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Sufficient sleep duration and good sleep quality are crucial to ensure normal physical and mental health, cognition and work performance for the common people, as well as astronauts. On-orbit sleep problem is very common among astronauts and has potential detrimental influences on the health of crewmembers and the safety of flight missions. Sleep in space is becoming a new medical research frontier. In this review we summarized on-orbit sleep problems of astronauts and six kinds of causes, and we presented the effects of lack of sleep on performance as well as mental and physical health, then we proposed seven kinds of countermeasures for sleep disturbance in spaceflight, including pharmacologic interventions, light treatment, crew selection and training, Traditional Chinese Medicine and so on. Furthermore, we discussed and oriented the prospect of researches on sleep in space. Keywords: Astronaut, On-orbit, Sleep, Countermeasure, Human spaceflight Background the countermeasures which gradually become a new fron- It is well known that good sleep is very important for tier of space medicine [1–4]. In this article, the research keeping normal physical and mental health, cognition progress in this field was reviewed and analyzed to provide and work performance for common people. Good sleep reference for the study of sleep medicine in medium and generally includes sufficient sleep duration and good sleep long-term human spaceflights, so as the circumstances for quality. Unfortunately, evidence has consistently shown similar extreme environmental practitioners in China. that disrupted sleep is a very common and important problem among astronauts [1, 2]. In human spaceflight, On-orbit sleep problems of astronauts and causes sleep duration and sleep quality of astronauts were ad- Sleep time versely affected by combined special factors including Unlike other medical problems in human spaceflight, sleep microgravity, isolation, monotonous repetition, high vigi- in space did not attracted much attention until 1976. For lance workload and so on. Sleep problems could impair the the first time, Kanas et al. and Frostetal. reported work performance and health of crewmembers which could the sleep condition of three American Skylab astronauts by ultimately influence the safety of flight missions. NASA polysomnographic analysis. The results presented that the (National Aeronautics and Space Administration) has listed daily sleep time on orbit was only 6 h on average which sleep deprivation and circadian rhythm changes as import- was 1 h less than on the ground. In 1988, Santy et al.  ant risk factors during long-term flight . On the basis of found that 58 shuttle astronauts slept for an average of 6 h several times of short-term manned spaceflight practices, each night during spaceflight with the comparison of 7.9 h China has attached more and more importance to on-orbit sleep time on the ground. Many of them reported less than sleep problems of astronauts and considered it as one of 5 h sleep on some nights, even less than 2 h. It should be the key factors for keeping human performance capabilities mentioned that scheduled rest-activity cycles were 20– in medium and long-term spaceflight . In recent years, 35 min shorter than 24 h in shuttle missions. In 2014, Bar- researchers focus on the effects of space flight on sleep and ger reported that 64 shuttle astronauts and 21 International Space Station (ISS) astronauts slept 6 h and 6.1 h respect- * Correspondence: email@example.com ively on average each night through the analysis of the acti- State Key Laboratory of Space Medicine Fundamentals and Application, graphy data and the flight log. Further analysis showed that China Astronaut Research and Training Center, No. 26 Beiqing Road, Haidian District, Beijing 100094, People’s Republic of China the crewmembers of shuttle missions slept 20 min shorter © The Author(s). 2018 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Wu et al. Military Medical Research (2018) 5:17 Page 2 of 12 than the pre-launching period (2 weeks), and 47 min space missions, occasionally complained that their sleep shorter compared with the post-landing period (1 week), became easily affected (data not shown). But Dinges et while ISS astronauts slept 19 min longer than that in al.  studied sleep logs and found that astronauts 2 weeks before the flight each day, and 52 min shorter rated their overall orbital sleep quality at “good” grades. compared with the 1 week after landing. They believed that Whitmire et al.  also reported their interviews and due to preparations of the flight missions and other work- surveys of astronauts after the flight, of 52% saying that loads, the astronauts had already lacked of sleep 2 weeks they had better sleep during flight, and only 6% with the before the flight . reverse feedback. Since these evaluations were retro- In 2015, NASA summarized the data of 177 astronauts spective, the reliability could be questionable. Based on from 7 studies including the study above and found that the analysis of ISS astronauts’ diary, Stuster et al.  researches in different years, by different researchers or found that astronauts felt much tired in the first quarter with different methods went to a consistent result that of flight compared to the late phase of flight, which was astronauts had about 6 h daily sleep time on average related to the decreased sleep quality. during spaceflight . Obviously, on-orbit sleep time of the astronauts was significantly less than the time rec- Other evidences of sleep disturbance in spaceflight ommended by National Sleep Foundation and the Other compelling evidences were the reports of sleep American Academy of Sleep Medicine to maintain ideal medication used in flight by astronauts. In 1988, Santy alert performance and health [8, 9]. It was 2 h less than et al.  reported that 50% (11/22) of shuttle crewmem- the 8 h specified in the NASA-STD-3001 (Vol.1) . bers on dual-shift missions used sleep medications at In Shenzhou-9 and -10 missions of China, the average least once inflight compared to 19.4% (7/36) of single- daily on-orbit sleep time of 6 astronauts was generally shift. In 1999, NASA