REVIEW Advances in Vestibular Research: A Tribute to Bernard Cohen, MD
Challenges to the central nervous system during human spaceﬂight missions
Gilles R. Clément,
Richard D. Boyle,
Kerry A. George,
Gregory A. Nelson,
Millard F. Reschke,
Thomas J. Williams,
and William H. Paloski
KBR, Houston, Texas;
National Aeronautics and Space Administration, Ames Research Center, Moffett Field, California;
Division of Biomedical Engineering Sciences, School of Medicine Loma Linda University, Loma Linda, California; and
National Aeronautics and Space Administration, Johnson Space Center, Houston, Texas
Submitted 29 July 2019; accepted in ﬁnal form 7 April 2020
Clément GR, Boyle RD, George KA, Nelson GA, Reschke MF, Williams TJ,
Paloski WH. Challenges to the central nervous system during human spaceﬂight
missions to Mars. J Neurophysiol 123: 2037–2063, 2020. First published April 15,
2020; doi:10.1152/jn.00476.2019.—Space travel presents a number of environmen-
tal challenges to the central nervous system, including changes in gravitational
acceleration that alter the terrestrial synergies between perception and action,
galactic cosmic radiation that can damage sensitive neurons and structures, and
multiple factors (isolation, conﬁnement, altered atmosphere, and mission parame-
ters, including distance from Earth) that can affect cognition and behavior. Trav-
elers to Mars will be exposed to these environmental challenges for up to 3 years,
and space-faring nations continue to direct vigorous research investments to help
elucidate and mitigate the consequences of these long-duration exposures. This
article reviews the ﬁndings of more than 50 years of space-related neuroscience
research on humans and animals exposed to spaceﬂight or analogs of spaceﬂight
environments, and projects the implications and the forward work necessary to
ensure successful Mars missions. It also reviews fundamental neurophysiology
responses that will help us understand and maintain human health and performance
behavior; cognition; conﬁnement; emotions; isolation; vestibular; weightlessness
The central nervous system (CNS) of astronauts, cosmo-
nauts, and animals has been studied before, during, and after
spaceﬂight missions for nearly 60 years now. Most missions
were conducted in low Earth orbit, ~200 miles above the
Earth’s surface, with mission durations ranging from a few
days to more than a year. Nine lunar missions, conducted from
1968 to 1972, carried humans beyond the Van Allen belts into
deep space, and 12 crewmembers landed and ambulated on the
lunar surface, 240,000 miles from Earth, for up to 3 days.
Missions now being planned to destinations as distant as Mars
will far exceed the health and performance challenges previ-
ously endured by any space traveler.
All space travelers are exposed to a set of hazards (or
stressors) that vary with the particular design of their space
mission. These hazards include, but are not limited to, altered
gravity (largely microgravity with intermediate periods of
hypergravity during launch and ascent into space and during
descent and landing from space, and also hypogravity on lunar
or planetary surfaces), isolation and conﬁnement, radiation
(comprising high-mass, high-energy ions known as galactic
cosmic rays and lower mass and energy solar particles), hostile
closed environment, and distance from Earth. The National
Aeronautics and Space Administration (NASA) and other
space agencies are beginning a new era of deep space explo-
ration, with missions to the Moon and on to Mars that will
expose space travelers to unprecedented levels of these haz-
ards. For 1,000 days or longer and distances from Earth of
10 –20 light minutes, crewmembers on board these missions
will be exposed to novel risks that scientists from many
physiological, behavioral, and medical disciplines are currently
working to mitigate.
Over the ﬁrst 60 years of human spaceﬂight, neurophysiolo-
gists have focused on elucidating the effects of the altered
gravity, including the very low gravitoinertial acceleration
g) experienced throughout the orbital phase of space-
ﬂight and the transient high gravitoinertial accelerations (3– 6
g) experienced during launch and return to Earth. No neuro-
science experiments have been performed with astronauts on
the lunar surface. Exposure to microgravity transiently affects
Correspondence: W. H. Paloski (e-mail: firstname.lastname@example.org).
J Neurophysiol 123: 2037–2063, 2020.
First published April 15, 2020; doi:10.1152/jn.00476.2019.
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spatial orientation, sensorimotor coordination, and cardiovas-
cular dynamics, whereas prolonged exposure drives more pro-
found neurological system responses and physiological adap-
tive responses in many homeostatic aspects of the cardiovas-
cular, muscle, and bone systems. To date, the main objectives
of space neurological research have been to understand how
prolonged exposure to microgravity affects the health and
performance of the crewmembers ﬂying aboard those missions,
and to investigate mechanisms of adaptive responses in hu-
mans or model organisms.
Neuroscience research has also focused on the psychological
effects of isolation and conﬁnement during spaceﬂight. The
neurological effects of exposure to space radiation have also
been studied, primarily in ground-based models using facilities
that simulate cosmic radiation. This review summarizes how
microgravity, isolation and conﬁnement, and radiation affect
the CNS of animals and humans, and concludes with recom-
mendations for future neuroscience research that are needed
before humans can safely undertake exploration missions to the
Moon and Mars.
VESTIBULAR AND SENSORIMOTOR CONTROL STUDIES IN
Animals were used in the early years of the space age to help
determine if humans would be able to survive short-duration
spaceﬂight. On May 28, 1959, Miss Baker, a squirrel monkey,
was the ﬁrst animal to ﬂy in a United States spacecraft and
return alive. Although Miss Baker’s ﬂight lasted just 16 min-
utes, it made headlines. A year later, the Soviets successfully
launched Sputnik 5 (ofﬁcially Korabl-Sputnik 2) and returned
the following animals alive from orbit for the ﬁrst time: 2 dogs
(Strelka and Belka), a rabbit, 42 mice, 2 rats, and fruit ﬂies.
Although the advent of spaceﬂight provided an opportunity
to study fundamental biological principle(s) of how an ani-
mal’s CNS responds to weightlessness, we still do not know
how the CNS adapts to rapid transitions in gravity levels or
whether animals and humans respond in a similar manner. In
general, the primary animal model to study the neurological
effects of spaceﬂight has been the rodent, but other species
such as monkeys, birds, amphibians, ﬁshes, mollusks, and
insects have also been used to study a wide range of neural
mechanisms. Below we review the pertinent results of these
animal studies related to crew health and performance on
exploratory missions and the potential causes of the observed
changes. APPENDIX A provides the interested reader with a brief
review of additional behavioral and physiological results in
model organisms that might offer clues in understanding the
underlying mechanisms affecting human neural processing in
Vestibular Neural Activity
In the mid-1960s, Gualtierotti and colleagues (Gualtierotti
and Alltucker 1966; Gualtierotti and Bailey 1968) designed a
new type of “ﬂoating” electrode that could continuously record
the activity of neurons for an extended time. This electrode was
ﬁrst used to record the activity of otolith afferents in the
bullfrog during short periods of weightlessness (20 s) gener-
ated by parabolic ﬂight. The frog’s vestibular afferents exhib-
ited an immediate increase in activity when the animal was
introduced into weightlessness, and activity recovered to base-
line levels on return to 1 g(Gualtierotti and Gerathewohl
1965). These results conﬁrmed the earlier ﬁndings of Fiorica et
al. (1962) that the cats’ vestibular neurons are more active
during free fall. Gualtierotti (1977) modiﬁed the electrodes
further so they could record the activity of otolith ﬁbers in the
bullfrog during launch and during centrifuge spins in orbit. The
data indicated a signiﬁcantly larger periodic change in back-
ground discharge at rest than on Earth and a hypersensitivity to
an applied acceleration above baseline levels beginning at
around day 3 of the mission. These changes in otolith activity
persisted through day 4 of the mission, then returned to
baseline levels at day 5, after which the electrodes no longer
worked (Bracchi et al. 1975).
Boyle et al. 2001 attempted to extend Gualtierotti’s work by
using infrared telemetry to continuously record the activity of
a larger sample of otolith afferents in toadﬁsh over the course
of the Space Shuttle Program’s STS-90 and STS-95 missions,
which lasted 16 days and 9 days, respectively. Unfortunately,
the in-ﬂight measures were unsuccessful. However, the toad-
ﬁsh were returned to the laboratory within8hoflanding, and
the activity of the otolith afferents was recorded using conven-
tional electrophysiological techniques during controlled accel-
erations. During the ﬁrst day after landing, the magnitude of
response to an applied translation was on average three times
greater in the ﬂight animals than in the control animals (Boyle
et al. 2001). The activity of the otolith afferents nearly satu-
rated at a displacement of ⫾0.25 mm (Fig. 1A).
In weightlessness, the toadﬁsh apparently increased their
afferent sensitivity to restore their ability to detect acceleration.
As mentioned above, these ﬁsh behaved erratically when
provoked during the ﬁrst day after landing. Although some
afferents remained hypersensitive for days after spaceﬂight, on
average, afferent sensitivity (and behavior) returned to normal
within 24 –36 h of landing, similar to the recovery time for
vestibular disorientation in astronauts after they return from
space (see below). The mechanisms involved in these periph-
eral vestibular changes during transitions between gravity lev-
els could include 1) changes in sensitivity of the hair cell
transducer, for example, a reconﬁguration of the transmem-
brane channel-like proteins of the transducer pore (Pan et al.
2018); 2) temporary structural alterations affecting the mech-
anoreception of the otolith, for example, an alteration of
otolith-stereociliary coupling that adjusts bundle deﬂection for
a given movement (Fredrickson-Hemsing et al. 2012); or 3)
pre- or postsynaptic alterations in the strength of synaptic
Ross (2000) provided evidence that weightlessness-induced
hypersensitivity of the otolith afferent could be due to presyn-
aptic adjustment of synaptic strength in the hair cell. In rats, the
number of synaptic ribbons in certain type II hair cells in-
creased by ~55% after exposure to weightlessness, whereas the
type I hair cells were less affected. Because toadﬁsh possess
only type II hair cells, an increase in synaptic strength could be
an initial adaptive response to restore the absence of gravity
detection, which is then followed by a deletion of the added
synaptic bodies (Graydon et al. 2017), leading to restoration of
normal function after return to a gravity environment.
Two key publications offer summaries and interpretations of
selected neural studies conducted in space. The ﬁrst publica-
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tion is by Cohen et al. (2005). Investigators recorded the
activity of central vestibular neurons and monitored ocular
gaze in alert monkeys during spaceﬂight. Vestibular neurons
increased in sensitivity early in the missions, which corrobo-
rates with data collected using bullfrogs (see above). A recent
study showed that astronauts’ otolith-mediated responses elic-
ited by centrifugation were decreased immediately after return
from 6 months of spaceﬂight and fully recovered within ~9
days of return (Hallgren et al. 2016).
The second publication provides an in-depth analysis of the
16-day Space Shuttle Neurolab mission, a space mission ded-
icated to studying how the central and autonomous nervous
systems respond to spaceﬂight (Buckey and Homick 2003).
This mission included 26 experiments addressing the follow-
ing: balance in humans, rats, and ﬁsh; integration of different
senses and navigation in humans and rats; neural development
in rodents; blood pressure control mechanisms in rats and
humans; and sleep and circadian rhythms in humans and rats.
Animal studies showed that hippocampal “place” cells retain
their three-dimensional spatial selectivity, suggesting a re-
markable resolution of self-motion and external landmark cues
in such a novel environment (Knierim et al. 2000, 2003).
Electron microscopic examination of the cellular organization
of the adult rat cerebellar nodulus, a zone that receives signif-
icant input from vestibular otolith afferents, revealed structural
changes, namely, the formation of lamellar bodies and evi-
dence of degeneration, perhaps the result of an overexcitation
of otolith targets (Holstein and Martinelli 2003). Molecular
changes were discovered in adult rat brain stem regions that are
associated with autonomic function, such as area postrema and
nucleus of tractus solitarii (Pompeiano et al. 2004), and
changes to precerebellar processing, such as inferior olive,
lateral reticular nucleus, and basal pontine nuclei (d’Ascanio et
al. 2003). In addition, exposure to weightlessness attenuated
the function of the arterial baroreceptor reﬂex in young rats that
were still developing, and this blood pressure control system
returned to baseline level 30 days after landing (Waki et al.
2005). The absence of gravity during a 16-day space mission
permanently prevented the maturation of motor tactics for
surface righting in postnatal rats, whereas the loss of contextual
Fig. 1. Effect of reduced and enhanced gravity on maximum response sensi-
tivity [Smax; in impulses per second per g(or 9.81 m/s
), ips/g] of toadﬁsh
utricular afferents. A: data collected after weightlessness exposure during the
STS-90 and STS-95 Space Shuttle missions show the afferent Smax as a
function of time after landing in hours from ﬁrst (10 –16 h) to last (112–117 h)
recording session [adapted from Boyle et al. (2001)]. During the ﬁrst day after
landing, Smax (red column) of ﬁsh subjected to an applied linear acceleration
was signiﬁcantly (*P⬍0.01) greater than for controls (black column).
Sensitivity returned to near normal values ~30 h after landing, as revealed by
the data collected in the same ﬁsh at varying hours of delay after landing and
indicated by different colors. B: mean afferent Smax (ips/g ⫾SD) is plotted
against days of centrifugation at 2.24 g[data adapted from Boyle et al. (2018)].
The recording session began immediately after cessation of centrifugation.
Mean Smax of control afferents (C; black column) to a standard translation is
2,103 ⫾1,314 (SD) ips/g (n⫽162 afferents). A signiﬁcant elevation of Smax
at day 3 (orange column; n⫽228 afferents) and day 4 (red column; n⫽153
afferents) was observed (***P⬍0.0001); 90 –100% of the afferents in these
groups had a markedly greater Smax than the 162 control afferents. The
elevation was followed by several days (5 to ⱖ8 days) of normal afferent
sensitivity and then by a signiﬁcant decrease at day 16 (blue column; n⫽245
afferents; ***P⬍0.0001), day 24 (green column; n⫽177 afferents; **P⬍
0.005), and day 32 (violet column; n⫽192 afferents; **P⬍0.005). The
number of afferents recorded in each group is given above its column in the SD
error bar. C: afferent Smax as a function of number of days (indicated by
number inside of each column) in normal 1 gafter 4- and 16-day exposures to
centrifugation. Initial hypersensitivity recorded immediately after 4-day expo-
sures (red unlabeled column) required ⬎4 days to recover to control levels.
