. The cluster resides at about 35,000 light-years away in the southern constellation of Scorpius (The Scorpion).

Text Credit: European Space Agency Image Credit: ESA/Hubble and NASA, Acknowledgement: Judy Schmidt Back Cover NASA’s Curiosity at Site of Clues About Ancient Oxygen This scene shows NASA’s Curiosity Mars rover at a location called "Windjana," where the rover found rocks containing manganese-oxide minerals, which require abundant water and strongly oxidizing conditions to form.

In front of the rover are two holes from the rover’s sample-collection drill and several dark-toned features that have been cleared of dust (see inset images). These flat features are erosion-resistant fracture fills containing manganese oxides. The discovery of these materials suggests the Martian atmosphere might once have contained higher abundances of free oxygen than it does now. The rover used the Mars Hand Lens Imager (MAHLI) camera in April and May 2014 to take dozens of images that were combined into this self-portrait. A version of this portrait without the insets is at PIA18390.

Image Credit: NASA/JPL-Caltech/MSSS.

STEM Today , June 2016

Special Edition on Long Duration Spaceflight

STEM Today, June 2016, No.9

Effect of long-duration spaceflight on Sensory System Cognitive Neuroscience in Space The first studies on space neuroscience go back to 1962 during the Russian Vostok-3 mission, when some sensory-motor studies were carried out. On Earth, new brain imaging techniques, neuropsychological assessment tools and other physiological measures have been developed to enable very detailed studies of brain activity and cognitive functioning. For neuroscientists, as well as psychologists, it is of high relevance to understand the underlying neurocognitive and neuropsychological parameters of space flight. Unfortunately, standard brain imaging techniques (e.g., functional magnetic resonance imaging (fMRI)) are not applicable in space, due to the payload restrictions of space missions and costs. The European module "Columbus", a part of the International Space Station (ISS), was equipped with an electroencephalography (EEG) system as a tool to research the link between weightlessness and central nervous system (CNS) activity. Neurocognitive tests, electrophysiological measurements and other related methods are commonly used in space to assess brain activity, neurocognitive and behavioral status and the mental health of astronauts.

Results from Earth-based research highlight the importance of studying the effects of stress on cognitive performance. Cognitive and perceptual motor performances deteriorate under stress . We can thus expect similar effects in the stressful environment of a space mission and in extreme environments and simulations. Previous work has shown that various psychomotor functions are degraded during space flight, among them central postural functions involving hierarchically organized brain areas, including motor cortex in frontal lobes, basal ganglia, vestibular system in the midbrain and cerebellum, the speed and accuracy of aimed movements associated, among others, with primary motor cortex, cerebellum and visual cortex, internal timekeeping related to prefrontal cortex and striatum, attentional processes distributed in different brain areas, such as frontal and parietal cortex, superior colliculi subcortical region, frontal eye field and anterior cingulate cortex, limb position sense , including the primary somatosensory cortex and cerebellum, and the central management of concurrent tasks involving mainly prefrontal, temporal and parietal cortex and basal ganglia (Figure 1). Such psychomotor deficits have been implicated as the causes of accidents in space . It remains unknown to what extent these observed deficits might change during long-term space missions, as on a flight to Mars, for example. Results from Mars-500, one of the longest space mission simulations ever, revealed that a variety of neurological and psychological factors, such as circadian rhythms and social behavior, were affected by characteristics of the mission and the special environment.

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Special Edition on Long Duration Spaceflight

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Microgravity and Space Motion Sickness Gravity has shaped life on Earth. It is perceived by all organisms, from unicellular forms to humans, determines our orientation in space and helps control posture. We have specialized organs, such as the vestibular system in the inner ear, for gravity perception. Sensory information about motion, equilibrium and spatial orientation is provided by the vestibular apparatus in each ear, which includes the utricle, saccule and three semicircular canals.

The utricle and saccule detect gravity (vertical orientation) and linear movement. The semicircular canals, which detect rotational movement, are located at right angles to each other and are filled with a fluid called endolymph. When the head rotates, the direction is sensed by a particular canal. The endolymphatic fluid within the canal lags behind, due to inertia, and exerts pressure against the canal’s sensory receptors. The receptors then send impulses to the brain conveying information about movement. When the vestibular organs on both sides of the head are functioning properly, they send symmetrical impulses to the brain (Figure 2). Balance information provided by the peripheral sensory organs-eyes, muscles and joints and the two sides of the vestibular system-is relayed to the brain stem. There, it is processed and integrated with learned information contributed by the cerebellum (the coordination center of the brain) and the cerebral cortex (the thinking and memory center). A person can become disoriented if the sensory input received from his or her eyes, muscles and joints, or vestibular organs conflict with one another, and this can produce what is called motion sickness (Table 1). Approximately 70% of astronauts experience space motion sickness (SMS) during the first week of the mission.

On Earth, gravity is also a neural reference that influences how we perceive an object’s movement and orientation, an ability frequently disrupted in space. For example, moving the head while looking at a control panel can induce the perception that instruments are being displaced . Perception is a cognitive process, and the way we perceive objects in the environment affects our perception of that environment. In space, this is a challenge, due to microgravity. Microgravity alters how we perceive the environment, producing illusory perceptions that have persistent after-effects in astronauts who spend long periods in space. If perception is affected by microgravity conditions, gravity may actually have an inner representation in the brain that is needed for important functions, such as proper motor control and motor planning. This has been confirmed by studying the effects of microgravity on covert and overt actions. Furthermore, this inner representation may affect anticipation actions. However, microgravity does not affect verticality perception. Indeed, systematic behavioral observations of the motor behavior of astronauts during short-duration space flight suggest that they preferably align their posture with the vertical polarity of the spacecraft.

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Brain Activity and Sleep in Space Human sleep occurs with circadian (circa = about, and dis = day) periodicity. Circadian clocks evolved to maintain appropriate periods of sleep and wakefulness, in spite of the variable amount of daylight and darkness in different seasons and at different places on the planet. To synchronize physiological processes with the daynight cycle (photoentrainment), the biological clock must detect decreases in light levels as night approaches. The receptors that sense these light changes include poorly understood cells within the ganglion and amacrine cell layers of the retina that project to the suprachiasmatic nucleus of the hypothalamus. Other structures are also implicated, such as the pineal gland, which synthesizes the sleep promoting neurohormone, melatonin (N-acetyl-5-methoxytryptamine), from tryptophan and secretes it into the bloodstream to help modulate the brainstem circuits that ultimately govern the sleep-wake cycle. Melatonin synthesis increases as light intensity decreases through the night. To study brain activity, especially during sleep, neuroscientists use EEG. The EEG detects abnormalities in the waves and electrical activity of the brain. During the procedure, electrodes consisting of small metal discs with thin wires are pasted on the scalp. The electrodes detect tiny electrical charges that result from the activity of the brain cells. The charges are amplified and appear as a graph on a computer screen or as a printed recording. Sleep loss, fatigue and poor quality of sleep have been reported on numerous space missions.

During the space shuttle era, astronauts usually had between 5-6 h of sleep and lesser in the case of emergencies. On long-duration missions, there can be changes in the quality of sleep. Problems related to this may appear and compromise the performance levels of astronauts . Although the use of drugs is not indicated in general in the aviation work environment, some sleep medication has been used in long-duration missions upon the approval of the medical team. These sleep problems seem to be related to the lack of environmental cues, such as natural light, which produces circadian rhythm disturbances and consequent psycho-physiological effects.

However, other factors, not directly related to the environmental aspects of space missions, may play a role in sleep problems, including anxiety, workload, stress or isolation. Several sleep studies using EEG tests during Columbia and NeuroLab missions showed contradictory results . Sleep patterns were not substantially altered in space compared to prior mission tests; but, a reduction of total sleep was registered, and a clear alteration of circadian cycle was observed.

Cheron et al. examined the alterations of alpha cortical activity during the experience of weightlessness in space and showed an increase of power in the peak alpha frequency (PAF) activity. PAF is the most dominant rhythm in the relaxed, eyes-closed state and is regarded as a marker of cortical activity. Furthermore, this oscillation is considered to be involved in mental and cognitive processes. As there is an inverse relationship between

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Special Edition on Long Duration Spaceflight PAF power amplitude and the blood oxygen level-dependent signal , it is hypothesized that the alpha power increase during the stay at the ISS is due to a general lowering of cerebral blood oxygenation of astronauts and cosmonauts undergoing weightlessness, as recently shown by Schneider et al. . Although it has been argued that impairments in cognitive and perceptual motor performance in weightlessness are caused by changes in cerebral blood flow leading to changed electro-cortical signals registered on EEG, there currently is no evidence that a systemic shift of blood volume to the brain during weightlessness is correlated with neural activity.

Consequences of chronic bed-rest depend on the duration and the level of inactivity. As in weightlessness, the circulation is rearranged during the prolonged maintenance of a supine position. Initially, the central blood volume increases; perfusion and hydrostatic pressure in the lower half of the body decreases, and the slightly higher preload and stroke volume can lead to bradycardia, increased renal blood flow and mild polyuria. Over the course of weeks and months, the plasma volume and the efficacy of orthostatic reflexes regulating blood pressure decrease. When the astronaut is back on Earth again, the low blood volume is insufficient to maintain cerebral blood flow in an orthostatic position.

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Therefore, orthostatic hypotension may develop and dizziness may appear. A comprehensive return accommodation is required, and astronauts should be monitored for some time after prolonged time in space (Figure 3). Nevertheless, it so far remains unclear whether neurocognitive or neuropsychological impairments and changes are provoked by microgravity itself or by secondary, environmental-related factors. In the first study using low-resolution brain electromagnetic tomography (LORETA) in low gravity , it was demonstrated that the microgravity phases during parabolic flights result in considerable changes in frontal lobe activity, a brain region that is known to play a major role in emotional processing and the modulation of performance.

Space Neuropsychology Among all neuropsychological aspects, attention is one of the most important. Attention is a complex cognitive function that is essential for human behavior. Attention is a selection-based process required to maintain an external (sound, image, smell, etc.) or internal (thought) event at a certain level of awareness. It is not a stable, but, rather, a fluctuating skill. It is not continuously sustained, often subconsciously let up during a task. For a further review, studies on attention were performed during the Soyuz/Salyut (26/6 and T5/7) missions in the 1970s and 1980s .

Other neurocognitive aspects commonly affected in space are spatial orientation, mental rotation and recognition, spatial perception and representation and other perceptual skills (Table 2). Most perceptual problems are related to the microgravity environment characteristics that make astronauts see objects in non-customary orientations. In addition, the interaction of spatial perception with the vestibular system can be a source of conflicts in neural processing, as explained previously. Proper perception of objects may be negatively affected by non-customary orientations. One well-known example is the perception of faces. This problem also exists in space, and it is easy to understand how this may have an effect on face-to-face communication. However, other aspects of perception, such as perceived verticality, as mentioned before, are not affected. This effect is defined as the difficulty of face recognition when a face is inverted.

More recently, research has focused on developing assessment tools to detect and monitor these deficits and problems and counteract them. A decline in attentiveness may primarily occur in space, because of stress-related factors. Problems in attention performance can also indicate the possible compromise of other neuropsychological aspects, such as memory. Having accurate and helpful assessment tools is very important for monitoring performance levels and the mental health of astronauts in space. The unique environmental constraints and characteristics of space have required the development of some specific tools over the years to assess and combat these issues.

Moreover, this continues to be an important field of research. Although some now dated cognitive tests and batteries, such as MINICOG or the AGARD test, have been used in space and simulations before. The Spaceflight Cognitive Assessment Tool for Windows (WinSCAT) is the current standard for this type of assessment in space operations. WinSCAT is a time-constrained test of cognitive abilities, such as attention, math and memory . Right now, WinSCAT is routinely performed by astronauts aboard the ISS every 30 days, before or after their periodic health status test. It is also administered on special crewmembers upon the flight surgeons’ request.

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Special Edition on Long Duration Spaceflight

Effects of long-duration space flight on target acquisition The need to accurately shift gaze from one target to another, and to maintain the newly acquired image on the retina is a complex process that can be modified, authors believe, in part by behavioral requirements that are driven by changes in the environment. For example, it has been previously demonstrated that exposure to the microgravity of space flight induces modification in eye-head coordination during target acquisition . To achieve changes in sensorimotor function, current models of eye-head coordination postulate that a vestibular signal specifying head movement relative to space serves as an integral component underlying saccadic spatial programming when making head-free gaze shifts .

In these models, desired gaze position is compared to an internal representation of actual gaze position. Actual gaze position is derived by summing an efferent copy of eye position in the head with a vestibular and neck motor derived reconstruction of current head position. The difference between desired and actual gaze position produces a gaze position error signal that drives saccadic motor output until the error signal is nullified and the eye movement is stopped. Past studies have supported these models by demonstrating that saccadic eye movements generated in total darkness, successfully acquire a just seen Earth-fixed target after cessation of head angular displacement. Such saccadic eye movements are spatially targeted using remembered semicircular and otolithic vestibular information, respectively. The demonstration of this capability indicates that a functionally meaningful vestibular signal has access to the saccade generating mechanism and may therefore, play a pivotal

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Seven cosmonauts (4 high performance pilots and 3 non-pilots) who had flown between 186-198 days on Mir station served as subjects. The median age of the subjects was approximately 51 yrs. All subjects had the equivalent of an Air Force Class I physical. Study specifics were reviewed by both the Johnson Space Center Committee for the Protection of Human Subjects and the Russian Institute of Biomedical Problems Institutional Review Board. Subjects received written and verbal accounts of the test protocol and signed informed consent.

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Preflight data were collected four times; 100, 60, 30 and 14 days prior to flight (L-100, L-60, L-30 and L14) and 3 or 4 times postflight (R+1=2 days postflight, R+3=4 days postflight and R+8=7 days postflight).

During each test session the subjects were required to acquire targets that were randomly presented at 20◦ , 30◦ and 60◦ left or right from the central point of fixation with both a head and eye movement using a time optimal strategy (acquire the targets as quickly and accurately as possible). Data from a minimum of three and a maximum of five trials for each of the target locations were collected during a test session. The targets were represented by red lightemitting diodes at a distance of 75cm as measured from a class III laser mounted parallel to the target display and projected onto the outer canthus of the right eye prior to testing. All testing was done under normal room illumination. The signal to acquire a target was triggered by a computer generated tone.

At the tone the center fixation point was extinguished and a new peripheral target was illuminated. Following each target acquisition the eyes and head were returned to the center fixation position.

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Horizontal eye movements were recorded with nonpolarizing electrodes positioned at the outer canthus of each eye with the reference electrode located on the mastoid process behind the right ear. Head movements were obtained with a tri-axial angular rate sensor mounted on a headband that was attached firmly to the subjectŠs head. Analog signals from both the eye electrodes and rate sensors were amplified, digitized, and acquired on a computer for subsequent offline analysis.

Results Before flight, all cosmonauts demonstrated a conventional pattern of horizontal target acquisition that consisted of three phases. During the first phase, with a 181-240ms latency, an emerging saccade was directed toward the target. This initial saccade was followed 15-40ms later with a head movement towards the target. During this second phase, gaze reached the target with a joint eye and head movement and the saccadic movement was completed. During the third phase, the head was still moving toward the target, with a compensatory movement of the eyes approximately equal to that of the head permitting gaze stabilization to occur ( Fig. 1).

In spite of this relatively common pattern of gaze stabilization, the variability of the major parameters (peak head, eye velocity and amplitude) was extremely mutable. That is, while there is a common pattern of acquiring specific targets with the head and eye free to move from straight ahead gaze to a new peripheral target; it is believed that trade-offs in head and eye velocities and peak amplitudes can be selectively varied according to a preferred strategy. A simple cluster analysis that involved partitioning the data into related subsets according to flight crew assignment showed two distinct groups (pilot and non-pilot) where unique head and eye movement strategies were used for target acquisition (Table 1).

Specifically, non-pilots employed what was termed a Type-I strategy consisting of high velocity head movements with large peak amplitudes, while pilots used primarily low velocity, small amplitude head movements (Type-II) to acquire the targets (p<0.02). Fig. 1 shows the analog responses recorded for both Types-I and -II strategies before flight and immediately (2+days) postflight. For both strategies peak head velocities increased as the angular distance to the target increased (p<0.01) resulting in greater discrimination between the two distinct strategies for the 60◦ targets (Fig. 2). These differences in peak head velocities were also reflected in the time it took to stabilize gaze.

These data suggest that extended exposure to long duration microgravity affected the target acquisition process substantially. After landing we observed changes in both the amplitude and kinematic parameters for the head and eye movements related to the Type-I and -II strategies. As seen in Fig. 2, and consistent with the newly adopted strategy, during the early stage of recovery after space flight (R+1/+3) peak head velocities for the Type-I group significantly decreased when compared to the preflight values for the 30◦ and 60◦ targets (p<0.02)(Fig. 2-A). Changes in head velocity for the Type-II group showed an increase that was also expressed

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primarily for the 30◦ and 60◦ targets (p<0.02) (Fig. 2B). When peak head amplitude was examined there was not a significant difference in the 20◦ and 30◦ target compared to preflight.

At the same time peak head amplitudes did not change significantly in response to the 20◦ , 30◦ or 60◦ targets (primarily because of the variability across trials) but did show a trend towards significance when acquiring the 60◦ target (Fig. 3).