The later hyposensitivity observed after 16-day exposures (blue unlabeled
column) required at least 2 days to recover. In A–C, error bars are ⫾SD and left
column (C) is the control response value. *P⬍0.05; **P⬍0.005; ***P⬍
0.0001, level of signiﬁcance compared with control measures.
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interaction in space was transient in postnatal rats that spent 9
days in space (Walton et al. 2005a). Young rats that were
reared in space from postnatal day 14 (P14) to P30 exhibited
modiﬁed swimming behavior on the day they returned from
space (altered posture in the water, swimming speed and style),
apparently due to adaptive response to weightlessness, and
some of these characteristics persisted for 30 days after the
mission (Walton et al. 2005b). The study of critical periods for
adaptation to weightlessness is not unique to the Neurolab
mission: studies during spaceﬂight and in ground analogs of
spaceﬂight have assessed the development of vestibular system
(reviewed by Jamon 2014) and other neurally driven behaviors
in various species, such as the clawed toad Xenopus laevis,
cichlid ﬁsh (Oreochromis mossambicus), and crickets (Acheta
domesticus,Gryllus bimaculatus) (Horn 2003; Horn and Ga-
Artiﬁcial gravity has been proposed as a countermeasure for
the adverse effects of weightlessness. In 2016, the Japan
Aerospace Exploration Agency assessed the feasibility of cen-
trifugation as a tool to counter the loss of gravity by subjecting
one population of mice to continuous centripetal acceleration
on the International Space Station (ISS), while another group
of mice remained exposed solely to weightlessness (Shiba et al.
2017). Results revealed that artiﬁcial gravity provides some
protection from the spaceﬂight-induced increases in apoptosis
of retinal cells and changes expression of proteins related to
cellular structure, bone, and muscle mass (Tominari et al.
2019), immune response (Horie et al. 2019), and metabolic
function (Mao et al. 2018). Although partial gravity can only
be generated for brief moments on Earth, hypergravity can be
delivered for extended periods in ground-based studies and can
be used to determine whether structures and their function
respond linearly to gravity levels.
Boyle et al. (2018) used toadﬁsh to study how utricular
afferents respond to translational accelerations after a 16- or
9-day orbital Space Shuttle mission (STS-90 and ⫺95, respec-
tively), and after 1–32 days of centrifugation at 2.24 g. The
responses after centrifugation are given in Fig. 1B. Because the
afferents were hypersensitive after spaceﬂight, the authors
expected they would be hyposensitive in hypergravity. Unex-
pectedly, the toadﬁsh utricular afferents exhibited hypersensi-
tivity after 3 days of centrifugation, which intensiﬁed on the
fourth day and then returned to normal levels during days 5– 8,
and the (anticipated) hyposensitivity occurred during days
16 –32. The initial hypersensitivity and later hyposensitivity
required more than 4 and 2 days, respectively, of exposure to
1gto recover to control levels (Fig. 1C). Since the initial
afferent response is elevated in toadﬁsh during centrifugation,
and the afferent response in bullfrogs and central vestibular
neuron response in primates are elevated during the ﬁrst days
of spaceﬂight, this might reﬂect a consistent early neural
reaction to a gravity challenge in either direction: weightless-
ness or hypergravity. Prolonged exposure to hypergravity leads
to a later reduction in afferent sensitivity. While the afferent
response to prolonged exposure to weightlessness is still un-
known, it might also develop a hyposensitivity over time. This
initial reaction is in line with the astronauts’ disorientation
during the ﬁrst days of a space mission. As discussed above,
presynaptic modiﬁcation of synaptic ribbons (or bodies) in the
hair cells might adjust the response magnitude of the contacted
utricular afferents. Synaptic ribbons in utricular hair cells were
counted in two separate areas of the utricular macula of control
ﬁsh and ﬁsh exposed to 4- and 16-day centrifugation. Despite
the very signiﬁcant differences in the magnitude of afferent
responses in these two groups, the number of ribbons per hair
cell was equivalent, clearly indicating that the number of
synaptic bodies in hair cells is not directly correlated with its
sensitivity to otolith stimulation (Boyle et al. 2018). Recently,
Sultemeier et al. (2017) showed that spaceﬂight decreases
synaptic densities in the mouse extrastriolar utricle, which is in
opposition to ﬁndings from a study in rats (Ross 2000) that
showed synaptic densities increased in rats during spaceﬂight.
Interestingly, the horizontal semicircular canal afferent sensi-
tivity to angular rotation was unaffected by centrifugation in
ﬁsh (Boyle et al. 2018), and synaptic densities of hair cells in
the horizontal semicircular canal of rats were unchanged by
spaceﬂight (Sultemeier et al. 2017).
Despite our best efforts, we have suggestive, but neverthe-
less marginal data on how weightlessness affects neural struc-
ture and function in animals, and even less data on the long-
term effects of hypergravity in ground-based studies. During
their ﬁrst days in space, and for some time after returning from
a relatively short exposure to weightlessness, the astronaut
experiences the same difﬁculties in orientation and stability
that are often seen in animals and humans with vestibular
disorders. Adaptive mechanisms, including possibly a tempo-
rary change in transduction process(es) or synaptic strength,
allow the astronaut to recover to normal function after a few
days. This is not the case for people with vestibular disorders,
who are in it for the “long haul” and must learn new strategies
to manage even simple behaviors. The CNS effects from
long-term exposure to microgravity likely involves more com-
plex adaptive mechanisms. Without sufﬁcient countermea-
sures, such as the use of continuous or intermittent exposure to
an applied gravity via centripetal acceleration during the mis-
sion, some of these mechanisms might lead to changes in
neuron structure and connectivity that could be maladaptive
when the organism is reintroduced into a gravity environment.
The use of animal models can help accelerate the development
of protocols to assess the magnitude and duration of the applied
gravity load. A wealth of clinical and experimental data exists
on the long-term consequences of inner ear damage on motor
control function along the neuraxis, and we need to delve into
these data to design new translational studies that will elucidate
the scope and extent of the neural compensatory mechanisms.
The behavior and plasticity of synaptic organization and neural
function will be particularly relevant to crew health and per-
formance during exploration of space.
VESTIBULAR AND SENSORIMOTOR CONTROL STUDIES IN
Perception of orientation and movement depends on the
integration of sensory information from vestibular, visual,
proprioceptive, and somatosensory systems, and it involves
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comparison between the actual sensory feedback and the ex-
pected feedback. An altered gravitational environment changes
the sensory signals originating from the vestibular system,
particularly the signals from the otolith organs. On Earth, the
otoliths respond to gravitoinertial acceleration by changing the
pattern of their output signals, which provide information
about head orientation relative to gravity. In weightlessness,
the otoliths are effectively unloaded and cannot provide useful
information about static head orientation. Consequently, dur-
ing spaceﬂight the CNS is thought to interpret all otolith output
signals as due to head translation, not head tilt, and this
reinterpretation continues for several hours after the return to
Earth. Alterations in the control of astronauts’ eye movements,
posture, and gait after spaceﬂight support this hypothesis
(Young et al. 1993). An alternative hypothesis suggests that in
weightlessness, the CNS is no longer able to use rotational cues
to help accurately estimate the relative orientation of gravity,
and this change in the ability to estimate gravity consequently
inﬂuences the ability of the CNS to estimate linear acceleration
An astronaut’s ability to successfully complete a task in
altered gravity will therefore require their CNS to adapt effec-
tively to these altered inputs to the otolith organs (Paloski et al.
2008). If astronauts do not adapt to weightlessness, their
performance of sensorimotor tasks, including piloting the
spacecraft or making an emergency egress during a mission to
Mars, could be profoundly affected.
Sensorimotor disturbances occur when sensory modalities
no longer transmit information (due to disease or absence of an
effective stimulus) or when signals are incorrectly integrated.
Astronauts experience a number of sensorimotor disturbances
during critical periods of spaceﬂight, such as entry into weight-
lessness and during return to Earth’s gravity. Common senso-
rimotor issues include motion sickness, spatial disorientation,
delays in eye-head coordination, and difﬁculty walking. Inter-
individual differences exist in the speciﬁcity and magnitude of
these issues, which may depend on the frame of reference,
weighting of sensory information, rates of adaptation, and
previous spaceﬂight experience. The longer the duration of
space travel, the more intensely astronauts experience these
sensorimotor disturbances, and complete recovery can take
weeks or months (Clément and Reschke 2008). This poses a
challenge for future long-duration space exploration missions,
during which astronauts will experience various gravitational
environments. Countermeasures to prevent and reduce the
sensorimotor issues caused by spaceﬂight include medication,
self-assessment tools, and training. It is expected that future
studies will lead to in-ﬂight measures that will help crewmem-
bers to identify and facilitate their own adaptation to different
gravitational environments. Below we review the disturbances
that are likely to affect the crews of Mars missions and the
countermeasures required to maintain crew health and perfor-
Gravity plays a fundamental role in spatial orientation be-
cause the vestibular, proprioceptive, and haptic receptors are
all particularly sensitive to gravitational stimulation. In the
absence of gravity, astronauts initially rely on vision alone.
This causes them to misperceive their orientation with respect
to the environment, and they experience visual reorientation
illusions. Eventually, astronauts adapt to weightlessness and
develop new ways of relating to the external world (Oman
2010; Young et al. 1993), for example, by switching between
reference frames (see APPENDIX B).
Spaceﬂight also affects visual spatial cognition, which is
important for the astronauts to properly perceive distance and
determine the size of objects. On the ISS, astronauts overesti-
mate height and underestimate depth and distance. These
changes may occur because the perspective cues for depth are
less salient in weightlessness, or perhaps because a person’s
scaling of size at eye height may be different when they are not
standing on the ground (Clément et al. 2013). If astronauts
experience distortions of the visual space during spaceﬂight,
this may inﬂuence their ability to accurately perform cognitive
and sensorimotor tasks such as those involved in robotic
operations. Additionally, this misperception will alter how
astronauts view the volume of their habitat and workspace.
Recent evidence suggests that spaceﬂight induces change in
neuroplasticity, speciﬁcally in the motor and the vestibular
cortical regions (Koppelmans et al. 2016; Roberts et al. 2017;
Van Ombergen et al. 2019). Both positive and negative plas-
ticity occur, including reorganization and decrease in volume
of the cortical areas associated with behavioral experience. We
have known for some time that the brain’s topographical
organization is not ﬁxed, and even adult brains can undergo
extensive remodeling. These changes occur in response to skill
learning (Karni et al. 1998), sensory deprivation (Kraft et al.
2018), or as a result of compensatory strategies after a stroke
(Desmurget et al. 2007). The changes in cortical topographic
organization for sensory and motor regions during long-dura-
tion spaceﬂight may reduce vestibular function and motor
control abilities during landing on Mars (Demertzi et al. 2016).
Astronauts must adapt their representation of space and
movement to adjust to the changes in sensorimotor signals that
occur in weightlessness. Furthermore, during future explora-
tion missions, astronauts will have to adapt to the reduced
gravity on Mars and readapt to normal gravity when they return
to Earth. These are important considerations for future human
planetary exploration missions and warrant further investiga-
tion and consideration for countermeasure development.
Potential countermeasures include visual or tactile aids that
could help astronauts orient themselves relative to their envi-
ronment and allow them to properly stabilize the spacecraft
during landing. The astronauts’ ability to control the tilt of
spacecraft is compromised after they return from a long-
duration ISS mission, and the number of errors they make
corresponds to changes in their perception of self-motion
(Clément et al. 2018). Tactile spatial awareness systems can
help astronauts to control the vehicle. These tactile spatial
awareness devices use small tactors attached to the torso that
vibrate when the body tilts relative to gravity, alerting the
subjects when their body is misaligned. Tactile feedback has
helped astronauts control their body tilt after spaceﬂight and
has restored their early postﬂight performance to the level of
their performance before the mission (Clément et al. 2018). It
is also possible that a cockpit display that aligns the visual
horizon perpendicular to gravity after the spacecraft has
splashed down in the ocean could provide information that will
help astronauts to egress the vehicle. This concept is currently
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The vestibulo-ocular reﬂex (VOR) that compensates for
head movements in yaw remains intact in weightlessness,
suggesting that gravity does not inﬂuence the primary response
of the semicircular canals (Benson and Viéville 1986; Correia
et al. 1992). However, the time constant of decay of horizontal
nystagmus is shorter in weightlessness than in 1 g(DiZio and
Lackner 1988; Oman and Kulbaski 1988). In addition, ocular
counter-rolling, a reﬂex that rotates the eyes around the line of
sight in the opposite direction of a head tilt, is absent in
weightlessness (Reschke et al. 2018a) and reduced after space-
ﬂight (Hallgren et al. 2016). When astronauts rotate about the
roll axis during spaceﬂight, this elicits torsional and horizontal
nystagmus (Reschke and Parker 1987; Reschke et al. 2017a).
These changes are presumably due to the inﬂuence of gravity
on the velocity storage that is responsible for prolonging the
inputs from the semicircular canals after the cupula has re-
turned to its rest position and for orienting the slow-phase eye
velocity toward the perceived vertical (Raphan et al. 1992).
Exposure to weightlessness also induces modiﬁcations in
eye-head coordination during target acquisition. Coordinated
eye-head movements toward an offset visual target require a
combined saccadic eye movement (compensatory) and a ves-
tibulo-ocular response (anticompensatory) that shifts gaze onto
a visual target. A recent study showed that Space Shuttle pilots
took signiﬁcantly longer to acquire visual targets immediately
after spaceﬂight than they did before the ﬂight. This delay in
acquiring visual targets was due to increased latencies and
decreased peak velocities of eye and head movement relative to
preﬂight values. The longer latency and lower velocity of head
movement after spaceﬂight induces a series of large anticom-
pensatory eye saccades that are required to direct gaze back on
target (Reschke et al. 2017b).
Interestingly, spaceﬂight does not affect horizontal smooth
pursuit eye movements when the head is in a ﬁxed position or
when it is moving freely (André-Deshays et al. 1993). How-
ever, astronauts experience changes in vertical pursuit eye
movements. During spaceﬂight and immediately after landing,
upward pursuit is interrupted by saccadic eye movements.
These saccadic intrusions are presumably due to neural strat-
egies that have evolved to assist in directing the moving image
onto the retina (Reschke et al. 2002). Few studies have dem-
onstrated a direct effect of spaceﬂight on saccade gain; how-
ever, ground-based studies have shown that spatial targeting of
saccades may depend on the gravity level. For example, on
Earth, eye saccades systematically tilt as a function of head tilt
(Wood et al. 1998), and during spaceﬂight, directional errors of
saccades to recollected targets increase (Israël et al. 1993).
If pilots are unable to adapt their eye-head coordination to
the changes in gravitational environment, they will have difﬁ-
culty acquiring information from instrumentation or will have
delays capturing visual targets. The risk is greater in situations
that require constant vigilance, timely responses, and accurate
identiﬁcation and location of a visual target, such as during
landing. Most studies of the effects of spaceﬂight on vestibulo-
ocular responses were conducted during short-duration Space
Shuttle missions, so it is difﬁcult to predict whether these
changes are more pronounced after long-duration exposure to
weightlessness. Computerized dynamic visual acuity, active
and passive visual-vestibular interaction tests, and hand-eye-
head coordination tests have been performed on crewmembers
immediately after they return to Earth (Clément and Reschke
2008). However, ocular vestibular evoked myogenic potentials
and cervical vestibular evoked myogenic potentials tests have
not been performed, and these vestibular tests are needed to
better understand the changes in otolith function and to rapidly
habilitate the astronauts to gravity level transitions.
Posture and Gait
The effects of spaceﬂight on astronauts’ postural stability
has been assessed using dynamic posture platforms that trans-
late or tilt the subject (Anderson et al. 1986; Kenyon and
Young 1986) or provide more sophisticated means of posture
control such as stabilization of ankle rotation and/or vision
(Paloski et al. 1993). For the last 30 years, NASA has used
computerized dynamic posturography (CDP) to objectively
quantify astronauts’ posture and to determine how visual,
vestibular, and somatosensory information controls postural
stability after spaceﬂight. Results have clearly shown that
postural stability is disrupted regardless of the length of the
spaceﬂight; however, it is much more severe and persists
longer after long-duration ISS ﬂights (Fig. 2). The astronauts’
posture is most unstable when their eyes are closed and the
support platform rotates in direct proportion to anterior-poste-
Pre 0 2 4 6 8 10 12
Median Equilibrium Score
Fig. 2. Computerized dynamic posturography (CDP) using the EquiTest has
been used to assess the recovery of postural control in crewmembers after
spaceﬂight on board the Space Shuttle (short-duration ﬂights, typically 1–2
wk) and International Space Station (long-duration ﬂights, typically 4 –6 mo).
In one of the sensory organization tests (SOT5), CDP detects postural sway by
measuring shifts in the center of gravity (COG) when subjects stand with the
eyes closed on a sway-referenced support surface. This condition determines
how the participant uses vestibular cues when visual cues are absent and
somatosensory cues are inaccurate. The subject performs 3 trials lasting 20 s
each. An equilibrium score is computed, taking into account the maximum
normal postural sway in the anterior-posterior direction (12.5°) and the
calculated maximum anterior-posterior COG displacements. A score of 100
represents perfect stability; a score of 0 indicates a loss of balance. In
astronauts, the median equilibrium score during SOT5 decreases drastically
immediately after landing (session day 0) compared with preﬂight (Pre).
Severity of disequilibrium increases and recovery is prolonged with increasing
exposure time to weightlessness. Return of postural control to baseline occurs
~4 days after short-duration spaceﬂights (open columns) and ~12 days after
long-duration spaceﬂights (shaded columns). Error bars show 25% and 75%
percentiles. Equilibrium scores are signiﬁcantly different between short- and
long-duration crewmembers on postﬂight session days 0,2, and 4(unpaired t
test, P⬍0.05). [Adapted from Wood et al. (2015).]
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rior body sway. Removing vision and disrupting somatosen-
sory feedback changes how vestibular feedback controls pos-
ture (Paloski et al. 2006). When dynamic pitch head tilts were
added to the postural tests on the unstable platform (Jain et al.
2010), most ISS crewmembers considered this test too chal-
lenging and did not even attempt it after landing (Wood et al.
2015). Most astronauts continued to have difﬁculty standing
when making dynamic head tilts on the unstable platform for
the ﬁrst week after they returned from space, and several fell
during testing in the second week after return. These deﬁcits
suggest that balance control after long-duration spaceﬂight also
relies on a sensory reweighting toward somatosensory cues
(Wood et al. 2015).
Changes in vestibulo-spinal reﬂexes may also contribute to
postural decrements after spaceﬂight. The Hoffmann reﬂex
(H-reﬂex), which detects changes in the otolith-spinal reﬂexes,
was dramatically reduced during spaceﬂight, but differences
between pre- and postﬂight responses were not signiﬁcant
(Watt et al. 1986). Reschke et al. (1986) observed a potentia-
tion of the H-reﬂex 40 min after astronauts underwent an
unexpected drop during ﬂight (Earth-vertical fall with bungee
cords); this potentiation disappeared after 7 days. Such changes
in the H-reﬂex predict change in the gain of the spinal reﬂex
pathway; however, it is unclear how gain changes in this
pathway are linked to preprogrammed muscular activity such
as posture maintenance. A potential increase in otolith mass
during spaceﬂight (see APPENDIX A,Otolith Mass) could also be
responsible for the alterations in the vestibulo-spinal and oto-
lith-ocular reﬂexes and the spatial orientation during as well as
Although terrestrial patterns of locomotion are extremely
gravity dependent, astronauts move accurately and precisely in
weightlessness once they have adapted to modes of body
locomotion that do not depend on gravity. However, after
landing, their gaze is unstable, they restrict movements of their
head, their balance control is diminished, and their step cycle
varies (Bloomberg et al. 1997; Layne et al. 1997). When
astronauts walk shortly after they return from space, they
increase the angle of motion at their knee and ankle, which
increases their dynamic stability but reduces their walking
speed (Bloomberg et al. 1997). Although astronauts recover
their gait during the ﬁrst 12 h after return from short-duration
spaceﬂight, it may take weeks to return to preﬂight baseline
values after long-duration spaceﬂight (Mulavara et al. 2012).
We do not know which gait strategies will be favored in
Martian gravity because computational models are only using
data obtained from simulated gravity studies (Ackermann and
van den Bogert 2012).
Most astronauts also experience some degree of ataxia
immediately after they return from space; they report a sensa-
tion of turning when they attempt to walk a straight path, they
abruptly lose postural stability when they turn corners or
experience unexpected perturbations, and they lose orientation
in unstructured visual environments. In addition, some astro-
nauts report oscillopsia (illusory movement of the visual ﬁeld)
when they move (Reschke et al. 2017c; Reschke and Clément
2018), similar to symptoms of labyrinthine defects (Pozzo et al.
1991), which suggests a disruption in head-trunk coordination
due to conﬂicting sensorimotor input during transition between
gravitational environments. In addition, astronauts use altered
strategies to maintain stability when they jump; most individ-
uals fell backward during the ﬁrst three jumps (likely due to a
potentiated stretch reﬂex) and used their arms more to maintain
balance. In fact, the vestibular-induced changes after long-
duration ISS missions are so severe that NASA has imple-
mented CDP as a medical requirement. An astronaut’s CDP
performance must return to its preﬂight baseline value before
NASA allows the astronaut to ﬂy again. In addition, as part of
their “postﬂight reconditioning,” astronauts must participate in
2 h of vestibular rehabilitation therapy each day for 2 wk after
long-duration spaceﬂight. This rehabilitation therapy includes
speciﬁc exercises to eliminate or signiﬁcantly reduce symp-
toms by promoting CNS compensation for inner ear deﬁcits
(Wood et al. 2011).
To date (except for a few ballistic landings of Soyuz),
astronauts and cosmonauts have been met at landing by a large
cadre of medical and operations experts who have helped them
to egress their vehicles and cope with the readaptation, disori-
entation, and cognition issues. No such landing welcome will
be available on the Moon or Mars, and NASA must therefore
develop measures to mitigate the disruption of posture and gait
that will be induced by these extended-duration ﬂights. Before
these risks can be identiﬁed and mitigated, we must gather
vestibulo-spinal data from individual crewmembers during
changing gravity levels and after long-duration missions.
A major component of neurological adaptation to novel
environments (or tasks) is interacting with the environment or
repeating the task (practice makes permanent). Thus it has been
proposed that if the astronauts were to perform systematic head
movements during reentry, this could help them adapt to Mars’
gravity or readapt to Earth’s gravity (Wood et al. 2011).
However, it has not been possible to systematically study this
effect due to operational constraints. Anecdotal reports from
Space Shuttle crewmembers have indicated that performing
head movements that slowly increase in amplitude can mini-
mize oscillopsia and motion sickness. The astronauts per-
formed these head movements ﬁrst in the yaw plane and then
in the pitch and/or roll planes while progressively increasing
the tilt of their head. The conﬁguration of crewmembers in the
Soyuz at landing, the volume of the spacecraft, and the higher
gproﬁle makes head movement more difﬁcult than it was in
the Space Shuttle, but systematic head movements during and
after reentry are still recommended to crewmembers (Wood et
Motion sickness during the ﬁrst few days of spaceﬂight and
after returning to Earth is the most clinically signiﬁcant neu-
rosensory phenomenon experienced by astronauts. Space mo-
tion sickness has many symptoms, such as somnolence, vom-
iting, stomach awareness, fatigue, and cognitive performance
decrement. A subject’s susceptibility to motion sickness on
Earth does not predict their susceptibility to space motion
sickness (Reschke 1990). During the ﬁrst days of spaceﬂight,
about two-thirds of astronauts and cosmonauts experience
motion sickness. The incidence is no different for career or
noncareer astronauts, commanders and pilots or mission spe-
cialists, different age groups, and ﬁrst-time or repeat ﬂyers
(Davis et al. 1988). Space motion sickness usually resolves
within 3– 4 days after entering weightlessness but will likely
recur when astronauts enter the fractional gravity near Mars,
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and this could impair an astronaut’s ability to operate complex
equipment during a Mars landing.
During landing, 27% of astronauts experience motion sick-
ness after short-duration ﬂights (Ortega and Harm 2008), and
100% after long-duration ﬂights (Reschke et al. 2017c). Post-
ﬂight symptoms tend to be more intense than those experienced
during ﬂight. Female astronauts have a slightly higher inci-
dence of motion sickness than male astronauts when ﬁrst
entering weightlessness. Conversely, men experience more
severe motion sickness symptoms upon return to Earth (Jen-
Many drugs have been used to treat space motion sickness.
Although some drugs have proven somewhat effective, no drug
or drug combination protects all individuals (Reschke 1990).
An intramuscular injection of 25–50 mg of promethazine is
recommended for moderate-to-severe cases of space motion
sickness (Reschke et al. 2018b), whereas oral and suppository
routes are recommended for less severe symptoms. Prometha-
zine has effectively reduced space motion sickness (Graybiel
and Lackner 1987), but a number of dose-dependent side
effects are associated with this drug, including sedation, diz-
ziness, and confusion, that could impair an astronaut’s ability
to navigate a vehicle during a Mars landing. Subjects on Earth
had substantially impaired alertness and coordination after
receiving promethazine (Cowings et al. 2000). Promethazine
may also have effects on basic vestibular function (Diaz-
Artiles et al. 2017). Several highly effective antiemetic medi-
cations with much more benign side effects have been devel-
oped over the past two decades to treat nausea and vomiting
associated with chemotherapy (see Navari 2009 for a review).
These drugs, which are mostly serotonin antagonists, block
receptors and could be used to treat space motion
An alternate approach would be to use a drug that modulates
the mechanism in the brain that is responsible for motion
sickness. Recent studies have suggested that motion sickness
on Earth relates to the velocity storage integrator in the brain
stem (Clément and Reschke 2018; Cohen et al. 2008, 2019; Dai
et al. 2003; Ventre-Dominey et al. 2008). Suppressing velocity
storage with GABA agonists, such as baclofen, may suppress
space motion sickness more directly than treating the symp-
toms of motion sickness. If any of these alternate drugs are
considered as potential treatments for space motion sickness,
they would have to be extensively evaluated on Earth and
during parabolic ﬂight, and potential cognitive or motor side
effects would also need to be carefully characterized.
The incidence of space motion sickness in Russian cosmo-
nauts is similar to the incidence of space motion sickness in
United States astronauts (Davis et al. 1988); however, NASA
does not screen astronaut applicants for resistance to motion
sickness, whereas the Russian space program does. In addition,
the Russian space program uses Coriolis (cross-coupled angu-
lar) acceleration as preﬂight vestibular training to prevent or
control the symptoms of space motion sickness (Clément et al.
2001), although this training has proved unsuccessful (Reschke
1990). Cowings (1990) found that autogenic feedback training
was signiﬁcantly more effective than promethazine in prevent-
ing symptoms of motion sickness. However, this physiological
training was discontinued because the 6-h training program
distributed over 3 wk was too time-consuming (Cowings et al.
Various mechanical devices have been explored to alleviate
the symptoms of space motion sickness. These mechanical
devices were designed to prevent the astronaut from com-
pletely adapting to weightlessness by counteracting decondi-
tioning during long missions and relieving motion sickness
symptoms during the ﬁrst days of ﬂight. One mechanical
device, the neck pneumatic shock absorber, has a cap with
rubber cords that provide a load to the cervical vertebrae and
neck muscles, which stretches the user’s neck muscles to
maintain an erect head position and restrain any turning or
tilting of the head (Matsnev et al. 1983). More recently, both
NASA and the US Army investigated stroboscopic vision as a
simple and easily managed treatment for postﬂight motion
sickness. Stroboscopic illumination prevents retinal slip,
thereby treating symptoms related to visual-vestibular con-
ﬂicts. Shutter glasses with a cycle frequency of 4 or 8 Hz and
a short dwell time (10 –20 ms) have proven effective against
motion sickness symptoms in car and helicopter passengers
(Reschke et al. 2007). The main driver for postﬂight motion
sickness appears to originate from visual-vestibular conﬂict
(Reschke et al. 2017c). The stroboscopic shutter glasses, by
reducing retinal slip, could potentially minimize this conﬂict.
Understanding the impacts of prolonged exposures to partial
gravity is important to the success of long-duration missions to
the Moon and Mars. Preventing the effects induced by partial
gravity would minimize the operational consequences of ves-
tibular and sensorimotor changes associated with spaceﬂight,
but so far, prevention has not been possible to implement.
Instead, guidelines are used to limit astronauts’ activities after
they transition between gravity levels, giving the astronauts
time to adapt. Astronauts are prohibited from performing
extravehicular activities until their third day on orbit to reduce
the risk of emesis in the spacesuit, and they are prohibited from
driving or ﬂying until the third day after they return from a
Adaptation training before ﬂight, with booster training dur-
ing the ﬂight, may help the astronaut’s vestibular and sensori-
motor systems to adapt faster to gravity level transitions.