In the Type-I strategy group, postflight testing showed a significant decrease in eye velocity compared with preflight performance (p<0.02) for all target locations (Fig. 4A). These changes were largest in response to 60◦ targets. Saccades showed a slight tendency to decrease in amplitude while saccade duration remained fairly constant. For the Type-II group (Fig. 4B) the decrease in peak eye velocity decrease was smaller than that for the Type-I group, but was significant for only the 20◦ targets (p<0.05).

It is interesting to note that while peak eye velocity decreased for all target displacements for both the Type-I and -II strategy groups, the pattern of the decrease has a tendency to be somewhat opposite in nature for the two groups. That is, postflight peak eye velocity for the Type-I strategy has a tendency to decrease from the 20◦ target to the 60◦ target, while for the Type-II strategy, postflight eye velocity tends to increase from the 20◦ to 60◦ target. At the same time saccade amplitudes for both groups showed a non-significant tendency to decrease across all target displacements.

On R+1, latency measurements for the eye and head movements to the 60◦ target increased on averaged by 25-40ms with the exception of the Type-I group in which the head latencies in response to the 60◦ targets increased by 100ms (Fig. 5). A gradual return to baseline values was observed by R+8. Preflight, it took each cosmonaut 450-640ms to stabilize their gaze after the presentation of the target. This time (gaze latency) increased as a function of the angular position of the target (Fig. 6). On the initial days of recovery all cosmonauts took longer for gaze stabilization to occur. For example, on R+1/2 gaze latencies exceeded the cosmonaut’s preflight baseline values by 110-10 ms. These changes were more characteristic of the Type-I strategy for all the target distances. This difference gradually diminished, and by R+8 gaze latencies for the Type I group approached that of the baseline values.

The observation that a particular strategy in acquiring targets was adopted by some cosmonauts, but not all, contributed to the variability in our data samples. Further analysis combining all responses by both groups (Types-I and -II) across all target displacements revealed an interesting pattern of statistical variation related to the different parameters associated with the acquisition of the targets used in this investigation. Specifically, after space flight, the spread in values for eye latency reached 42.6% (vs. 6.67% before flight), and head latency had a value of 37.5% (vs. 14.22% before flight). The range of variation for gaze latency was also increased following flight during the first week to 34.3% (vs. 15.78% before flight). For the head and eye peak amplitudes, the variability decreased after space flight to 24.1% (vs. 44.1% from preflight) for the head and 17.6% (vs.

30.1% preflight) for the eye.

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Overall the data also suggest that regardless of the preflight strategy associated with the acquisition of different targets in the horizontal plane, adaptation to microgravity will drive a change in that strategy. However, authors believe based on the data that the original strategy serves as the base around which change is manifested. It is not possible to identify specific sensorimotor systems that may be responsible for driving adaptation to a space flight environment. However, most believe that the otolith organs and their interactions with the semicircular canals and the muscles controlling movement are the likely candidate associated with the drive for adaptation.

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Special Edition on Long Duration Spaceflight

The increased variability associated with the different parameters of target acquisition during the readaptation process suggests something of a CNS searching strategy. This same finding has been reported by other investigators when describing the adaptation process to space flight (and to simulated microgravity) in the other systems. We can make a supposition that with altered activities of the gravity-dependent sensory systems the normal neural program control of target acquisition precision becomes impossible. Deprived of programmability, target acquisition relies predominantly on feedback which explains the increase of time for task implementation.

Gaze Control and Vestibular-Cervical-Ocular Responses After Prolonged Exposure to Microgravity Microgravity does not affect visual function directly. However, because of the altered afferentation from vestibular, support, and tactile-proprioceptive systems, it could lead to disturbances in visual tracking and inhibit the cosmonautâ&#x20AC;&#x2122;s activity. Therefore, it is necessary to obtain quantitative evaluations of spaceflight effects upon gaze control and vestibular-cervical-ocular responses.

The study involved 26 Russian crewmembers of the ISS-3 to ISS-24 expeditions from 2001 to 2010. Their ages ranged between 35 and 50 yr, with their average age being 41.5 yr. Length of stay on the ISS was between 129 and 215 d. All cosmonauts had undergone extensive medical examinations (including examination by an ophthalmologist and neurologist), had normal vision with no oculomotor abnormalities, had no known clinical vestibular problems, and were not taking drugs which affect the nervous system.

The study protocol (science experiment "Sensory Adaptation" and clinical-physiological investigation "Vestibular Function Check up") was reviewed and approved in advance by the Bioethics Board of the Institute of Biomedical Problems and Human Research Multilateral Review Board. All cosmonauts gave written, informed consent before participating in the experiment. Data was acquired twice prior to spacefl ight (L-45 and L-30) and after landing on R+1-2, R+4-5, R+8-9, and sometimes R+14-19 where the exact date of examination (for example, R+1 or R+2) depended on landing conditions and health status of the cosmonaut.

Results Spontaneous Eye Movements (SpEM) with Eyes Closed In terms of clinic neurology and according to our accumulated data for postflight examinations,"normal SpEM with eyes closed" means: stable EOG, no spontaneous nystagmus, no slow wave drifts, and no square-wave jerks,

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Special Edition on Long Duration Spaceflight no gaze-evoked nystagmus in ’extreme’ positions. It should be mentioned that even in a healthy individual an end-point nystagmus could occur, once the angle of eye deviation is greater than 40◦ . But preflight there was no gaze-evoked nystagmus in such ’extreme’ positions for all cosmonauts and its sudden appearance postflight should not be counted as a normal physiological reaction.

Before spaceflight, all cosmonauts but one had normal SpEM. This one cosmonaut developed a persistent spontaneous nystagmus in the central position in both horizontal and vertical planes (AN y = 2.5 ± 0.3◦ ; VN y =4.3 ± 0.8◦ *s−1 ; FN y = 0.5 ± 0.04 Hz). On R+1-2, 12 cosmonauts had normal SpEM and 7 cosmonauts had disturbed SpEM with an increased saccadic activity (square-wave jerks) and slow wave drifts. The remaining seven cosmonauts had spontaneous nystagmus (A N y = 3.5 ± 0.5◦ ; VN y = 6.1 ± 0.7 ◦ * s−1 ; FN y =1.5 Hz) and gaze evoked nystagmus (AN y = 2.5 ± 0.5◦ ; VN y = 3.9 ± 0.7 ◦ * s−1 ; FN y = 0.5± 0.08). Gaze evoked nystagmus was again observed in three cosmonauts on R+4-5. On R+8-9, six cosmonauts demonstrated increased squarewave jerks and slow wave drifts, whereas other cosmonauts regained normal SpEM. On R+13-14, SpEM had returned to normal for all cosmonauts.

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Fixation Saccades (FS)

Analysis of saccadic eye movements in horizontal and vertical planes on R+1-2, R+4-5, and R+8-9 has showed that the majority of cosmonauts required an increased number of corrective saccades to foviate the target (Fig. 1). This increase of corrective saccades as well as a significant decrease of amplitude and peak velocity of the primary saccade resulted in delay to acquire both horizontal and vertical stimuli by up to 2-3 times from the normal baseline time required for a target acquisition. Total reaction time was increased significantly until R+89, although latency differed significantly from the baseline only on R+1-2. Parameters of pre- and postflight FS are presented in Table I .

To emphasize effects of microgravity upon various parameters of saccades (amplitude ratio, peak velocity etc.), authors analyzed not only the actual parameters but also their differences in comparison with the baseline (i.e., samplings did not contain parameters per se, but the delta/difference between a parameter on postflight day and its baseline value). Both approaches for parameters themselves and for parameters’ differences have shown identical results concerning significant changes postflight in comparison with the baseline. Cosmonauts demonstrated a statistically significant degradation of all parameters except latency until R+8-9. Postflight there was a significant increase in variation of corrective saccades (increased coefficient of variation) which can be caused by intragroup differences. Prior to spaceflight, 62% of cosmonauts had no corrective saccades and the remainder had them in the range of 5 to 10%, but on R+1-2 and R+4-5 all cosmonauts without exception had increased numbers of corrective saccades between ≈ 20 - 35% for horizontal stimuli and ≈ 30 - 45% for vertical stimuli.