Ground-based studies have shown that the increased adaptabil-
ity arising from the “learning to learn” approach endures for up
to a month after initial training (Bock et al. 2001; Roller et al.
2001). For example, the astronauts could train on a treadmill
mounted onto a base that moves as the subject walks. This
system would challenge the subject’s gait stability. Additional
sensory variation and challenge could be imposed using a
virtual scene that presents the subject with various combina-
tions of discordant visual information while they walk on the
treadmill. This experience would allow the subject to practice
resolving challenging and conﬂicting novel sensory informa-
tion (Bloomberg et al. 2015). This sensorimotor adaptability
training could then help astronauts make rapid modiﬁcations in
their motor control strategies during the ﬁrst hours after land-
ing (Igarashi et al. 1989; Seidler 2004).
It is possible that the exploration vehicles can be designed to
spin, producing centrifugal forces that create a gravitoinertial
environment on board, i.e., artiﬁcial gravity. Before this strat-
egy could be implemented, NASA would have to determine
how gravity thresholds affect sensorimotor function to estab-
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lish sufﬁcient ground reaction forces that enable the astronaut
to walk, and to determine the minimal gravity level required.
Large-radius centrifugation might not be necessary; a short-
radius centrifuge in which subjects can perform exercise might
be sufﬁcient to maintain gravity-dependent physiological sys-
tems (Clément et al. 2015). However, the minimum effective
duration and frequency of artiﬁcial gravity exposure would
have to be determined, and the effects of gravity gradient
would have to be elucidated, i.e., the difference between the
gravity experienced at the head and the gravity experienced at
the trunk and the feet (Clément 2017).
When astronauts enter weightlessness at the start of a space
mission, their inner ear mechanisms are functioning normally,
but soon they lose gravitational stimulation to the otolith
organs, resulting in vertigo, spatial disorientation, and postural
instability, similar to symptoms experienced by individuals on
Earth who have vestibular disorders. Just as a patient with a
vestibular lesion must acquire new strategies to improve day-
to-day living, an astronaut must voluntarily and reﬂexively
process the changing vestibular signals and initiate compensa-
tory responses to better match the new environmental demand
while in space and after returning to Earth. The neural pro-
cesses that are directly affected by the novel gravity environ-
ment, such as balance, equilibrium, and motor control, adapt
rapidly and over time. The end result of these processes is to
optimize performance in the space environment but might in
some cases be maladaptive in a dynamic, quickly changing
setting, or could even be an immediate or long-term threat
upon reentry to a gravity environment.
Without sufﬁcient countermeasures, some of the mecha-
nisms to counter the loss of gravity signal that develop during
spaceﬂight might lead, for example, to structural changes in the
inner ear and plasticity of interconnectivity between neuronal
populations involved in perception and spatial cognition. It is
likely that the longer the astronauts stay in space, the more
their vestibular, sensorimotor, and spatial orientation distur-
bances will intensify. A wealth of clinical and experimental
data exist on how inner ear damage affects motor control and
orientation functions, but less is known about the role of the
vestibular organs in other functions. For example, we know
that most space travelers will experience motion sickness in
orbit and immediately after they return, but we do not know if
this response is due to utricular organ asymmetry or due to
changes in otolith mass or vestibular neural activity. We also
know that astronauts quickly learn to move effectively inside a
spacecraft and that this learned behavior carries over to sub-
sequent ﬂights. However, we do not know how the astronauts
will adapt their postural behavior and orthostatic tolerance on
the surface of Mars after a 6-mo ﬂight in weightlessness
(Paloski et al. 2008). The interaction between vestibular adap-
tation and blood pressure regulation is also important, partic-
ularly as it might be related to postﬂight orthostatic intolerance.
Also, the spaceﬂight-associated neuro-ocular syndrome
(SANS) issue, which almost certainly is microgravity dose
dependent, may well result from prolonged ﬂuid shifts (Mader
et al. 2011), affects the visual system, and may result in brain
changes that could have long-term effects on the individual—a
blurring between neural and cardiovascular function. To elim-
inate the ambiguity of this new input-output context, the
vestibular signals must be properly integrated with processes in
other areas of the brain (Reinagel 2001). The sensorimotor,
oculomotor, postural, and cardiovascular adaptive mechanisms
are mostly or completely independent of each other and likely
vary over a range of timescales. How well the astronauts adapt
to the novel environment will determine their fate.
COGNITIVE AND BEHAVIORAL STUDIES IN MODEL
Future exploration missions will present much greater chal-
lenges to crewmembers’ behavioral health and performance
than the challenges currently faced by astronauts working and
living on the ISS. Deep space missions will include unprece-
dented duration, distance, isolation, and conﬁnement under
increasingly autonomous operations, and these stressors, in
combination with prolonged periods of exposure to micrograv-
ity and space radiation, might alter the astronaut’s cognitive
Although many performance measures can be directly as-
sessed in humans, human epidemiology data from space-like
radiation are limited. NASA must rely on translational models
to study the effects of the neurochemical, functional altera-
tions, and structural changes in the brain and to assess how
these alterations relate to operationally relevant performances
associated with radiation exposures similar to spaceﬂight mis-
sions. Many different species of animals have been used to
study mechanisms underlying adaptation of complex behaviors
(e.g., learning and memory, social interaction, anxiety, and
sleep) during spaceﬂight. APPENDIX C provides a brief review of
the behavior of invertebrates, amphibians and reptiles. How-
ever, the primary models to assess behavioral effects of space-
ﬂight and spaceﬂight analogs have been rodents. A relatively
large number of mice can be ﬂown per spaceﬂight, and the life
span of a mouse is much shorter than the life span of a human;
therefore, a few months of observation in rodents is represen-
tative of many years of observation in humans. In addition,
rodents can be suspended by their tails to simulate the mechan-
ical unloading and cephalic ﬂuid shifts induced by spaceﬂight,
allowing investigators to conduct ground-based studies of the
effects of hypogravity without the limitations imposed by
spaceﬂight. To conduct a comprehensive risk assessment and
manage health risks for astronauts of future exploration mis-
sions, the combined effects of radiation and other spaceﬂight
stressors must be assessed using animal models and behavioral
constructs that can bridge the gap between the radiation-
induced effects observed in animal models and the predictions
of human performance changes in space. Structural and func-
tional changes to the CNS of rodents exposed to combined
spaceﬂight stressors indicate that important processes underly-
ing information processing are altered. This could lead to
impairments in multiple behavioral domains including, affect,
learning, memory, and cognitive ﬂexibility, all of which could
negatively impact operationally relevant performance.
Spatial learning and memory behaviors have been most
widely examined to probe behavioral changes induced by
spaceﬂight stressors. Mazes, novel object and place recogni-
tion, object in place recognition, and contextual fear condition-
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ing have commonly been used to test memory that is dependent
on the hippocampus and has a strong association with the
cortex. Cognitive behaviors, which are associated with the
frontal cortex, can be tested using operant conditioning, atten-
tional set sifting, and psychomotor vigilance tests. Anxiety and
fear are commonly assessed with open ﬁeld tests, elevated plus
mazes, or zero mazes, while forced swim and tail suspension
tests can indicate depression-like behavior. However, behav-
ioral effects are difﬁcult to quantify in animals, and outcomes
depend on the animal species, strain, age, sex, and assessment
method used (Buckner and Wheeler 2001). The future chal-
lenge will be to rigorously translate animal behavioral effects
to human behavior and establish the signiﬁcance of the results
for astronaut performance during a Mars mission.
Behavior of Rodents During Spaceﬂight
Numerous rodent studies have shown that gravity transitions
modify anxiety levels and memory and learning behaviors.
After being subjected to 2 wk of hindlimb unloading (HLU) to
simulate the effects of weightlessness, rats had impaired mem-
ory as determined using the Morris water maze and shuttle box
tests (Qiong et al. 2016). During parabolic ﬂights, which
generate different levels of partial gravity, rats’ behavior
changed according to the gravity level: between 0.4 and 0.2 g
they exhibited startle response and crouching (anxiety-like
behaviors), while between 0.01 gand 0.15 gthey extended
their hindlimbs, which suggests that different thresholds may
exist for emotional behavior and balance or posture-related
effects (Zeredo et al. 2012). Rats’ spatial learning in the radial
arm maze was signiﬁcantly impaired for 5 days after 2 wk of
rotation at 2 g, and then their performance returned to normal,
suggesting that animals need a constant gravity reference to
maintain performance but can effectively adapt to gravity
transitions (Mitani et al. 2004). However, it is important to note
that complications can be introduced when centrifugation is
used as a model of hypergravity: in one study, rats showed
signs of “rotation sickness” that increased in severity with the
duration of the rotation and recovered somewhat after 12 h (Cai
et al. 2005).
Young rats that were exposed to both 14 days of HLU and
radiation (3 Gy of
Cs gamma rays on day 7 and 1.5 Gy of
a broad energy spectrum of protons on day 14) had only a
slight decrease in working memory and no change in spatial
memory. However, open ﬁeld and elevated plus maze results
indicated decreases in anxiety-like behavior (more time spent
in center of ﬁeld or open arms) (Kokhan et al. 2017).
A series of spatial memory tests were performed on rats after
they ﬂew on board the biosatellites Cosmos 605, 690, 782, or
936, for spaceﬂights lasting from 19.5 to 21.5 days. Radial arm
maze (Lachman-type) protocols conducted from 2 days to 4 wk
after the ﬂights indicated that the rats’ spatial memory was
impaired, and this effect was enhanced when the animals had
higher workloads, indicating this effect may have been asso-
ciated with fatigue or decreased cognitive reserve (Gurovsky et
The absence of gravity seems to have minimal long-term
impact on development of spatial cognitive navigation systems
in rodents. Cognitive mapping abilities were assessed in rats
that spent 16 days on a Space Shuttle mission starting from
postnatal days 8 or 14. Two days after landing, the spatial
learning and memory behavior of the ﬂight rats in the Morris
water maze, radial arm maze, and open ﬁeld paradigms was
similar to the behavior of Earth-bound, age-matched control
rats, and only subtle differences were detected in search pat-
terns, which resolved within a few days (Temple et al. 2003).
In addition, the offspring of rats exposed to 5 days of weight-
lessness on the Cosmos 1514 mission during gestation days
13–18 were assessed when they were 1– 4 mo old, and they had
no impairments in maze-based cognitive tasks; however, their
exploratory behavior was reduced in an open ﬁeld paradigm
and grooming increased, which together suggest enhanced
anxiety (Apanasenko et al. 1986). Temple et al. (2002) as-
sessed the performance of 8- and 14-day old rats for a month
after they returned from 16 days on the Space Shuttle Neurolab
mission, and determined their memory, spontaneous activity,
and anxiety levels were unchanged by the spaceﬂight. How-
ever, for a short time the rats did swim faster than they did
before ﬂight and took longer to reach the platform in the water
In 2009, three transgenic mice that overexpress pleiotrophin
(a cytokine that is upregulated in tissue injury and wound
repair, and is involved in bone formation, neurite outgrowth,
and angiogenesis) spent 91 days on the ISS to evaluate whether
the transgenic mice were less susceptible than wild-type mice
to the negative effects of microgravity on bones. The trans-
genic animals exhibited more “ﬂoating” behavior (rodent ﬂoat-
ing behavior in water is generally associate with passive
behavior, anhedonia, and stress response; in space it could
reﬂect adaptation to the environment) but less grooming (a
displacement activity) than the wild type, suggesting the strains
use different procedural and emotional coping mechanisms to
adapt to weightlessness (Cancedda et al. 2012). Unfortunately,
only half of the mice survived the 91-day ﬂight because of
payload or health issues. The brains of the three remaining
mice (2 transgenic and 1 wild type) were analyzed after the
mission, and ﬂight animals had decreases in hippocampal and
cortical levels of nerve growth factor compared with ground-
based control animals (Santucci et al. 2012).
In-ﬂight video recordings of 45 male mice during the 30-day
unmanned Bion-M1 mission revealed higher levels of aggre-
gative behavior (huddling contact) near the feeder relative to
the behavior of identically housed ground controls (Andreev-
Andrievskiy et al. 2014), although the cause of this behavior
was not discernible from the videos. Observations of the
behavior of individually housed mice ﬂown for 35 days on
board the ISS indicated that mice ﬂoated freely throughout the
habitat and used their tails to maintain their posture while
resting (Shiba et al. 2017). Recently, video images were
acquired of 16- and 32-wk-old female mice inside the NASA
Rodent Habitat on board the ISS. Physical activity was greater
in younger ﬂight mice than in identically housed ground
controls and followed the circadian cycle. Animals developed
a directed coasting behavior, used tails for position stabiliza-
tion, and ambulated using front paws, and only a small per-
centage of their locomotion involved free ﬂoating. Within 7–10
days after launch, younger (but not older) mice began to
exhibit distinctive circling or “race-tracking” behavior that
evolved into group activity (Ronca et al. 2019). This race-
tracking behavior may represent an attempt by the animals to
self-generate artiﬁcial gravity via self-motion.
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Unlike mice, male gerbils (Meriones unguiculatus) moved
chaotically throughout a 12-day ﬂight (Foton-M3) and never
attempted to stabilize their positions by grasping the wire mesh
of the cage system (Il’in et al. 2009).
Behavior in Nonhuman Primates During Spaceﬂight
To assess accuracy of eye-head-hand movements and reac-
tion time during spaceﬂight, Rhesus monkeys were trained to
touch their hands to lights on a horizontal display panel that
were positioned at different angles around the animal. Early in
the 14-day Bion 11 ﬂight, the monkeys performed the coordi-
nation task up to 60% slower and up to 40% less accurately
than when they performed this task before the ﬂight, although
performance did improve during the second week of the
mission (Antsiferova et al. 2000). In addition, Washburn et al.
(2000) reported that spaceﬂight impaired psychomotor activity
in rhesus monkeys that were trained to place computer screen
cursors over randomly appearing targets within ﬁxed time
intervals, make selections from a ﬁve-choice menu, or follow
moving targets using a joystick. The performance of both the
ground control monkeys and the ﬂight monkeys in this study
was impaired, but the magnitude of impairment was much
greater for the ﬂight animals. A confounding issue was the
personalities of the monkeys and their willingness to perform.
Effects of Space Radiation on Behavior in Animals
One of the major concerns for long-term exploration mis-
sions beyond the Earth’s magnetosphere is how to protect
astronauts from sporadic solar particle events (SPEs), which
are largely composed of low- to medium-energy protons, and
from chronic, low-dose-rate galactic cosmic rays (GCRs),
which are composed of high-energy protons (85%) and high-
energy and charge (HZE) particles (Nelson 2016). When HZE
particles penetrate tissue, they can produce a track of heavily
irradiated and potentially damaged cells along their path, and it
is possible these tracks can seriously damage the CNS. Clus-
tered, repair-resistant patterns of DNA damage occur, and it is
also possible that unique tissue level forms of damage occur
due to spatial correlation of tracks with neural cell arrange-
ments. The maximum annual radiation exposure from GCR
during a Mars mission is predicted to be of the order of 20 cGy
a year with less than 50% of the dose from HZE particles
(Cucinotta et al. 2014). Recent studies have reported that doses
of HZE particles of less than 10 cGy can induce behavioral and
structural changes. Two recent reviews detail many of these
ﬁndings (Cekanaviciute et al. 2018; Kiffer et al. 2019).
Overall, evidence from animal studies indicates that space-
like radiation generated by particle accelerators induces per-
sistent measurable changes in the functional status of the CNS
that are analogous to changes that occur during aging and in
some neurological diseases associated with oxidative stress,
neuroinﬂammation, and dendropathies. However, the dose re-
sponses can be complex and nonlinear, and some investigators
have suggested that repair or compensatory processes may be
elicited at doses higher than those that induce damage per se.
Observations of hippocampus-dependent memory formation,
frontal cortex-dependent executive function and cognition, and
amygdala-dependent anxiety and fear in rodents has provided
convincing evidence that space-like radiation induces quanti-
ﬁable behavioral impairments that may appear acutely or over
many months, but very little is known about the mechanisms
that cause these cognitive changes.
The age at evaluation and irradiation affects the behavioral
responses to accelerated particles (Rabin et al. 2012), as do sex
and genotype (e.g., ApoE allele, hybrid strains vs. inbred)
(Acevedo et al. 2008; Haley et al. 2012; Villasana et al. 2010).
Krukowski et al. (2018b) showed that charged particles in-
duced a variety of sex-speciﬁc responses in mice, and females
were more radioresistant: males’ social interaction and mem-
ory were more diminished than those of females, and their
anxiety, microglia activation, and synaptic loss were greater.
Considerable interindividual variation exists in the susceptibil-
ity of Wistar rats’ development of neurocognitive impairment;
some irradiated rats maintain a level of spatial memory per-
formance comparable to that seen in the sham-irradiated rats
(Britten et al. 2012), suggesting that some rats are able to
ameliorate the deleterious effects of the GCR while others are
not. In addition, rats that are preselected for their suitable or
superior baseline performance and are exercised regularly are
less susceptible to detrimental behavioral effects from radiation
exposure than a randomly selected population (Jewell et al.
Exposure to low doses of HZE particles accelerated the
appearance of age-related electrophysiological properties in
transgenic mice that overexpress human Alzheimer amyloid
precursor protein, decreased cognitive abilities (contextual fear
conditioning and novel object recognition), and accelerated
plaque pathology, including deposition and clear-
ance (Cherry et al. 2012; Vlkolinsky et al. 2010).
Rodents that were exposed to HZE particles at doses ex-
pected on a Mars mission have pronounced deﬁcits in hip-
pocampus-dependent learning and memory, including novel
object recognition and spatial memory. The extreme sensitivity
of these processes may be attributable to the perturbation of
multiple functional processes, especially synaptic plasticity, in
addition to low levels of killing of neuronal precursor cells,
especially in the dentate gyrus. There is evidence that changes
in microglial activity may mediate these changes and account
for sex-speciﬁc differences (Krukowski et al. 2018a). Six, 15,
and 52 wk after C57Bl/6 male mice were irradiated with 5 or
30 cGy of helium, their memory was impaired, their anxiety
and depression-like behaviors increased, and their cognitive
ﬂexibility decreased. These changes were also accompanied by
increased microglial activation as measured by CD68 immu-
noreactivity (Parihar et al. 2018). Two weeks after mice were
irradiated with Fe particles, novel object recognition and spa-
tial memory retention were impaired at doses as low as 10 cGy
(Haley et al. 2013); however, no effects of irradiation were
detected on contextual fear conditioning or spatial memory
retention in the water maze for the same animals.
Recently, Carr et al. (2018) examined the effects of 0.1,
0.25, and 1 Gy of accelerated oxygen particles on 6-mo-old
male C57Bl/6 mice 2 wk after exposure. The animals irradiated
with 0.1 and 0.25 Gy had impaired short-term memory,
whereas memory in the animals irradiated with 1 Gy was
unchanged. This inverted U-shaped dose response was also
evident for levels of NR1 and NR2B N-methyl-D-aspartate
(NMDA) receptor subunits and presynaptic marker synapsin1,
which were signiﬁcantly reduced, and type 1 glutamate
-amino-3-hydroxy-5-methylisoxazole propionic acid
(AMPA) receptor, which was elevated at the lower doses.
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Using the Barnes maze test, Britten et al. (2012) showed that
20 cGy of accelerated Fe particles induced persistent reduction
in the spatial learning ability of rats. Although it has been
shown that Fe exposures as low as 25 cGy can reduce rats’
motivation and responsiveness to environmental stimuli, the
reduction in spatial learning was not caused by the rats’ lack of
motivation to escape the Barnes maze, because the total num-
ber of head pokes (and especially incorrect head pokes) re-
mained constant over the test period.
Neurocognitive tasks that involve executive function, which
depend on the hippocampus, striatum, and are regulated by the
prefrontal cortex, are also impaired after exposure to low doses
of HZE particles. Executive function is a complex process that
requires the operation of a number of more basic cognitive
processes to optimize performance. Impairment of executive
function is undesirable under any circumstance but will be
particularly dangerous during a Mars mission because astro-
nauts will be required to perform complex functions through-
out the mission. Britten et al. (2014) showed that less than
Mars mission-equivalent doses of Fe particles led to impair-
ment of attention set-shifting performance (ATSET), a mea-
sure of executive function, in rats 3 mo after exposure. The
exact nature of the impaired ATSET performance varied de-
pending on the age of the rat, the radiation dose, and the nature
of the exposure (whole body vs. cranial irradiation). Behavioral
decrements were associated with a reduction in the readily
releasable pool of neurotransmitters from isolated cortical
synaptosomes, which have been shown to play a major role in
regulating the activity of the prefrontal cortex and suggest an
important presynaptic site of radiation action.
In one of the few studies of charged particles effects on
nonhuman primates, Belyaeva et al. (2017) exposed rhesus
monkeys to 3 Gy of 170-MeV protons followed 40 days later
by 1 Gy of 160-MeV carbon ions, doses that are signiﬁcantly
higher than would be expected during a Mars mission. The
animals were trained to use a joystick and computer monitor
system to position a cursor over various sizes of moving targets
for food rewards (“circle test”). Proton irradiation did not
impair cognitive function whereas a subsequent carbon ion
exposure led to reduced cognitive function in terms of test
success rates and attempts. However, interindividual differ-
ences were observed that were ascribed to personality differ-
ences in the animals. No biochemical changes were detected
shortly after proton exposure, but 1 mo after irradiation, L-3,4-
dihydroxyphenylalanine (L-DOPA) concentrations in the blood
were elevated. Eight days after irradiation with
C ions, the
concentrations of all the dopamine metabolites assessed in this
study had decreased, with signiﬁcant changes obtained for the
dopamine metabolite homovanillic acid. Altered dopamine
metabolism and receptor expression would likely affect reward
systems and motor control.
Most studies of HZE particles have assessed the effect of
just one particle type at a time delivered in a single dose over
a few minutes, which does not represent the chronic low-dose-
rate exposures to mixed particles that will occur in space.
Recent rodent experiments have shown that sequential irradi-
ation with multiple ions may lead to behavioral outcomes not
predicted from exposure to individual ions (Krukowski et al.
2018b; Raber et al. 2016). To address this complication, NASA
is now facilitating experiments at Brookhaven National Labo-
ratory with a complex set of 33 ions and energies designed to
simulate the full GCR spectrum as it would appear inside the
body of a female astronaut on a deep space mission behind
vehicle shielding (Slaba et al. 2016). A simpliﬁed ﬁve-ion
GCR ﬁeld has also been used for higher throughput studies,
and both of these ﬁelds can be delivered in daily fractions 6
days/wk over 6 wk to combine a more accurate radiation ﬁeld
with low dose rates on rodent timescales representative of a
3-yr Mars mission. Chronic (6 mo) low-dose-rate neutron
studies also were recently completed to address the dose rate
issue (Acharya et al. 2019).
Effects of Radiation on Human Central Nervous System
Radiotherapy patients receive high (e.g., 50 Gy), localized
doses of radiation, far above doses that space travelers will
encounter. This can have deleterious effects on their CNS
(Greene-Schloesser and Robbins 2012; Greene-Schloesser et
al. 2012), and they routinely exhibit behavioral changes, such
as chronic fatigue, cognitive impairment, and depression.
When childhood leukemia is treated with fractioned whole
body exposures of radiation in the 20-Gy range (lower than the
localized doses to tumors but still much higher than during
spaceﬂight), adult survivors exhibit dose-dependent deﬁcits in
information-processing speed, memory, attention, and learning
(Armstrong et al. 2013). Atomic bomb and Chernobyl accident
victims who received low-to-moderate doses of radiation (ⱕ2
Gy) exhibited evidence of memory and cognitive impairments,
and higher frequencies of psychiatric disorders and altered
electroencephalographic patterns (Bromet et al. 2011; Lo-
ganovsky and Yuryev 2001). A study of A-bomb survivors by
Yamada et al. (2009) found no increased risk of dementia, but
mental retardation was observed in some prenatally exposed
children of A-bomb survivors (Otake and Schull 1998). These
A-bomb studies, many of which were conducted on small
cohorts, all involve low-linear energy transfer (LET) expo-
sures, and it is difﬁcult to extrapolate the data to the high-LET
charged particle exposures found in space. The “Million Man
Study” in progress will be the largest epidemiological study of
radiation-exposed humans and will include worldwide assess-
ment of occupational and accidental exposures (Boice et al.
2018). It will include exposures from internally deposited
alpha particle-emitting radionuclides that produce high-LET
tracks and will provide the best baseline for human exposures
Mechanisms Underlying Radiation-Induced Behavioral
Space-like radiation can induce persistent oxidative stress
and inﬂammatory responses that alter the microenvironment of
the brain, inhibiting proliferation and differentiation of hip-
pocampal neuronal precursor cells slated to differentiate into
neurons, astrocytes and oligodendrocytes. Low doses of many
different HZE particles can reduce the complexity of dendritic
branches and the number of dendritic spines (and associated
synapses), possibly via microglia-mediated pruning, which
could change how the brain processes information. Space-like
radiation alters electrical and membrane properties of individ-
ual neurons (resting membrane potential, rheobase, input re-
sistance), and impairs their ability to transfer information
across synapses (synaptic efﬁcacy and connection probability)
and to strengthen their connections after they are stimulated
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(e.g., long-term potentiation). The levels of numerous mole-
cules associated with synapse structure change in response to
radiation exposure, as do ion movements across membranes,
inﬂammatory signaling, and cell survival. Most importantly,
these changes are associated with altered cognitive abilities and
In murine and human neurospheres, less than 1 cGy of
accelerated particles increases oxidative stress involving both
cellular and mitochondrial sources of reactive chemical species
(Tseng et al. 2013). In addition, in vivo radiation exposure is
associated with acute and chronic elevation of oxidative stress,
which may alter membrane properties and activation states of
glutamate and GABA receptor ion channels (Derkach et al.
Radiation elicits persistent neuroinﬂammation that affects
immune cells, endothelia, and microglia and alters production
of cytokines and chemokines and their receptors (Moravan et
al. 2011). Temporary microglia depletion in mice irradiated
with helium particles has been shown to preserve cognitive
function (Krukowski et al. 2018a). Accelerated O and Ti
particles at doses as low as 5 cGy reduce arborization in
hippocampal neurons, reduce dendritic spines in the hippocam-
pus and in the medial prefrontal cortex (Carr et al. 2018;
Chakraborti et al. 2012), and reduce the number of myelinated
(but not unmyelinated) axons in the hippocampus (Dickstein et
Electrophysiological studies of the hippocampi of irradiated
mice have identiﬁed acute changes in presynaptic glutamate
release, recurrent inhibition, synaptic efﬁcacy, and long-term
potentiation, modulations that are consistent with dysregula-
tion of the balance between excitatory and inhibitory activities
(Marty et al. 2014; Rudobeck et al. 2014; Vlkolinsky et al.
2010). A recent report describes alterations in long-term de-
pression of neurons in the frontal cortex of Si-irradiated rats
(Britten et al. 2020). Using the patch-clamp technique to
evaluate effects in mice 3 mo after exposure to 1-Gy protons,
Sokolova et al. (2015) found reduced excitability in CA1
pyramidal neurons, as determined by hyperpolarized resting
membrane potentials, decreased input resistance, upregulated
persistent sodium current, and increased frequency of minia-
ture excitatory postsynaptic currents. These small alterations in
passive membrane properties had a dramatic impact on com-
putational model predictions of network function of the CA1
microcircuit: Lee et al. (2017) have demonstrated impaired
connection probability in a hippocampal-frontal cortex micro-
circuit and have found differences in radiation responses for
different inhibitory neuron subtypes.
Experiments with low doses of high-LET charged particles
similar to cosmic rays have consistently induced impairments
in mouse and rat behavior and in the underlying cellular and
tissue-level CNS outcome measures. Most of the parameters
evaluated show statistically signiﬁcant changes (usually detri-
mental) after exposures of 25 cGy or above, and some param-
eters are sensitive below 10 cGy. Changes are typically detect-
able by 1 mo after irradiation, and many persist for more than
1 yr after exposure. Sensitive behavioral measures have ad-
dressed executive function (including reaction time, vigilant
attention, and impulse control), short- and long-term spatial
and recognition memory, fear memory, anxiety, and depres-
sion-like behaviors, and some sensorimotor parameters. Ob-
served responses at the tissue and cell level include impaired
synaptic plasticity, altered intrinsic membrane parameters, re-
duced of synapse number and dendritic complexity, reduced
neurogenesis, and elicited neuroinﬂammatory responses such
as microglia activation and elevation of proinﬂammatory cy-
tokines. Observed responses at the molecular level include
altered levels of neurotrophic factors (brain-derived neu-
rotrophic factor, BDNF), glutamate, and GABA-gated ion
channels and expression of networks associated with proteo-
toxicity and neurodegenerative phenotypes.