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Smooth Pursuit (SP) Analysis of SP has shown not only disturbances in the pursuit function, but also a complete breakdown of the reflex which was observed in nine cosmonauts. These cosmonauts were unable to smoothly pursue either the linear or sinusoidal stimulus (or both stimuli) and unconsciously chose a new, saccadic strategy for the VT. This change is clearly revealed in Fig. 2 . A stepwise rather than smooth gaze motion (i.e., a sequence of corrective saccades) while tracking the sinusoidal and linear stimuli was enhanced on R+1-2 and R+4-5. Table II contains gain of the SP (gSP) pre- and postflight. gSP was analyzed by both repeated measures parametric ANOVA (F-test and post hoc analysis by Tukeyâ&#x20AC;&#x2122; s method) and nonparametric (Friedmanâ&#x20AC;&#x2122;s test and post hoc pairwise comparisons made by Wilcoxon with a Bonferroni correction). Significant differences were revealed for horizontal gSP on R+4-5 and R+8-9.

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During preflight velocity of the VT was practically equal to velocity of the stimulus (gSP â&#x2030;&#x2C6; 1.0). After spaceflight gSP was significantly decreased during the entire examination period. Despite the process of readaptation to terrestrial conditions (gSP was signifi cantly increased on R+4-5 and R+8-9 in comparison with the previous day of examination), SP function had only partially recovered on R+8-9.

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Gaze Holding (GH) on Real and Imaginary Targets Before spaceflight, cosmonauts were quite successful in their ability to hold their gaze on the imaginary target (last observed position of the stimulus). However, after spaceflight all GH parameters were significantly degraded and the success of the reaction was decreased. Parameters of the GH pre- and postflight are presented in Table III , and it is clearly evident that the reflex was not fully recovered even on R+8-9. Fig. 3 shows eccentric GH on real and imaginary targets in the horizontal and vertical plane preflight and on R+2. It should be noted that on R+1-2 gaze-evoked nystagmus was registered during the eccentric gaze on an imaginary target.

Static Torsional Otolith-Cervical-Ocular Reflex (OCOR) Preflight amplitude of the compensatory torsional ocular counter-rolling remained within the expected 4-8◦ normal range and the torsional reflex was symmetrical except for one cosmonaut. This cosmonaut had an asymmetrical reflex: his eyes counter-rolled by 4◦ during head tilt to the left shoulder and by 8◦ during head tilt to the right shoulder. Tests performed on R+1-2 did not produce torsional compensatory counter-rolling in four cosmonauts. A reversed reflex was registered in three cosmonauts (torsional counter-rolling took same direction as the head tilt), and the amplitude of OCOR was reduced by half in another seven cosmonauts. Several cosmonauts showed square wave jerks in the horizontal plane and an almost continuous upward beating nystagmus in the vertical plane. No changes were found in only three cosmonauts.

On R+4-5 and R+8-9 only six cosmonauts showed a decreased OCOR. For other cosmonauts the amplitude of torsional counter-rolling was either equal to or close to the baseline. Dynamics of these changes are shown in Table IV . Statistical analysis was made by ANOVA F-test and Friedman’s test. Both methods with a significance level being α= 0.01 have shown that there were significant differences within the whole group both for head tilts rightward and leftward. Post hoc multiple comparisons with significance level α= 0.01 made by a parametric (Tukey’s test, Newman- Keuls’ and Dunnet’s tests) and nonparametric (Wilcoxon test with a Bonferroni correction) methods have shown similar results. For both directions of the head tilt, amplitudes of the OCOR on R+1-2 and R+4-5 were significantly decreased in comparison with the baseline and R+8-9, and also there was a significant difference between R+1-2 and R+4-5 for leftward head tilt. Amplitude of the OCOR reached its preflight level only on R+8-9. Gain of the OCOR was analyzed with α= 0.01 by the same methods as the amplitude mentioned above. This analysis has shown identical results and allows us to conclude that signifi cant changes in static torsional OCOR found postflight should not be explained by differences of the head tilt angle.

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Dynamic Horizontal Vestibular-Cervical-Ocular Reflex (HVCOR) During Head Yaw Rotations with Eyes Closed Gain of the HVCOR (gHVCOR) before spaceflight was within the normal range of 0.4-0.5 in all cosmonauts. The gHVCOR analyzed pre- and postflight is presented in Table IV . After spaceflight cosmonauts were divided into three groups depending on a trend in gain values: 1) gHVCOR was increased; 2) gHVCOR was decreased; and 3) there was no change in the gHVCOR. It was found that for the first two groups (with increased and decreased gain), postflight changes were significant and prolonged up to R+9.

Vestibular Reactivity (VR) During Head Yaw Rotations with Eyes Closed Before spaceflight active head yaw rotations produced a short-term nystagmus in only three cosmonauts. However on R+1-2, 19 cosmonauts demonstrated an increased VR. Of these 19 cosmonauts with an increased VR, 11 had a constant nystagmus (AN y ≈ 6-10◦ ; VN y ≈6-20◦ *s..1 ; FN y ≈ 2-4Hz). In another eight cosmonauts along with an increased VR there was a sharp decrease of compensatory eye movements during head yaw rotations, although nystagmus was observed throughout the test. For the remaining seven cosmonauts, VR did not

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change from the baseline values. VR preflight and on R+1-2 is shown in Fig. 4 . On R+4-5, seven cosmonauts maintained an increased VR, while for other cosmonauts it was returned to the baseline, and by R+8-9 VR was back to normal in all but one cosmonaut.

Characteristics of the vestibular-induced nystagmus are presented in Table IV . They were analyzed by parametric ANOVA (F-test + post hoc analysis by Tukey’s method). As mentioned earlier, there was almost no vestibular-induced nystagmus preflight and postflight on R+8-9, but on R+1-2 and R+4-5 nystagmus was clearly manifested and significantly increased in comparison with baseline and R+8-9. In addition to the variance analysis, we used Pearson’s and Spearman’s correlation criteria to detect the existence (or absence) of direct (linear) relationship between readaptation changes in individual’s levels of the vestibular system and various parameters of the VT (FS,SP, GH). In other words, for each parameter the sampling contained 3 slices (points): a subtraction (delta) between parameter’s value preflight and on R+1-2, a subtraction between values on R+1-2 and R+4-5, and a subtraction between values on R+4-5 and R+8-9.

Analysis of correlation between postflight changes in OCOR and VR showed a significant negative correlation (r = -0.76, P < 0.05) on R+1-2. On R+4-5 it was increased up to r = -0.44 and remained practically unchanged on R+8-9 (r = -0.42). The most marked correlation was the one between amplitude of OCOR and FS amplitude ratio (r = 0.7 ... 0.9, P <0.05) and peak velocity (r = 0.7 ... 0.95, P < 0.05). This correlation between OCOR and FS was strong during the whole readaptation period both for horizontal and vertical saccades. Along with the vestibular system, central structures of the CNS (SpEM) were also correlated with visual tracking. Both postflight changes in smooth pursuit (SpEM/gSP r ≈ -0.6) and fixation saccades (SpEM/ amplitude ratio ≈ 0.7; SpEM/peak velocity ≈ 0.8; SpEM/ corrective saccades ≈ -0.8) were correlated with SpEM on R+1-2 and R+4-5. However, it concerned only VT in the horizontal plane and there was no correlation between SEM and any parameter of the vertical VT. Results shown in this work demonstrate that most parameters, which characterize the state of the vestibular and oculomotor function during readaptation to terrestrial gravity, undergo significant changes in comparison to the baseline. As authors are continuing to observe, unique methods or strategies for gravitational compensation are adopted by individual astronauts and cosmonauts . For the most part authors believe that earlier data as well as data presented in this paper, show that these strategies are not conscious decisions; rather they represent the way that an individual’s CNS adapts to changes that affect performance and function. Along with

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Special Edition on Long Duration Spaceflight unique adaptive changes to the novel gravitational environment, authors were able to find regular, typical consistent changes that appeared across individuals. The postflight increase in SpEM, degradation of the GH ability, and the new saccadic tracking strategy instead of the SP indicate the involvement of central mechanisms of the vestibular system and reflect, probably, changes in functioning of the vestibular nuclei, reticular formation of the middle brain, and the cerebellum .

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Torsional ocular counter-rolling induced by a body or head tilt was examined after spaceflight as an indicator of the adaptation of otoliths to microgravity. In microgravity there is no otolith-induced compensatory torsional ocular counter-rolling in response to a sustained tilt . Previously it was shown that torsional ocular counterrolling was reduced both after short-duration and long-duration missions . Similar changes were observed in two primates after spaceflight. However, there was no change in torsional ocular counter-rolling in astronauts who flew in the 1998 Neurolab Mission (STS-90) . In this experiment four crewmembers were examined pre-, in-, and postfl ight. Astronauts were exposed to artifi cial gravity (1 g or 0.5 g centripetal acceleration) generated by centrifugation. Absence of differences between pre-,in-, and postfl ight torsional ocular counter-rolling could be explained by an intermittent exposure to artificial gravity during the 16-d mission, which had prevented deconditioning of otolith-ocular reflexes in microgravity. These data allow us to consider in-flight centrifugation as a countermeasure for vestibular disorders occurring during and after spaceflight. Postflight data (absence, inversion, or a sharp decrease of the OCOR) show that adaptation to microgravity is associated with a deep and long suppression of OCOR. Cortical reorganization in an astronautâ&#x20AC;&#x2122;s brain after long-duration spaceflight This study aimed at characterizing the impact of long-duration spaceflight on brain function in a single cosmonaut, measured by functional MRI. A 44-year-old male cosmonaut had his first long-duration mission (169 days) to the International Space Station (ISS) in 2014. During spaceflight, the cosmonaut strictly followed the physical and locomotor training in accordance with the Russian countermeasure system. His overall physical performance showed no abnormalities according to the Institute of Biomedical problems (IMBP, Moscow), monitoring the health of the space travelers in the Russian segment of the ISS. On the day of landing, the sensorimotor assessment showed vestibular ataxia, indicating a dysfunctional vestibular system and proprioception.