Most data accumulated to date were from studies of acute
exposures to single species of charged particles, although
ongoing studies are now addressing effects of dose-rate reduc-
tion and responses to complex mixtures of particles and ener-
gies designed to better emulate the space radiation environ-
ment. Overall, the data suggest that spaceﬂight-induced cellu-
lar and tissue changes are to be expected in humans and that
these changes could impair proper information processing or
lead to dysregulation of compensatory reactions. However,
humans will likely moderate the degree of impairments in
performance because they have greater cognitive reserve and
ﬂexibility than do mice. Nevertheless, it will be important to
continue developing countermeasures such as training, exer-
cise, and antioxidant and anti-inﬂammatory approaches to
ensure that astronauts perform at peak efﬁciency.
COGNITIVE AND BEHAVIORAL EFFECTS IN HUMANS
Human space missions to Mars are the next great leap in
space exploration. However, we should carefully consider the
complex interplay of psychological and physical stressors that
humans will endure during these missions. In fact, the human
element has been identiﬁed as the “most complex component
in the design of long-duration missions into space” (Ball and
Evans 2001, p. 137). To ensure the crewmembers are safe and
perform adequately in the extreme environments associated
with long-duration spaceﬂight, we must understand and antic-
ipate how adaptation to the complex entanglements of physi-
ology, psychology, and behavior could alter an astronaut’s
capability to perform an operational task (Kaas 1995). For
example, the incapacitating effects of spaceﬂight-induced mo-
tion sickness and the associated effects on astronaut’s physio-
logical, psychological, and performance highlight a causal link
between space motion sickness, vertical orientation, and sig-
niﬁcant disruptions of the basic aspects of perception and
behavior (National Research Council 1998).
Below we review the psychological challenges of long-
duration spaceﬂight and identify cortical projections that link
psychological factors, social domains, and mood states to the
vestibular system. In particular, we focus on the integrated
spaceﬂight-induced risks, and adaptations to those risks that
either directly or indirectly affect the crewmembers’ behavioral
health and their performance.
Spaceﬂight is both physically and psychologically demand-
ing. The physical demands, including vibrations, noise, accel-
erations, weightlessness, and conﬁnement, are at the extremes
of human tolerance. These physical stressors increase psycho-
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logical stress (e.g., perceived dangerousness of the mission,
social isolation, monotony, restricted sensory stimulation, re-
duced activities, autonomy) and physiological adaptations
(e.g., ﬂuid shifts, spatial disorientation, lowered immune re-
sponses, muscle atrophy, and bone loss) (Garrett-Bakelman et
al. 2019; Löbrich and Jeggo 2019). Given the known stressors
of spaceﬂight, an important ﬁrst approach is to identify and
select astronauts who have characteristics that help them adapt
to these extreme demands (Santy et al. 1993). For example,
current selection programs assess astronauts for important
psychological factors such as personality characteristics (Mit-
telstädt et al. 2016; Musson et al. 2004), ability to self-regulate
(Derryberry and Rothbart 1988), expeditionary mindset, auton-
omy, and psychiatric risk factors (Santy 1994). Because any
long-duration mission will also likely involve a multinational
team (Kintz and Palinkas 2016), interpersonal strengths and
vulnerabilities, tolerance for differences in language and cul-
ture, and adaptability in leading and following are also impor-
tant to determine what has been described as the “right stuff”
Psychophysiological adaptations to spaceﬂight include dis-
ruptions in circadian rhythm and associated sleep loss, hor-
monal changes, and cognitive changes such as increased reac-
tion time. During prolonged conﬁnement inside a spacecraft,
astronauts have reduced sensory inputs, and these altered
sensory inputs affect the sensitivity of their hearing and their
perception of distance and motion (Clément and Reschke
2008). In addition, astronauts commonly experience “space
fog”— cognitive and perceptual changes that manifest as at-
tention lapses, short-term memory problems, confusion when
performing dual tasks, and psychomotor problems. It is very
difﬁcult to determine whether the effects of these stresses are
additive or synergistic and how much of the effect can be
attributed to workload or associated fatigue or to environmen-
tal factors such as CO
levels, lighting, and noise. In addition,
the crewmembers vary considerably in their response to the
stress and the environmental demands (Borle et al. 2017).
Mood and Affect: Risk to Behavioral Health and
An astronaut’s psychological well-being during a long-
duration space mission will depend on multiple factors. For
example, several early ground studies that focused on isolation
and space simulations identiﬁed a signiﬁcant linear dose-
response increase in symptoms related to depression, anxiety,
and group hostility (Kelly and Kanas 1992; Rohrer 1961;
Sandal et al. 1996; Santy 1994). This demonstrated how
important it is for astronauts to have the ability to self-regulate
the range and intensity of their affective states and sustain an
emotional state (i.e., mood) that does not interfere with or
deteriorate their performance. A full range of emotions, such as
happiness, elation, calmness, anxiety, irritability, anger, and
sadness, might occur over a long-duration mission. Research
must pay particular attention to the range of these emotions
(e.g., are they unchanging or constantly changing?) and
whether they are appropriate to thought content.
Early in the space program, the most important psycholog-
ical aspects of astronaut selection were based on how the
astronauts performed and adapted psychologically during ac-
celeration and deceleration (Sells and Berry 1961). As mis-
sions became longer and began to include three crewmembers,
NASA recognized and emphasized the importance of team
dynamics and composition, and teamwork (Kanas and Fedder-
son 1971; Landon et al. 2016). Several scientiﬁc reviews by the
National Academy of Sciences stressed the need to address the
“negative psychological reactions” that affect interpersonal
interactions, social dynamics, and group processes during
spaceﬂight. They noted that “the history of space exploration
has seen instances of reduced energy levels, mood changes,
poor interpersonal relations, faulty decision-making, and lapses
in memory and attention” (Committee on Space Biology and
Medicine 1998, p. 169). In 2001, the spaceﬂight-associated
risks to behavioral performance and psychology were again
addressed in the National Academy of Science publication Safe
Passage: Astronaut Care for Exploration Missions (Ball and
Evans 2001). Long-duration space exploration missions will be
autonomous and isolated from ground control assistance and
from the social support that helps promote human well-being.
This increased autonomy and isolation will require a spacecraft
that is designed to support both the psychological and the
social needs of the crew but will also increasingly involve
human integration and interactions with complex, more auton-
omous spaceﬂight systems (McCandless et al. 2007). Within
this dynamically changing demand for human systems integra-
tion, we must assess the complex interplay between adapta-
tions of the vestibular and psychological/behavioral perfor-
mance systems that are anticipated during long-duration space-
ﬂight. Potential alterations to neurophysiology must be
characterized and then mitigated by using countermeasures that
include technology, training, medical and psychological inter-
ventions, or changes in the designs of habitable volume of the
Evidence that long-duration spaceﬂight changes cognitive
functioning is equivocal. When they reviewed extensive cog-
nition data from studies conducted in space and in analog
environments, Strangman et al. (2014) found no consistently
predictable decrements in cognitive performance for the areas
of emotion and social processing, attention, memory, learning,
and executive or higher order functioning. However, an astro-
naut’s ability to sustain attention will become increasingly
important for missions of longer duration because the vast
distance from Earth will require the astronauts to operate more
autonomously. It is clear that the ability to sustain one’s
attention varies with the type of task (Heuer et al. 2003;
Manzey et al. 1995, 2000). Controlled simulations using space-
ﬂight analogs have revealed performance-related changes such
as reduced energy levels, changed mood, faulty decision-
making, and lapses in memory and attention (Palinkas 1991;
Palinkas et al. 1995). Given that negative emotions are asso-
ciated with decline in task performance and motivation (Kanas
1987; Santy 1983), strategies that increase and/or maintain
positive emotions are important mitigations strategies to ensure
successful performance of an operationally relevant task (Csik-
szentmihalyi 1990). At this point, we do not know how task
performance is affected by weightlessness-induced changes in
motor control, i.e., to what extent gravity inﬂuences learning,
memory, and cognitive processing (Hanes and McCollum
2006; Smith et al. 2005). Also, we do not know how to
distinguish, or parse out, the effects on both physiological
(Convertino and Tsiolkovsky 1990) and psychological dys-
regulations that are brought about by exposure to weightless-
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ness, radiation, and conﬁnement and isolation stress, or by
some synergistic impact of all these factors (Porte and Morel
2012). For example, the hippocampus is important for memory
consolidation and retrieval of long-term memories and is par-
ticularly sensitive to both stress and radiation (Lupien et al.
2005; Monje 2008; Obenaus et al. 2008).
Relationship Between Vestibular Processing and Emotions
As described throughout this review, exposure to weight-
lessness results in changes in the sensitivity of the otolith
system. Vestibular neuroanatomical projections extend from
the vestibular nuclei to the cerebral hemispheres (Bush et al.
2000), and this raises intriguing questions about the conse-
quences of vestibular changes during a long-duration space-
ﬂight: To what extent are the functional systems of emotion
and vestibular modalities integrated? How do the adaptations
of the vestibular system contribute to the crewmember’s mood
and social cognition? Here we identify potential associations
between vestibular physiology and behavioral health, perfor-
mance, and cognition that are relevant to long-duration space-
The vestibular system detects linear and angular head mo-
tions, which are used for gaze stabilization, postural control,
verticality perception, navigation, and spatial memory. The
vestibulo-sympathetic efferents also contribute to postural
blood pressure regulation, bone density, muscle composition,
and circadian rhythms (Besnard et al. 2018). It is well known
that vestibular stimulation by means of whole body passive
rotation produces autonomic changes (Golding and Stott 1997)
and that prefrontal limbic circuits are involved in vestibular-
induced nausea. Neuroimaging reveals that vestibular-induced
nausea inﬂuences the same prefrontal areas of the brain (Miller
et al. 1996) that are associated with autonomic regulation of
emotions (Demaree and Harrison 1997). Research using ani-
mals has demonstrated that the physiological adaptations to
nonterrestrial gravity levels can evoke dysregulations in mood,
affect, and arousal systems (Porte and Morel 2012). These
ﬁndings imply that vestibular-induced motion sickness can
stress prefrontal areas of the brain and result in a disruption of
autonomic mechanisms. Relevant terrestrial evidence indicates
that people who suffer from vestibular dysfunction are at
higher risk than healthy controls of developing anxiety disor-
ders (Best et al. 2009), and patients diagnosed with anxiety
disorders frequently report greater sensitivity to vestibular
stimuli (Staab and Ruckenstein 2003; Staab et al. 2014).
Accordingly, vestibular sensory function integrates with mood
states and arousal (Porte and Morel 2012), which affects
autonomic systems such as mood states, social cognition,
emotion, perspective, and perception.
The importance of characterizing the integration of auto-
nomic and vestibular demands on cognitive processes is of
particular relevance when considering psychological risk fac-
tors associated with long-duration spaceﬂight. For example, the
networks that process vestibular signals and anxiety responses
have a reciprocal inﬂuence, and evidence indicates they are
functionally intertwined (Bednarczuk et al. 2018). Interest-
ingly, the degree of an individual’s vestibulo-cortical hemi-
spheric dominance correlates with their anxiety level; individ-
uals with right hemispheric dominance exhibit the lowest
levels of anxiety. This suggests a potential link between ves-
tibular disruptions and anxiety (Godemann et al. 2004; Pollak
et al. 2003). Additional research highlights potential links
between hostility and vestibular interactions. For example,
Carmona et al. (2008) rotated 20 healthy participants in yaw
and found that the induced autonomic arousal was related to
higher hostility level. Other studies have shown that vestibular
stimulation can affect an individual’s perception of negative
emotional faces (Herridge et al. 1997), proper interpretation of
emotional prosodic speech (Borod et al. 1992, 1998), inhibition
during stressful vestibular challenges (Brandt 1999; Brandt et
al. 2002), and response to appropriate sensory input (Sander et
al. 2005). The right hemisphere is the dominant brain hemi-
sphere for 1) the interface between the vestibular system and
affective components and 2) the expression, reception, and
experience of negative emotions (Carmona et al. 2009). During
the Salyut 6 and 7 missions, cosmonauts became increasingly
disturbed by loud sounds and by the manner of speech from
mission controllers (Grigoriev et al. 1988; Lebedev 1988).
These heightened perceptual sensitivities reinforce the impor-
tance of addressing how emotions and vestibular changes
brought about by spaceﬂight may affect crew health, perfor-
mance, and safety.
Another important contributor to interindividual variability
in operationally relevant performance is the crewmember’s
systematic neurobehavioral responses and vulnerabilities to
sleep deprivation (Van Dongen et al. 2004). This variability
presumably reﬂects individual circadian differences (Sletten et
al. 2015), which are affected by environmental factors (e.g.,
amount and timing of ambient light; Czeisler et al. 1986) and
contribute to biological processes such as brain wave activity,
hormone production, and cell regeneration. Although temper-
ature, noise, elevated CO
levels, voids, rumination, and heavy
workload contribute to reduced sleep in space (Hobson et al.
1998), vestibular changes induced by weightlessness could
also affect sleep architecture (Hobson et al. 1998; Mizuno et al.
2005). Quarck et al. (2006) have shown that sleep deprivation
altered vestibular-related oculomotor responses: after sleep
deprivation, the VOR gain increases during an unpredicted
head rotation that is a potential threat to postural balance.
There is also ample evidence that vestibular pathologies induce
sleep disturbances (see Besnard et al. 2018 for a review).
Vestibular signals can also modulate affective control of
emotions and decision outcomes (Preuss et al. 2014a, 2014b),
which, as noted earlier, provides evidence that the vestibular
and emotional brain networks share common subcomponents
(Carmona et al. 2009; Dodson 2004; Levine et al. 2012). As an
example, emotional processing inﬂuences performance of cog-
nitive tasks (Buodo et al. 2002; Lindström and Bohlin 2011),
whereas the vestibular system plays an important role in
precise motor reactions during performance of some tasks.