Clinical investigations 3 days postflight revealed continued impairment of motor coordination, similar to earlier reports (Paloski et al. 1993), but disappearance of vertigo.

The fMRI protocol was applied twice: 30 days before launch and 9 days after Earth re-entry. During both assessments, the cosmonaut had a 10-min scanning session in a resting condition and a session while executing active mental imagery tasks (i.e., imagining playing tennis, imagining walking around the rooms of his house).

These protocols were chosen on the grounds that they can, respectively, identify changes at the whole-brain level (Heine et al. 2012), at the motor system (Monti et al. 2010), while the navigation task was used as a control task where no changes were a priori expected. The resting state assessment encompassed (1) a hypothesis- free exploration of changes in the strength of global connectivity pattern as estimated by the intrinsic connectivity contrast (Martuzzi et al. 2011) (voxel-to-voxel connectivity analysis) and (2) a hypothesis-driven estimation of connectivity changes in six brain networks, namely the default mode, the fronto-parietal, the salience, the auditory, the sensorimotor, and the visual network (seed-to-voxel connectivity analysis). With regards to the measure of intrinsic connectivity contrast, it was found that at postflight there was reduced connectivity in the right insula (Fig. 1a; x = 48, y = -6, z = 4, z value = -4.24, pFDR<0.05 at cluster-level) and ventral posterior cingulate cortex (x = 6, y = -22, z = 24, peak voxel z value = -3.95, pFDR<0.05 at cluster-level).

With regards to the network-level approach, all networks were characterized by their typical spatial pattern across the group of healthy volunteers (SOM, Fig. 1). Network-level functional connectivity changes at postflight were identified for the default mode network only. Specifically, reduced connectivity was indentified in areas not typically belonging to the network but classically anticorrelating with it, such as in the precentral gyrus (x = 34, y = -22, z = 64,peak voxel z value = -3.85) and the postcentral gyrus (x = 30, y = -22, z = 48, peak voxel z value = -3.75); seed-by-seed secondary connectivity analysis identified that the connectivity changes resulted from the seed region placed on the left cerebellum (Fig. 1b). No functional connectivity changes were identified in the other networks. The analysis of the active mental imagery tasks showed that the cosmonaut had higher activation of the supplementary motor area (x = 9, y = -1, z = 67, peak voxel z value = 3.11, puncorrected <0.001) post-flight compared to pre-flight for the tennis paradigm. No difference in brain activation was identified for the spatial navigation task as expected.

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Authors identified altered brain function in the cosmonaut induced by long-duration spaceflight. Specifically, resting state connectivity decreases were identified for the right insula as well as between the left cerebellum and the right motor cortex. The findings that the motor cortex appeared less connected during resting-state and was activated more during the active task could be considered as a compensatory/adaptive response to the microgravity environment as well as to the early post-landing phase. The precentral-,postcentral gyrus and cerebellum, affected in the cosmonaut, are associated with voluntary motor initiation, proprioception, and motor coordination, respectively. Deficits in these brain areas are therefore concomitant with problems of speed and accuracy of aimed movements [primary motor cortex, Brodmann area (BA) 4], somatosensory problems (primary somatosensory cortex, BA3), and movement-timing problems (cerebellum). Earlier studies on the physiological consequences of spaceflight on motor behavior , e.g., deficits in head-trunk coordination , postural instability, and changes in lower limb kinematics with implications on gaze stabilization , support the current findings.

A decreased resting state connectivity in the right insula postflight, which is part of the vestibular cortex where the afferents from the otolith organs and semicircular canals converge. This cortical vestibular network is involved in the integration of neurosensory input (i.e., vestibular, visual and proprioceptive input) and its functions include processing of self-motion, spatial orientation, and memory , perception of vertical and visual processing related to gravitational cues. The reversible problems after spaceflight summed up above have often been attributed to the vestibular system and in particular to the deconditioned gravity sensing otolith system.

The current study, however, suggests that several of these problems originate from alterations at the cortical level, rather than being merely attributed to the peripheral neurosensory organs. Changes in brain function could account for the fact that second time flyers are less prone to some of these problems than first-time flyers, given the process of neural adaptation .

In conclusion, functional MRI investigation of brain function in a cosmonaut after 6 months exposure to microgravity indicates alterations in vestibular and motor-related regions. These dysfunctions can account for reduced vestibular function and motor control abilities at re-entry.

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Individual predictors of sensorimotor adaptability Effect of Space Flight on Upper Limb Sensorimotor Function A number of studies of eye-hand coordination have been performed during space flight missions. The following subsections summarize some of the key evidence for eyehand control performance decrements associated with space flight.

Control of Aimed Arm Movements When astronauts first encounter an altered gravity environment, arm movements are often inappropriate and inaccurate . During the Neurolab Space Shuttle mission (STS-90), Bock et al. (2003) performed an experiment in which subjects pointed, without seeing their hands, to targets located at fixed distances but varying directions from a common starting point. Using a video-based technique to measure finger position they found that the mean response amplitude was not significantly changed during flight, but that movement variability, reaction time, and duration were all significantly increased. After landing, they found a significant increase in mean response amplitude during the first postflight session, but no change in variability or timing compared with preflight values. In separate experiments, Watt (Watt et al., 1985; Watt, 1997) reported reduced accuracy during space flight when subjects pointed to memorized targets. This effect was much greater when the hand could not be seen before each pointing trial. When subjects pointed at memorized locations with eyes closed, the variability of their responses was substantially higher during space flight than during sessions on Earth. In other studies (Berger et al., 1997; Papaxanthis et al., 1998), the investigators found that when crewmembers on the Mir station pointed to targets with eyes open, variability and mean response amplitude remained normal, but the movement duration increased by 10-20% over the course of the mission (flight day 2-162).

Reaching and Grasping Thornton and Rummel (1977) showed that basic tasks such as reaching and grasping were significantly impaired during the Skylab missions. Later, Bock et al. (Bock et al., 1992, 1996a, b; Bock, 1996; Bock and Cheung, 1998) investigated pointing, grasping, and isometric responses during brief episodes of changed gravity, produced by parabolic flights or centrifugation. These experiments provided converging evidence suggesting that during either reduced or increased gravity, the mean amplitude of responses is larger than in normal gravity, while response variability and duration remains unchanged. During the Neurolab Space Shuttle mission, Bock et al. (2003) found that the accuracy during flight of grasping luminous discs between the thumb and index fingers was unchanged from preflight values, but task performance was slower.

Manual Tracking Changes in the ability of crewmembers to move their arms along prescribed trajectories have also been studied in space. For example, Gurfinkel et al. (1993) found no differences in orientation or overall shape when crew members drew imagined ellipses oriented parallel or perpendicular to their long body axes with their eyes closed. In another study, Lipshits et al. (1993) examined the ability of crewmembers to maintain a cursor in a stationary position in the presence of external disturbances. They found no performance decrements when the disturbances were easily predictable. However, in a follow-on experiment using more complex disturbances, Manzey et al. (1995, 1998) found that tracking errors were increased early in flight, but gradually normalized within 2-3 weeks of exposure to the space environment. Later, Sangals et al. (1999) reported a series of steptracking experiments conducted before, during, and after a 3-week space flight mission. Accuracy was affected only marginally during and after flight. However, kinematic analyses revealed a considerable change in the underlying movement dynamics: too-small force and, thus, too-low velocity in the first part of the movement was mainly compensated by lengthening the deceleration phase of the primary movement, so that accuracy was regained at its end. They interpreted these observations as indicating an underestimation of limb mass during flight. No reversals of the in-flight changes (negative aftereffects) were found after flight. Instead, there was a general slowing down, which could have been due to postflight physical exhaustion.