Therefore, it is important to determine how microgravity (and
other unusual force environments) affects the coordination of
eye, head, torso, arm, and leg movements during task perfor-
mance that must adapt to these conditions (National Research
Council 1998). During exploration missions, crewmembers
will be more autonomous, and they will have to respond to
crisis situations. We cannot underestimate the importance of
understanding how the vestibular and emotional processing
systems interact during dangerous or threatening situations
when vestibular perceptions will drive adaptive motor re-
sponses, for example, during the “ﬁght or ﬂight” responses.
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Emotional processes would signal and mobilize the crewmem-
ber for action (Frijda 1986, 2007; Lang 1993), whereas ves-
tibular processes would generate the crewmember’s motor
responses. Given this commonality of purpose, it is not sur-
prising that the vestibular and emotion systems share parts of
the insular and anterior cingulate cortex (Carmona et al. 2009;
Preuss et al. 2014a, 2014b).
It has been proposed that the functional connectivity of the
brain helps establish interdependent and interconnected func-
tions of brain stem and the higher cognitive domains (Luria
1966). To minimize the risk due to an astronaut’s mood and
mood states during a long-duration expedition mission, we
need to identify the cerebral pathways that link the motor,
somatosensory, and vestibular responses to mood and mood
states. This integrated approach will allow investigators to
assess how competition for shared cerebral pathways contrib-
utes to decrements in operationally relevant performance as
vestibular responses adapt during spaceﬂight.
Given that crewmembers experience space radiation, isola-
tion, and altered gravity simultaneously, it is important to
assess whether the individual effects from each stressor on
operationally relevant performance remain distinguishable
when experienced in combination. Evidence to date suggests
that each crewmember has a certain capacity to tolerate all
three stressors. The null hypothesis therefore is that the risks
from each of these hazards are noninteracting. To fully char-
acterize these risks, we must quantitatively predict if combined
exposure produces additive or synergistic effects and then
categorize the stressors according to their effects on receptors,
systems, or domains of action, whether observed singly or in
IMPLICATIONS AND FUTURE DIRECTIONS
In recent years, the focus of NASA’s human spaceﬂight
program has shifted from 6-mo orbital missions in low Earth
orbit to future missions to the Moon that will last ~45 days,
ﬂights to Mars and back that will last ~14 mo, and exploration
missions to the surface of Mars that will last ~30 mo. To ensure
that these missions are successful, astronauts must be able to
perform at peak efﬁciency under extreme conditions. Evidence
clearly shows that spaceﬂight can adversely alter the astro-
nauts’ ability to control vehicles and other complex systems
during a space mission. These tasks require accurate eye-hand
coordination, spatial and geographic orientation perception,
and cognitive function. When astronauts return to Earth after 6
mo on board the ISS, they also exhibit alterations in posture
and locomotion, such as ataxia, muscle fatigue and hypo- or
hypertonia of major muscle reﬂexes, saccadic intrusion during
smooth pursuit, and oscillopsia, which could compromise their
ability to egress the spacecraft during emergencies. These
symptoms occur even after the astronauts have exercised ex-
tensively during the mission, which indicates that these deﬁcits
are primarily due to the lasting effects of adaptation of both the
central motor programs and the vestibular and proprioceptive
Missions to the Moon and Mars will require multiple tran-
sitions between varying gravitational levels (1 gon Earth to
weightlessness, weightlessness to 0.16 gon the Moon, 0.16 g
to weightlessness, weightlessness to 0.38 gon Mars, 0.38 gto
weightlessness, weightlessness to 1 gon Earth), which will
dramatically increase the scope of the challenges and demands
facing astronauts. In addition, prolonged exposure to isolation,
conﬁnement, and extreme conditions pose serious challenges
to the astronauts’ metal health and cognitive function. The
Belgian Antarctic Expedition of 1898 –1899 exposed the dan-
gers of isolation; the ensuing malady of the crew was revealed
in log entries by Frederick Cook, the ship’s physician, and
Roald Amundsen, the ship’s ﬁrst mate (Stuster 1996). A more
successful polar expedition that offers timely insights into the
preparation for and survival from a lengthy 3-yr space mission
is the Norwegian Fram expedition of 1893–1896, commanded
by Fridtjof Nansen (Stuster 1996). Furthermore, the possibility
exists that the crewmembers will develop CNS damage from
exposure to the high-energy protons and charged particles in
the space environment or to secondary by-products such as
neurons of potentially greater harm to the crew. These expo-
sures could lead to acute radiation sickness or to changes in
cognition, motor function, behavior, and mood and could
induce neurological disorders or hereditary effects.
As discussed throughout this review, multiple spaceﬂight
environmental factors affect the nervous system, and it is
possible that these affects could interact and increase risk to
crew health and performance when the crews are isolated,
conﬁned, and simultaneously exposed to space radiation and
partial gravity during future exploration missions (Greco et al.
1995). An integrated strategy is needed to assess and charac-
terize how the combined effects of spaceﬂight hazards affect
crew health and performance. This integrated strategy could
include studies that will help us understand the scope and
extent of neural compensatory mechanisms, which involve
multiple systems (Smith and Curthoys 1989), and will eluci-
date the important role the neurovestibular system plays in
regulating the autonomic nervous system (Steinbacher and
Yates 1996), which could affect mood and lead to performance
deﬁcits linked to the proprioceptive (Keshner and Peterson
1995) and oculomotor systems (Scudder and Fuchs 1992).
In 1998, as the focal point of the “Decade of the Brain,”
NASA partnered with the National Institutes of Health, other
United States research agencies, and ﬁve international space
agencies to ﬂy the Neurolab project during a 16-day Space
Shuttle mission (STS-90). The objective of the Neurolab proj-
ect was to assess how spaceﬂight affects the structure and
function of peripheral and central neural structures in animals
and humans (Buckey and Homick 2003). The 26 experiments
that comprised the Neurolab project were conducted on rats
(adults and neonates), mice, snails, ﬁsh, crickets and humans.
The results of the various studies provided a detailed look at
how the central and autonomic nervous systems adapt to
short-duration spaceﬂight, and the measures ranged from ana-
tomical and structural changes in the vestibular organs, to
electrophysiological changes at peripheral and central levels in
animal models, to crewmembers’ spatial orientation, vestibu-
lar, and sensorimotor responses. Neurolab was the ﬁrst attempt
at providing an integrated view of CNS adaptation to space-
ﬂight. Unfortunately, with the end of the Space Shuttle era, this
approach has remained a one-off. The roadmap for preparing
for Moon and Mars missions will provide valuable opportuni-
ties to assess and mitigate neural dysfunction in an integrated
approach that tackles fundamental problems by targeting mul-
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tiple peripheral and central neural structures using a wide range
of experimental tools. We propose extending the Neurolab
approach to longer duration spaceﬂight dedicated to the study
of changes in the CNS that include changes to anatomy,
electrophysiology, morphology, behavior, cognition, and oper-
ational performance. In preparation for deep space missions,
NASA plans to test up to 30 astronauts on ISS missions lasting
2 mo, 6 mo, or 1 yr and volunteers who will spend 4, 8, or 12
mo in Earth-based spaceﬂight analogs. Comparing the multi-
system responses of astronauts and volunteers during varying
durations of spaceﬂight and spaceﬂight analogs will help an-
swer many of the open neuroscience research questions iden-
Neuroscience research has made tremendous advancements
since the Neurolab mission of 1998. Many recent discoveries
have been fueled by the development and reﬁnement of new
genetic technologies: the fast-evolving omics revolution has
revealed previously unrecognized interactions among func-
tions, molecular changes within and between tissues, novel
ways of measuring outcomes, and noninvasive imaging, all of
which could provide greater insight into neurological mecha-
nisms. A Neurolab-like mission on the ISS would provide an
opportunity to directly assess the challenges presented in this
review in an integrated and uniﬁed fashion, applying the new
arsenal of tools to speciﬁcally interpret and validate ﬁndings in
the multiple areas. For example, omic technologies could be
used to detect genes, mRNA, and metabolites in healthy
animals and in genetically engineered animals lacking otolith
function that were reared in 0 gor reared in an in-ﬂight
centrifuge that rotates intermittently or continuously at 1 gor
at partial gravity (e.g., 0.16 gand 0.38 g). Batteries of behav-
ioral tasks could also be assessed before, during, and after
ﬂight to further characterize the responses of each animal. The
structure and function of multiple systems, such as the inner
ear, brain stem, CNS, baroreceptors, and weight- and non-
weight-bearing muscles, could be evaluated in the same ani-
mals. In addition to providing information to support crew
health and safety, these studies would provide answers to
fundamental questions in the areas of neural development, such
as transduction processes in vestibular hair cells, control of
antigravity muscles, and regulation of the cardiovascular sys-
tem during changes in body posture and during the regulation
of sleep patterns. To accomplish these goals, we will need to
identify appropriate animal models that can be used to assess
neural development in weightlessness over several generations.
In regard to human subjects, a Neurolab-like project on ISS
could study the coordination of complex human activities,
including reaching and locomotor movements involving com-
binations of eye, head, torso, arm, and leg activity. This
Neurolab-like project could also determine the sensory, motor,
and cognitive factors that inﬂuence the ability to adapt and to
retain adaptation to different gravity levels. It is possible that
changes in gravity levels affect neural coding of spatial navi-
gation, and if so, this may explain some of the orientation
illusions experienced by astronauts. Investigators could ex-
plore how altered gravity levels inﬂuence orientation and
geographical localization in parallel studies of humans and
animals using onboard and ground-based centrifuges, body
unloading paradigms, parabolic ﬂight conditions, virtual reality
conditions, and, eventually, lunar missions.
Vestibular pathways extend from the semicircular canals and
otoliths to the vestibular nuclei and the ocular motor nuclei (a
3-arc neuron) to mediate the vestibulo-ocular reﬂex. Connec-
tions between the brain stem and the thalamus help coordinate
eye-head movements. Projections to multisensory cortical ar-
eas in the temporal-parietal regions and the posterior insula
participate in motion perception, spatial orientation, and cog-
nition (Hitier et al. 2014). These areas in turn project directly
down to the vestibular nuclei to modulate vestibular brain stem
function (Brandt et al. 2014). The vestibular nuclei also have
connections with the hippocampus via the thalamus, which are
involved in spatial memory and navigation (Phelps 2004; Vitte
et al. 1996). Ground-based studies have shown that cortical
maps of both sensory and motor functions are highly plastic
and subject to rapid reorganization (Kaas 1995). Such plastic-
ity occurs at many relay stations in the CNS, not just the cortex.
Pre- and postﬂight MRI studies indicate that long-duration
exposure to microgravity produces anatomical and structural
changes in the brain stem, hippocampus, and sensorimotor
cortex (Koppelmans et al. 2016; Roberts et al. 2017; Van
Ombergen et al. 2019). We do not fully understand the func-
tional implications and consequences of such reorganization in
terrestrial conditions, let alone in spaceﬂight. Integrated neu-
roscience studies on the ISS would allow investigators to
evaluate the implications and signiﬁcance of these changes in
regard to an astronaut’s performance before and after space-
ﬂight. Near-infrared spectroscopy (NIRS) could be used to
assess hemodynamic changes in the astronaut’s cerebral cortex
while they perform cognitive tasks in the spacecraft, thus
offering an in situ means of investigating the link between
cortical plasticity and cognition. Test strategies could be de-
veloped to determine the vestibular, sensorimotor, and cogni-
tive consequences of CNS reorganization resulting from expo-
sure to partial gravity and how this reorganization might affect
an astronaut’s performance when they land on Mars. It is
important that we understand how the crew will perform after
long-duration space exploration missions, especially in the
hours immediately after they land on Mars, because this
information could drive decisions regarding the design of a
Mars mission and of the vehicle. For example, if crewmembers
are not immediately able to don a heavy spacesuit, open a
hatch, and egress from their landing craft, the lander will have
to be large enough for the crew to live in until they reacclimate
to gravity. Knowing this duration of recovery will enable
spacecraft designers to properly size a Mars lander or seek less
risky options for the crew to transfer to a habitat. Metrics of
crew performance immediately after landing will also help
mission managers assess and plan for contingency operations
(Robinson et al. 2019). However, individual statistics alone
cannot tell the whole story. The crew will act as a team at
landing (and throughout the mission). It is possible that critical
tasks can be achieved even if only one of the landing crew-
members retains well-functioning neuromotor and neurocog-
nitive skills. Thus new approaches for estimating team capa-
bilities may lead to more robust assessments of risk and, in
turn, to the assumptions and capabilities that must be built into
mission and vehicle design.
In addition, crewmembers of long-duration ISS missions
who land on Commercial Crew Program vehicles will provide
an opportunity to thoroughly study crew performance for
functional Mars tasks from 0 to 24 h postlanding, or even
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longer. However, some of these crew vehicles will splashdown
in the ocean (SpaceX Dragon spacecraft), whereas others will
land in desert sites in the United States (Boeing Starliner
spacecraft). Water landings are likely to introduce signiﬁcant
additional sensorimotor challenges, so ground landings are
better analogs for crew performance after landing on Mars
(Robinson et al. 2019).
Stimulation of the vestibular system can inﬂuence behav-
ioral responses by regulating several higher centers in the
central and autonomic nervous system (Rajagopalan et al.
2017). The vestibular system modulates vegetative functions
via ascending and descending pathways, e.g., from the vestib-
ular nuclei to the locus coeruleus, the amygdala, the limbic
cortex, and the hypothalamus (Balaban 2004). The amygdala is
involved in the development of and habituation to motion
sickness (Nakagawa et al. 2003). Clinical and physiological
evidence suggests that the vestibular system participates in
autonomic control by stimulating the vagal system and inhib-
iting the sympathetic system (Holstein et al. 2014; Yates and
Bronstein 2005). The role of the hypothalamus in thermoreg-
ulation and other vital endocrine functions indicates that
changes in vestibular inputs during spaceﬂight are not limited
to sensorimotor functions. An integrated neuroscience research
project could be implemented to identify the relationship be-
tween vestibular adaptation during spaceﬂight and sleep cy-
cles, hormonal and immune changes, cardiovascular and pul-
monary changes, muscle physiology alterations, etc. For these
studies, we will need sample sizes that are large enough to
validate and characterize the range of individual differences.
Finally, relevant animal models should be developed for ex-
ploring the physiological and morphological basis of postﬂight
In the recent years, changes in visual acuity associated with
optic disk edema and medically signiﬁcant retinal changes
have been observed in astronauts during long-duration space-
ﬂight (Mader et al. 2011). These ocular changes seem to be
secondary to prolonged cranial ﬂuid shifts, which may cause
axial shifts of the brain within the cranial vault, perhaps putting
increased pressures on the cortex (Roberts et al. 2017). Since
the ocular changes seem to be dependent on duration of
microgravity exposure, the future 1-yr missions may reveal the
potential implications of prolonged ﬂuid shifts on neurological
Another hazard of spaceﬂight, the hostile closed environ-
ment, may further confound the interpretation of changes in
CNS functions. Every human spaceﬂight vehicle must pro-
vide an Earth-like atmosphere to support crewmembers, but
it is difﬁcult for any such system to maintain the carbon
) level in the crew compartment lower than
2– 4 mmHg within the mass, power, and volume constraints
of spaceﬂight vehicles. CO
is a potent vasoactive sub-
stance, which the body regulates using multiple control
systems involving the pulmonary and metabolic systems.
However, the long-term performance of these control sys-
tems in a chronically elevated ambient CO
not yet been established.
The CNS pathways associated with response to radiation
damage and neuropathology also need to be identiﬁed. To
date, most studies have been conducted at facilities such as
the NASA Space Radiation Laboratory, which can simulate
cosmic radiation. The ISS is within the magnetosphere, and
the radiation exposures on the ISS are not equivalent to deep
space radiation (La Tessa et al. 2016). A wealth of cognitive
data from rodents has been reported for acute doses of many
individual particle types and energies, but most studies have
used doses that are much higher than will be encountered on
a Mars mission (~1 Gy), and very few have considered
dose-rate effects or mixtures of particles representative of
the GCR environment; therefore, the threshold doses have
yet to be determined. A long-term colony of biological
systems established on the Moon would allow us to study
long-term effects of combined exposures of protons and
high-charged particles in conjunction with reduced gravity.
These colonies could include biological systems ranging
from brain tissue cultures to plants and small animals,
including small vertebrates, and these colonies could be
assessed for genetic alterations, tumor formation, and re-
duced life expectancy (Benaroya 2018). However, due to the
need to irradiate subjects, any study of radiation effects will
be limited to animals, and we must use translational models
(e.g., rodents) to study the effects of the neurochemical,
functional alterations, and structural changes in the brain
and to assess how these functional, structural, and biochem-
ical alterations relate to operationally relevant performances
associated with radiation exposures similar to those of
spaceﬂight missions. Extrapolating observations in animals
to operational signiﬁcance for CNS health risks in humans is
challenging and further complicated by different experimen-
tal conditions for radiobiological and neurobehavioral stud-
The distance from Earth during Mars missions is a hazard
that increases the farther crewmembers explore. Deep space
missions will include unprecedented duration, distance, iso-
lation, and conﬁnement under increasingly autonomous op-
erations, medical care will be limited, and there will be no
evacuation options. Communication between ISS crewmem-
bers and ground support personnel has a one-way delay of
⬍0.25 s but can be delayed for several minutes when the
Tracking and Data Relay Satellite (TDRS) system is in
certain positions. This one-way time delay will increase to
~1.25 s during Moon missions and to 4 –24 min during Mars
missions depending on the position in the trajectory and
could include blackouts or whiteouts of up to 2 wk during
solar conjunctions. Thus exploration crews will need to
operate much more autonomously than ISS crews. A med-
ical evacuation from the ISS could be completed within 3.5
h, but emergency evacuations during Mars missions have
extremely limited windows of opportunity due to celestial
mechanics (Robinson et al. 2019). A medical event during a
long-duration mission beyond low Earth orbit could be
assessed in microgravity on the ISS by testing how the crew
handles a simulated medical event autonomously or with
signiﬁcant communications delay. The effects of isolation
and conﬁnement during deep space transit could be studied
on ISS to validate current habitable volume requirements for
the Mars transit. In addition, if astronauts returning from a
6-mo mission on the ISS performed simulated Mars surface
operations, this could validate the ability of crews to per-
form critical ground tasks after the physiological decondi-
tioning during a 6-mo Mars transit, and these tests could
also aid in conceptual design of structures on Mars.
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APPENDIX A: CHANGES IN END ORGANS
Utricular Otolith Asymmetry
The possibility that weightlessness affects neural development,
structure, and function are of critical concern for long-term space
missions. We do know that short-term exposure to weightlessness
dramatically alters vestibular function: simple animal experiments
with clear hypotheses have provided particularly meaningful conclu-
sions. On Skylab in 1975, ﬁsh (mummichogs, Fundulus heteroclitus)
housed in a plastic bag were strongly disoriented and swam in loop at
day 3 (ﬁrst recording) of the mission. At day 22 (second recording) of
the mission, their behavior returned to normal; however, the aberrant
behavior could still be evoked by a slight shake of the bag (von
Baumgarten et al. 1975). Toadﬁsh (Opsanus tau) returning from
ﬂights on board the Space Shuttle were uncharacteristically agitated,
swam violently, and sought “terra ﬁrma” (Boyle et al. 2001). Cichlid
ﬁsh (Oreochromis mossambicus) that ﬂew on the Space Shuttle,
sounding rockets, or parabolic ﬂight also exhibited this “looping”
behavior (Anken and Rahmann 1999; Anken et al. 2000a; Hilbig et al.
2002). Researchers observed that the abnormal looping and spinning
were positively correlated with differences in the mass of the right and
left utricular otoliths, suggesting that weightlessness unleashed the
adapted response of ﬁsh to a normally occurring asymmetry between
their otoliths. In addition, the ﬁshes (salmon, trout, green swordtail,
tiger, or Sumatra barb) that exhibited abnormal swimming behavior
during off-vertical axis rotation on Earth had statistically greater
asymmetry in their otoliths than ﬁsh that swam normally in the same
experimental conditions (Scherer et al. 2001). The magnitude of the
otolith asymmetry in an individual animal is likely a key factor in
triggering abnormal behaviors in weightlessness (Lychakov et al.
2006). Along these lines, other ﬁshes, such as goldﬁsh and carp,
display both negligible structural asymmetry and marginal abnormal
behavior in weightlessness (Takabayashi and Ohmura-Iwasaki 2003).
As attractive as this otolith asymmetry hypothesis is in explaining the
susceptibility of humans to motion sickness induced by spaceﬂight or
other simuli (Lychakov and Rebane 2004; von Baumgarten 1987;
Yegorov and Samarin 1970), it is difﬁcult to correlate an overt
abnormal behavior in ﬁsh to a subjective sensation in humans, and the
human otoconia mass is more complex than that of the ﬁshes’ single
otolith. More data is needed from other vertebrate species, most
notably mammals including primates, to prove this theory.
Plasticity of Invertebrate Statocyst
Spaceﬂight also induces plasticity in the vestibular system of
invertebrates. Receptor cells in the statocyst of the land snail (Helix
lucorum) were studied using a variety of approaches after the snails
returned from the unmanned Foton orbital missions M2 or M3
(Balaban et al. 2011) or the Bion-M1 (Aseyev et al. 2017) Russian
biosatellite mission. The stereotypic behavior evoked by the “negative
gravitaxis” test, a reliable measure of vestibular function, was directly
compared with the discharge properties of individual statoreceptors in
the same animal after landing. About 13 h after landing, statoreceptor
responses to head-down pitch were faster and more sensitive in the
snails who had ﬂown in space than in the control animals. The snails’
tilt responses recovered to baseline ~20 h after return to Earth, similar
to the time required for recovery of afferent responses in toadﬁsh after
they returned from space. Although the snails’ statocyst activities
were recorded directly from the statoreceptors themselves, and the
hypersensitivity observed in the toadﬁsh was recorded in the afferent
that is postsynaptic to the receptor, the changes in sensitivity in
invertebrate statoreceptors match those seen in vertebrate afferents.
Invertebrates have genes for one or more subfamilies of transmem-
brane channel-like proteins (Keresztes et al. 2003), which are thought
to have a role in mechanosensory transduction channels in inner ear
hair cells. If these proteins are involved in a pore-forming component
of sensory transduction channels in the statoreceptors, then a common
mechanism might exist across the animal phyla. However, no direct
evidence exists on how otolith hair cells function in vertebrates during
Otoconia, small crystals of calcium carbonate in the mammalian
inner ear otolith sensory organs, are critical for spatial orientation and
balance. The CNS is believed to respond to weightlessness by increas-
ing the production of calcium carbonate. An increase in mass of the
otoconia could make the membranes more sensitive to linear accel-
eration as a means to increase the “system gain.” A number of studies
support the hypothesis that the mass of the otoconia increases in
weightlessness. For example, the mass of the sacculus and the utricle
in animals that matured in space, such as freshwater pond snail
(Wiederhold et al. 2000), marine mollusk (Wiederhold et al. 1997),
frog (Anken et al. 2000b; Lychakov and Lavrova 1985), newt (Wie-
derhold et al. 1997), and swordtail ﬁsh (Wiederhold et al. 2000), was
greater than that in ground-matured controls. As expected, the otoco-
nia mass was smaller in sea slugs Aplysia californica (Wiederhold et
al. 1997) and cichlid ﬁsh (Wiederhold et al. 2000) that were born in
hypergravity than it was in controls. Using cichlids, researchers
(Anken et al. 2000b, 2000c; Li et al. 2011) have shown that a neurally
guided feedback mechanism adjusts the biomineralization of otoliths
in response to changing gravity levels: hypergravity induced by
centrifugation slows down otolith growth, whereas weightlessness
leads to larger than normal otoliths. Aceto et al. (2015) reported a
decrease in otolith calciﬁcation in zebraﬁsh after prolonged centrifu-
gation. These changes are presumed to be the result of a regulation of
carbonic anhydrase and production of other matrix proteins (Anken et
al. 2004; Anken 2006).
APPENDIX B: SWITCHING BETWEEN REFERENCE FRAMES
On Earth, we use a stationary frame of reference to deﬁne our
position and orientation, and to determine the motion of objects.
Anecdotal reports from Space Shuttle astronauts indicate they select
from two basic frames of reference when they are in weightlessness:
an egocentric reference primarily based on an idiotropic gravity vector
(Mittelstaedt 1988) or an allocentric reference based on visual scene
polarity (Harm and Parker 1993). The astronauts may switch from one
frame of reference to another depending on the task they are perform-
ing. The type and magnitude of perceptual illusions the astronauts
experience may be related to whether they are using an idiotropic or
visual reference frame. When astronauts orient themselves with re-
spect to external references, they perceive themselves to be inverted or
sideways during spaceﬂight, they ﬁnd it difﬁcult to switch reference
frames and perform coordinate transformations, and they become
disoriented in the absence of visual cues. When the astronauts orient
themselves using an idiotropic frame of reference, this alignment of a
vertical along the longitudinal body axis allows them to better orient
themselves and easily switch between reference frames (Oman 2010).
APPENDIX C: INVERTEBRATES, AMPHIBIANS, AND REPTILES
Behavior of Invertebrates During Spaceﬂight
During the Shenzhou-8 mission, nematodes’ (Caenorhabditis el-
egans) speed of locomotion, frequency of reversals, and rate of body
bends were normal (Qiao et al. 2013), and during the Space Shuttle
STS-42, nematodes were able to mate and reproduce for two consec-
utive generations on a semisolid substrate, indicating that complex
controlled locomotion and mating behavior were stable in weightless-
ness (Nelson et al. 1994). Drosophila ﬂies are more active in micro-
gravity than on Earth, especially younger ﬂies, and spaceﬂight accel-
erated aging-like phenotypes of young males, which may have been
caused by alterations in mitochondrial metabolism. The ﬂies’ daily
2055CENTRAL NERVOUS SYSTEM IN SPACE
J Neurophysiol •doi:10.1152/jn.00476.2019 •www.jn.org
cycles of activity and inactivity are governed by their circadian
system, so increased activity in space could be associated with
disruption of sleep cycles. In hypergravity, the ﬂies’ activity changed
according to the gravity level: no effect at 2 g, increased activity at 6
g, and progressively less activity as gravity level rose to 20 g
(Benguría et al. 1996; Herranz et al. 2008).
Crickets have an external gravity sensory structure that is stimu-
lated by postural displacements and induces compensatory head
movements. The position-sensitive interneuron (PSI), which transfers
information from the cricket’s gravity sense organ to the CNS, was
signiﬁcantly less sensitive in weightlessness, and levels of a speciﬁc
neuropeptide were elevated, perhaps reﬂecting compensation (Horn et
al. 2002). However, the crickets’ behavior was not signiﬁcantly
impaired, suggesting they were able to compensate effectively to
weightlessness. Bees and moths also exhibited impaired locomotion in
weightlessness but learn to ﬂy over time, and the orb weaver spider’s
ability to build webs was impaired in space (Clément and Slenzka
Behavior of Amphibians and Reptiles During Spaceﬂight
Japanese tree frogs (Hyla japonica) on the Mir Space Station
arched their backs and extended their limbs during free ﬂoating,
similar to jumping or “parachuting” on the ground, and they were
unable to properly control their locomotion and orientation. When
they were on surfaces, these frogs bent their necks backward and
walked backward while pressing their abdomens against the surface,
which is similar to their posture on the ground when they are vomiting
and may reﬂect motion sickness. The frogs readapted to the Earth’s
gravity within a few hours of return from space, and structural
changes were detected in some of their organs, including the spine but
not the brain (Izumi-Kurotani et al. 1997; Yamashita et al. 1997).
Geckos in weightlessness exhibited behavioral reﬂexes similar to a
fall in normal gravity, i.e., ventral extension of the limbs, skydiving
posture, and postural righting reﬂexes (Barabanov et al. 2018). During
parabolic ﬂight, a striped rat snake (Elaphe quadrivirgata) assumed a
defensive posture during the shift from hyper- to hypogravity and
struck at itself. Three striped-neck pond turtles (Mauremys japonica)
actively extended their limbs and hyperextended their necks in
weightlessness, which is identical to their contact “righting reﬂex”
when placed upside down in normal gravity (Wassersug and Izumi-
This work was supported by the NASA Human Research Program.
No conﬂicts of interest, ﬁnancial or otherwise, are declared by the authors.
W.H.P. conceived and designed research; G.R.C. and R.D.B. prepared
ﬁgures; G.R.C., R.D.B., K.A.G., G.R.N., M.F.R., and T.J.W. drafted manu-
script; G.R.C., R.D.B., K.A.G., G.R.N., T.J.W., and W.H.P. edited and revised
manuscript; G.R.C., R.D.B., K.A.G., G.R.N., M.F.R., T.J.W., and W.H.P.
approved ﬁnal version of manuscript.
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