Force Discrimination and Control During a MIR station mission the ability of a cosmonaut to reproduce several positions of a handle from memory was tested. The accuracy with which the handle was set to a given position was reduced; however, the temporal parameters of the movement and the number of discernable handle positions did not change (Lipshits et al., 1993; Reschke et al., 1996). Fine Motor Control Campbell et al. (2005) evaluated the feasibility of survival surgery performed on rats during the Neurolab Shuttle mission. Craniotomy, leg dissection, thoracotomy, laminectomy, and laparotomy were performed as a part of physiological investigations. Surgical techniques successfully performed on rats during space flight include general anesthesia, wound closure and healing, hemostasis, control of surgical fluids, operator restraint, and control of surgical instruments. Although the crew noted no decrement in manual dexterity, the operative times were longer compared with on Earth due to the need to maintain restraint of surgical supplies and instruments. In another study, Rafiq et al. (2006) measured the effect of microgravity on fine motor skills by investigating basic surgical task performance during parabolic flight.

They found that forces applied to the laparoscopic tool handles during knot tying were increased while knot

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Dual Tasking and Manual Performance Manzey et al. (1995, 1998) investigated motor skills in space under dual-task conditions in single case studies.

They found interference between a compensatory tracking task and a concurrent memory search task to be greater in space than on Earth. The elevated interference was greatest early in flight, but gradually normalized, reaching the preflight baseline only after about 9 months in orbit. In one of these studies, Manzey et al. (1995) also found that task interference was independent of the difficulty of the memory search task, suggesting that the critical resources affected were probably not those related to memory, but rather those pertinent to motor control (both tasks required an immediate motor response). Bock and colleagues have also shown that motorcognitive dual tasking costs are higher during microgravity portions of parabolic flight (Bock et al., 2003) and when crewmembers are on the International Space Station (Bock et al., 2010). In the latter case, manual tracking of a target was particularly affected by concurrent performance of a rhythm production reaction time task, suggesting that complex motor planning resources are particularly affected by spaceflight.

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The laboratory tasks described above might actually underestimate the impairments with microgravity as many differ from real-life scenarios. For example, it was reported that microgravity slowed aimed arm movements by 10-30% on experimental tasks, but time and motion studies of routine activities on Skylab documented up to 67% slower movements in microgravity than on Earth.

Effect of Space Flight on Posture and Locomotion Behavioral Predictors Sensory Bias Subjects who rely more on vision for control of movement have more difficulty adapting their walking and postural control strategies in new environments, indicating that visual dependency may predict decreased ability to adapt to novel environments (Hodgson et al., 2010; Brady et al., 2012; Eikema et al., 2013). Interestingly, Lex et al. (2012) found that individual differences in cognitive representations of movement direction were associated with rate of adaptation on a visuomotor adaptation task. Participants were asked whether pairs of movement directions were similar or not. Those that made judgments reflecting a global cognitive representation of movement directions that was aligned to cardinal axes were faster adapters. In contrast, subjects that made judgments reflecting local cognitive representations that were aligned to neighboring directions were slower adapters. Although not discussed in the article, the latter representation strategy would be more visually based and global representations would be linked to gravitational cues.

Computerized dynamic posturography (CDP) tests, which can determine the extent to which an individual effectively uses vestibular, visual, or proprioceptive cues for balance, may also serve as predictive markers of adaptation to spaceflight. Postural ataxia following space flight reflects the adaptive changes in spatial processing of sensorimotor control and the unloading effects of microgravity (Wood et al., 2011a). CDP has been used to examine postural ataxia following both shortand long duration flights, using the Sensory Organization Tests (SOTs) provided by the EquiTest System platform (NeuroCom International, 2003). The greatest decrements following spaceflight are observed when the subjectâ&#x20AC;&#x2122;s eyes are closed and the support surface rotates in direct proportion to anterior-posterior body sway, disrupting somatosensory feedback, a protocol known as sway referencing (Paloski et al., 1992, 1994; Paloski, 1998). This condition is thus sensitive to adaptive changes in how vestibular feedback is utilized for postural control (SOT5). Most of the crewmembers had increased reliance on feedback from vision during their recovery process as a result of degraded performance of the other two feedback systems during adaptation to microgravity (Reschke et al., 1998). It has been recently demonstrated that the diagnostic performance of this test was enhanced with the addition of dynamic pitch head tilts. This finding is consistent with crewmember reports that activities of daily living requiring head tilts are more challenging during postflight recovery, presumably due to adaptive changes in the multisensory integration of the spatial vertical (Wood et al., 2011b).

In sum, an individualâ&#x20AC;&#x2122;s innate sensory weighting, or the rigidity with which they adhere to a particular sensory weighting, may predict their adaptability to microgravity and subsequent readaptation upon return to Earth.

Behavioral Measures of Individual Motor Learning Responses as Predictors of Adaptability Several studies have examined the time course of motor learning in different training paradigms such as a visual discrimination task (Karni and Sagi, 1993; Karni and Bertini, 1997) or while learning to adapt to either

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visual (Redding and Wallace, 1996) or mechanical distortions (Shadmehr and Mussa-Ivaldi, 1994; Kording et al., 2007). The time course of motor learning occurs in two stages: (1) a fast, within-session improvement that can be induced by a limited number of trials on a time scale of minutes; and (2) a slowly evolving, incremental performance gain, triggered by practice but taking hours to become effective (Karni and Bertini, 1997). Two distinct neural systems that differ from each other in their sensitivity to error and their rates of retention have been identified (Smith et al., 2006). Separate neural substrates may control the execution of these two motor strategies (Pisella et al., 2004; LuautĂŠ et al., 2009). Pisella et al. (2004) reported that a patient with a bilateral lesion of the posterior parietal cortex (PPC) was not able to implement online strategic adjustments in response to a prismatic shift in visual feedback during a pointing task, yet showed adaptive after-effects, suggesting that the strategic component was linked to the PPC, and the adaptive component was linked to the cerebellum.

Anguera et al. (2010) showed that cognitive processes such as spatial working memory contributed to the early and not the late stage of sensorimotor adaptation by comparing the rates of adaptation and overlap of the neural substrates underlying these two motor learning stages during a visuomotor adaptation task. Strategic motor control occurs early in the adaptation process once the subject becomes aware of the sensory manipulation and understands on some conscious level how to correct for it (Redding and Wallace, 1996; McNay and Willingham, 1998; Seidler, 2004). For example, subjects exposed to a prismatic lateral shift in vision make strategic corrections in pointing movements based on visual feedback to improve performance and eventually point directly to a target (Weiner et al., 1983; Rossetti et al., 1993; Welch et al., 1993). Bock and Girgenrath (2006) investigated the strategic and adaptive realignment components of sensorimotor adaptation of arm aiming movements in response to distorted visual feedback in young and older adults. They found that the recalibration processes were not impaired in older adults compared to young adults, as shown by the magnitude of after effects and transfer of adaptation to novel sensorimotor arrangements, but the strategic processes as represented by improvements during exposure were degraded (Bock, 2005; Bock and Girgenrath, 2006).

These findings support the notion that individual capability for strategic and plastic-adaptive responses shown in behavioral adaptability tests may predict the rate of adaptation to microgravity and re-adaptation upon return to Earth.

Cognitive Factors Visuomotor adaptation involves the recalibration of a welllearned spatial-motor association. There is evidence to support that visuomotor adaptation is cognitively demanding, at least in the early stages (Eversheim and Bock, 2001; Taylor and Thoroughman, 2007, 2008). For example, Eversheim and Bock (2001) used dual task paradigms to demonstrate that cognitive resources are engaged in a time-dependent fashion during adaptation: resources related to spatial transformations and attention were highest in demand early in adaptation, while those related to movement preparation were more in demand later in learning.

Authors have investigated whether individual differences in spatial working memory capacity relate to the speed of adaptive performance changes in a visuomotor adaptation paradigm (Anguera et al., 2010). Variation exists in the number of items that individuals can hold and operate upon in working memory (cf. Vogel and Machizawa, 2004), making it particularly amenable to individual differences research approaches. For example, individual differences in working memory capacity have been found to be predictive of math problem solving (Beilock and Carr, 2005). Authors investigated the contribution of working memory and other cognitive processes to sensorimotor adaptation by administering a battery of neuropsychological assessments which measured abilities in attention, processing speed, verbal and spatial working memory. Participants also adapted manual aiming movements to a 30â&#x2014;Ś clockwise rotation of the visual feedback display about the central start location. Authors divided the learning curve into "early" and "late" components for each individual. We found that performance on the card rotation task (Ekstrome et al., 1976), a measure of spatial working memory, was correlated with the rate of early, but not late, learning on the visuomotor adaptation task. Importantly, there were no correlations between measures of verbal working memory and either early or late learning, suggesting that spatial working memory capacity is a specific predictor of early visuomotor adaptation rate. These findings support the notion that individual differences in spatial working memory capacity may also serve as an effective predictor of spaceflight sensorimotor adaptation success.

Motor Variability Wong and Shelhamer (2014) reported that the rate at which participants adapt saccadic eye movements in response to a double-step target displacement (target location changes during a saccade) was predicted by the extent to which baseline saccade errors were correlated across trials. This suggests that common error detection and correction mechanisms may be at play both in normal motor control and during adaptive modifications to behavior. In a learning to learn paradigm where subjects progressively adapted pointing movements to several different visual distortions across test sessions, authors have reported that participants increase their adaptability; that is, they adapted to each subsequent perturbation faster than control subjects (Seidler, 2004). Authors

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When environmental changes are transient however, this sensitivity to motor errors would be disadvantageous, potentially resulting in behavioral modifications toward inappropriate goals.

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In a recent study, Wu et al. (2014) also reported that faster sensorimotor adaptation is associated with greater baseline variability, particularly in task relevant dimensions. For example, baseline variability related to velocity was predictive of adaptation to a velocity-dependent force field perturbation applied to arm movements. In sum, these studies suggest that baseline measures of motor variability may be useful predictors of subsequent adaptability.

Neural Predictors Brain Activity As part of our efforts to investigate cognitive predictors of sensorimotor adaptability described above (Anguera et al., 2010, 2011), we had participants perform a manual sensorimotor adaptation task and a spatial working memory task in an MRI scanner. Authors found that the neural correlates of early adaptation overlapped with neural substrates that participants engaged when performing a spatial working memory task, notably in the right dorsolateral prefrontal cortex and in the bilateral inferior parietal lobules. There was no neural overlap between late learning and spatial working memory. We also tested a group of older adult participants for comparison (Anguera et al., 2011), and found that across the young and older adults, the extent to which participants recruited the right dorsolateral prefrontal cortex explained individual differences in the rate of early adaptation.

That is, the more that participants recruited this brain region, known to be involved in spatial working memory processes, the faster they progressed through the early, strategic stage of sensorimotor adaptation regardless of their age. Engagement of this brain region may be correlated with spaceflight sensorimotor adaptation.

A study by Burke et al. (2014) investigated a number of potential clinical and neural predictors of recovery of lower limb function in patients that have experienced a stroke. They found that the leg Fugl-Meyer score-a clinical scale of function-and the extent of motor cortex that was recruited during movements of the ipsilateral foot (assessed with functional MRI) provided the best predictors of subsequent treatment gains (Burke et al., 2014). These findings support the notion that brain activity can provide a useful prediction of future learning/sensorimotor adaptability.

Brain Connectivity Recent approaches in MRI have been developed to assess brain functional (resting state functional connectivity, fcMRI) and structural (diffusion weighted MRI, DTI) network connectivity, allowing for more integrative assessments of distributed neural systems than in the past. Data acquisition for both techniques is rapid and non-invasive. Moreover, because participants are not performing a task, there are no confounds of the effects of fatigue, attention, or task difficulty that often complicate interpretation of task-driven fMRI studies. FcMRI has proven fruitful for the study of large-scale brain networks in healthy and diseased individuals. Low frequency blood oxygen level dependent (BOLD) signal fluctuations in remote but functionally related brain regions show strong correlations during the resting state (Biswal et al., 1995). These correlations are highly spatially structured, following known anatomical networks, and are therefore thought to reflect functional connectivity of the human brain. Functional networks that have been identified with fcMRI in healthy individuals by our group and others include motor cortical networks (Biswal et al., 1995; Peltier et al., 2005), striatal thalamo-cortical networks (Kelly et al., 2009), and cerebellar thalamocortical networks (Krienen and Buckner, 2009; Bernard et al., 2012, 2014).

Resting state network correlations have behavioral relevance. For example, default mode network connectivity is altered following visual (Lewis et al., 2009) or motor (Albert et al., 2009) learning. Furthermore, we have shown that the magnitude of corticostriatal network connectivity in Parkinsonâ&#x20AC;&#x2122;s patients is correlated with their motor (putamen networks) and cognitive (caudate networks) symptoms, and is modulated by dopaminergic medication (Kwak et al., 2010). Moreover, authors have documented that greater resting state motor interhemispheric connectivity in older adults is correlated with "motor overflow", or recruitment of the ipsilateral motor cortex during a unimanual task (Langan et al., 2010). Similarly, DTI metrics of white matter tract integrity exhibit network-selective correlations with behavior (Della-Maggiore et al., 2009). For example, white matter integrity underlying the left, but not the right, Brocaâ&#x20AC;&#x2122;s area is correlated with the ability to learn an artificial grammar (FlĂśel et al., 2009), while cerebellar white matter fractional anisotropy is correlated with individual differences in the rate of motor learning (Della-Maggiore et al., 2009; Tomassini et al., 2011).

The cerebellum plays a critical role in sensorimotor adaptation (Martin et al., 1996a,b). Authors have shown

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that individual differences in regional cerebellar lobule volumes are predictive of balance scores (Bernard and Seidler, 2013), and cerebellar network functional connectivity is predictive of sensorimotor and cognitive function in older adults (Bernard et al., 2013). Studies in patients with cerebellar damage following stroke support involvement of Crus I and lobule V in adaptive improvements with practice, whereas lobules V and VI are linked to aftereffects and retention of adaptation (Werner et al., 2010). Another resting state measure of neural function is corticospinal excitability, measured as the magnitude of a motor evoked potential (MEP) elicited with a transcranial magnetic stimulation (TMS) pulse applied to motor cortex. Interestingly, stroke patients with a lower baseline MEP benefited more from subsequent robotic training (Milot et al., 2014). These results, combined with the preceding discussion, support the notion that resting state measures of neural connectivity, excitability, and pathway integrity are predictors of future skill learning. A more thorough elucidation of the neural substrates of microgravity sensorimotor adaptation may yield similar predictive brain network metrics.

Genetic Predictors Genetic polymorphisms have been shown to be associated with factors including neuroanatomical phenotypes such as cortical size or integrity of gray and white matter in the brain (Rimol et al., 2010) and neuroplasticity (Pearson-Fuhrhop and Cramer, 2010). Recent findings of genotype associations with dopamine availability in the prefrontal cortex and corticostriatal circuits highlight the role of a single nucleotide polymorphism of the catechole-O-methyltranspherase (COMT) gene at codon 158/108 (Frank et al., 2009). The substitution of a Valine (val) with Methionine (met) allele at this codon (G to A) results in reduced COMT enzymatic activity, which leads to less dopamine degradation and higher prefrontal dopamine availability (Chen et al., 2004). COMT met homozygotes show comparatively better performance in working memory tasks and other measures of executive function (cf. Malhotra et al., 2002). In addition to COMT val158met, the DRD2 G > T polymorphism influences dopamine availability by regulating the expression of striatal dopamine receptors. D2 receptor activity in the striatum has been associated with motor control, coordination, and error avoidance (Xu et al., 2007; Doll et al., 2011). The T allele of the DRD2 genotype (rs 1076560) is associated with reduced D2 expression and consequently with declines in cognitive and motor processing (Bertolino et al., 2009). Individuals who are carriers for the DRD2 T allele show a greater area of activated brain regions and reduced levels of performance in working memory tasks, indicating less efficient neural processing (Zhang et al., 2007).

Another candidate gene that may be an effective predictor of sensorimotor adaptability is brain-derived neurotrophic factor (BDNF), which is associated with brain derived neurotrophic factor, an important modulator of brain plasticity and learning. BDNF val/met carriers have reduced BDNF in comparison to val/val and have recently been demonstrated to exhibit reduced manual sensorimotor adaptation and less retention of adaptive learning (Joundi et al., 2012). Finley et al. (2004) have also reported that variation in the α2-adrenergic receptor genetic polymorphism is associated with individual differences in autonomic responses to stress, including susceptibility to motion sickness, an important factor influencing functional performance and productivity in spaceflight that has been linked to vestibular system functioning (Oman and Cullen, 2014).

Authors evaluated whether a particular DRD2 polymorphism (rs 1076560, G > T), which codes for D2 dopamine receptors in the striatum, is associated with how well patients with Parkinson’s disease respond to exogenous administration of dopamine via L-DOPA (Kwak et al., 2012). DRD2 T allele carriers of this polymorphism have reduced D2S expression (short isoform of the D2 receptor); thus in comparison G allele carriers have higher D2 receptor availability. Our hypothesis that Parkinson’s patients who are minor T allele carriers would exhibit a greater benefit of levodopa on early stage motor sequence learning was tested in a behavioral study with 45 Parkinson’s patients. Patients were tested on two days following a single blind placebo controlled design, with administration of levodopa or placebo pill in a counterbalanced fashion across the two test days. Levodopa improved sequence learning over the level of placebo pill for only the TT and GT patients, whereas GG patients did not show a benefit from levodopa (Kwak et al., 2012). These findings support the notion that treatment plans for patients with Parkinson’s disease can be enhanced by taking into account measures of endogenous dopamine availability such as genotype. Similar findings were observed in a study of healthy participants by Pearson-Fuhrhop et al. (2013); individuals with a greater number of beneficial alleles for genetic polymorphisms involved in dopaminergic metabolism exhibit greater motor skill learning gains. Meanwhile, only participants with a lower number of beneficial alleles exhibited improvements in motor learning with levodopa administration.

Recently authors evaluated the proposed role of alleles for genes involved in dopaminergic transmission (COMT val158met, and DRD2 G > T) as an index of individual differences in motor sequence learning and visuomotor adaptation (Noohi et al., 2014). To test the hypothesis that individuals homozygous for high performanceassociated alleles (COMT-met and DRD2-G) would demonstrate faster rates of motor learning and adaptation we tested 70 young adult females. The minor allele groups (valval for COMT and TT for DRD2) exhibited overall slower reaction time on the motor sequence learning task for both random and sequence blocks, indicating

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Special Edition on Long Duration Spaceflight poorer performance but no difference in learning. Of particular interest, we found COMT val-val individuals adapted manual aiming movements to a visual distortion more slowly than met-met or val-met. We also combined COMT and DRD2 polymorphisms into a single model by quantifying the number of "high performance" alleles that each individual carries, and by using non-parametric linear regression we found an association between the rate of sensorimotor adaptation and number of high performance alleles. Thus, oneâ&#x20AC;&#x2122;s genotype for genes involved in dopaminergic metabolism may also serve as a predictor of spaceflight adaptability.

Effects of Sex and Gender on Adaptation to Space: Neurosensory Systems Specific Neurological and Sensory Differences Memory processing Studies consistently indicate a preferential involvement of the left amygdala in memory for emotional material (generally visual images) in women, but a preferential involvement of the right amygdala in memory for the same material in males. This laterality, "women left, men right," mirrors what is seen at rest, indicating that the response to emotional stimulation stems from a baseline that is already differentially "tilted" between the sexes.

Neuronal cell death Neuronal cell death pathways differ between men and women. Female neurons more often die through classical, caspase-dependent apoptosis, while male cells die more often through caspase-independent, apoptosis initiating factor-mediated cell death. This finding could potentially be important in developing treatment for neurodegenerative disorders or injuries following stroke.

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Opioid receptor binding Several brain regions show significantly different levels of opioid receptor binding in men versus women, including the amygdala and thalamus. These differences can lead to sex differences in response to pain analgesics.

Vision processing Men have significantly greater sensitivity for fine detail and for rapidly moving stimuli, while women exhibit better color discrimination, in part because many males suffer from color blindness, an X-chromosome related genetically inherited disorder.

Somatosensation Relatively little information is available on sex differences associated with tactile sensation, but some differences are known. On average, women are more sensitive than men, over the entire body, to touch and pressure.

Women appear to be more sensitive to temperature differences while men score better than females on a variety of haptic tasks (object or position recognition involving touch and proprioception). Reporting of pain and pain sensation is rife with many biases (social, gender, ethnicity, culture, etc.), but on average, women do appear to show a greater sensitivity to pain than men-probably due to biological mechanisms, as well as psychological and psychosocial factors.

Vestibular system The vestibular system is notoriously difficult to assess. Relevant research includes anatomy, central physiology, and functions affected by vestibular input including postural responses, spatial orientation, responses to intense motion stimuli, and the occurrence of disease.

Gross anatomy. Women have fewer total myelinated axons in the vestibular nerve than men, which may help explain the female bias (that has been verified via epidemiological studies) of developing many vestibular disorders, such as vertigo. In men, the otoliths, utricle, saccule, and superior semicircular canals are significantly larger than in women.

Vestibular nucleus and hormones In rats, some evidence suggests that the estrus (menstrual) cycle may influence the medial vestibular nucleus synaptic transmission and plasticity plasticity, with the levels of circulating 17β estradiol being the main factor in these differences.

Spatial task performance Sex differences have been found in circular vection (orientation within a spinning environment), field dependence (perceiving orientation based only on visual cues), perception of veridical vertical with body tilt (correctly identifying the true vertical to the ground when the body is tilted), and perception of the morphological horizon. These differences have been partially assigned to biological differences in the vestibular system, including the difference in otolith size, but some evidence suggests that cognitive training regarding attention to cues can decrease these sex differences.

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Special Edition on Long Duration Spaceflight Motion sickness-laboratory testing A commonly held belief is that females are more susceptible to motion sickness than males. Both social and research design have probably contributed to this bias. Research conducted in the NASA Johnson Space Center’s Neurosciences Laboratory has subjected over 200 subjects to a variety of motion sickness tests (coriolis sickness susceptibility [CSSI], sudden stop, offvertical rotation, parabolic flight, etc.). No difference was found in susceptibility between men and women nor did testing during any phase of the menstrual cycle for females have an effect. Responses to particular tests were variable. For example, some individuals became nauseous during a CSSI test but not during the off-vertical axis rotation test.

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Motion sickness: spaceflight The incidence of motion sickness obtained from post-flight debriefs of long-duration International Space Station, or "space station," (32 male, 10 female) and short-duration Space Shuttle (564 male, 100 female) astronauts show that, on average, female crewmembers that flew on both the space station and shuttle reported both space motion sickness and entry motion sickness (EMS) symptoms more frequently than male crewmembers (these data were mined from the NASA Lifetime Surveillance of Astronaut Health [LSAH] database). The one exception is that men who were crew members on the space station reported a higher incidence of EMS than women after returning from a long-duration spaceflight.

Postural ataxia: spaceflight On average, female crewmembers who flew on both the space station and space shuttle reported post-flight vestibular instability symptoms (feeling abnormally heavy, clumsiness, vertigo, persisting sensation after-effects, or having difficulty walking a straight line) more frequently than male crewmembers (these data were also mined from the LSAH database). All responses were subjective and were reported to a flight surgeon as part of a standard post-flight medical debrief. The debrief did not always specify the symptoms. In a study of computerized dynamic posturography before and after long-duration bed rest, analyses of sensory organization test scores suggest no differences between men and women.

Hearing/auditory function Numerous epidemiological studies have been conducted to compare differences in hearing sensitivity among men and women, confirming that hearing sensitivity declines with age, even in populations screened for a history of noise exposure. These studies have also shown that hearing sensitivity (when reported by conventional pure-tone audiometry) declines faster in men than in women at most ages and in most frequencies tested. The most recent National Health and Nutrition Examination Survey revealed that the odds of such hearing loss were 5.5-fold higher in men than in women.

Even when studies carefully screen for ear disease and noise exposures, however, hearing levels and longitudinal patterns of hearing change are highly variable. This variability has been attributed to smoking, genetic factors, and cardiovascular risks. Hearing sensitivity is particularly vulnerable to hazardous noise exposures (e.g., in industrial, military, and recreational environments), but sex differences in age-associated hearing loss occur even among populations with relatively low-noise occupations and with no evidence of noise-induced hearing loss.

In addition to pure-tone audiometry, distortion product otoacoustic emissions (DPOAEs) have also been used to assess peripheral hearing status. DPOAEs are believed to reveal subtle cochlear changes that may be overlooked by audiometry. Studies show that aging males experience greater decreases in DPOAEs amplitudes compared to aging females. This decrease in DPOAEs is often proportional to the degree of hearing loss.

NASA conducts a unique hearing-monitoring program, in which crewmembers undergo audiometric testing at least once per year during their active astronaut career (and even more frequently when assigned to space missions). Later, when participating in NASA’s LSAH program, former astronauts may continue to have their hearing tested for the rest of their lives. This database offers the opportunity to compare longitudinal differences in hearing sensitivity seen in male and female astronauts over asmuch as a 5-decade span of life (Fig. 1).

When comparing high-frequency hearing sensitivity, the LSAH database’s female population has better hearing thresholds than men at every epoch of life, starting in their mid-30s, approximately the age when most astronauts begin their careers. Female astronauts show no significant differences in hearing thresholds between ears except in those older than 55 (though the sample size for this population is rather small at that age), when the left ear thresholds are slightly better than those in the right ear. Male astronauts show greater hearing loss in the left ear than in the right ear at every age; this finding is consistent with many demographic studies, particularly those in which right-handed subjects have shot shoulder-fired weapons (exposing the left ear to most of the blast wave from the weapon’s muzzle). The vocational and avocational activities of many astronauts,

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military and nonmilitary, often include such firearms. An important finding from this database (unpublished data) is that although males and females show the expected age-related differences in hearing loss, spaceflight does not seem to affect men and women differently.

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