reviewed 219 records (each record less than 8 h, which was arranged in advance. Especially represented one crewmember) from 79 shuttle missions, in the early days of flights, sometimes astronauts slept 94% of crewmembers had used medications, and 45% of less than 5 h daily (data not shown). crewmembers using drugs to solve the sleep disorder . In 2014, Barger reported 78% (61/78) of the crews Sleep quality of space shuttle missions in 52% (500/963) of the nights With sleep recorder, some objective studies showed that took a dose of drugs to promote sleep, in the night of the sleep structure of the astronaut has changed during 17% (87/500) took twice to promote sleep, and 75% (12/ spaceflight. Gundel et al.  studied the sleep of astro- 16) of individuals on ISS had used drugs to promote nauts on the Mir space station and found that the latent sleep. A total of 852 sleep logs were collected, 96 reports period of the first rapid eye movement (REM) phase was had mentioned using sleep promoting drugs, and 18 short, and slow-wave sleep (SWS) was redistributed reports had mentioned using sleeping pills twice . between the first and the second sleep cycles. They also Further statistical analysis showed that sleeping problems, reported that one astronaut had extended sleep latency space motion sickness, and pain remained the top 3 com- and poor sleep efficiency, which was defined as “space plaints among astronauts. And the two most frequently insomnia”. A study on the American astronauts of Mir used drugs were sleep medicine and the drug for rash, and mission found that REM sleep time in the space was the use of sleeping pills was at least 10 times more than reduced by 50% compared to that of preflight. Although normal Americans on average [2, 18–21]. the longer bed rest during the flight, the overall sleep In addition, Stuster et al.  analyzed the astronaut time was 27% less than that before the flight [2, 12]. diaries with the evidence of sleep inertia existing during Moldofsky et al.  studied the EEG of eight astronauts spaceflight, that is, astronauts could not quickly switch in the Mir space station and found that SWS time was from sleep to wakefulness. These evidences support the significantly less than that before the flight. Dijk et al. apparent adverse effects of spaceflight on sleep.  reported that 5 astronauts performing the short shuttle flight tasks, during the last third period of the Causes of sleep problems in spaceflight flight, had increased waking time and decreased SWS, Studies demonstrated that some of the astronauts’ sleep and REM rebounded significantly after the flight. problems in space were often caused by uncomfortable Contrary to most objective studies reported that sleep ambient temperatures, higher noise levels, uncomfort- quality got worse in flight, results of subjective findings able sleeping bags, or the absence of familiar propriocep- were inconsistent with the objective ones. Barger et al. tive cues [11, 22].  and Dijk et al.  reported that compared with the During the flight, when sleep time was suddenly inter- sleep before the flight, the astronauts gave a “bad” sub- rupted by operational needs or social activities, astro- jective evaluation of the quality of in-flight sleep. Some nauts were prone to sleepless and fatigue. According to Chinese astronauts, who have flown short-duration reports, there was a sudden change of schedule in 13% Wu et al. Military Medical Research (2018) 5:17 Page 3 of 12 of 2043 days aboard ISS, and usually occurring during or on the US Challenger space shuttle accident posited that before the key operation (such as spacecraft docking or lack of sleep and irregular work schedule were important detachment, extravehicular activity etc.) . Sleep reasons for senior managers making critical decision would be also affected by the suddenly shifted opera- error . tions, tasks arranged at night or incomplete schedule Up to now, there is few research on cognitive perform- due to high workload, etc. Some astronauts believed that ance of human in spaceflight, especially related to sleep the unreasonable workload arrangement was the main insufficiency. In the retrieved eight tests on orbit, five reason of the poor sleep quality and the shorter sleep tests showed that there was a negative effect on cogni- time in flight [16, 17]. tive performance including attentive search, short-term Sleep changes may be related to impaired sleep homo- memory, tracking operation, careful operation or dual static regulation induced by space environment. Accord- task, two tests showed no effect, and one showed a ing to the accepted model, two interacting processes are slightly positive effect [2, 14, 27, 35–38]. Dijk et al.  involved in this regulation, and the first is called the “S analyzed the relationship between the cognitive perform- process”. It represents a homeostatic process that is ance and sleep in flight and found that the performance reflected in an increase of sleep propensity over the wak- of most astronauts declined one week before the ing phase and a decline of this propensity during sleep. launch, with a further reduction in flight and slow re- A direct physiological marker of this process is the por- covery after flight. Both performance degradation in tion of slow wave activity in the human EEG . SWS flight and performance improvement post flight were reduction could be seen as a sign of changes of “S related to REM sleep. Nechaev et al. analyzed the process” in space . error data of 28 astronauts and 342 weeks of 14 mis- The absence of circadian cues, including light cycles sions on the Mir space station and found that the or even attenuated light, seems to disrupt human bio- error rate was significantly related to the deviation logical rhythms [14, 25]. Some studies have found that, degree of the normal sleep-wake cycle . compared with the ground control, some physiological Compared with the relatively scarce space tests, a large parameters related to the circadian rhythm, such as body number of studies based on ground simulations, which fo- temperature and cortisol, decreased or lagged in phase cused on the effects of sleep insufficiency, have been carried for the astronauts in space [11, 14, 26, 27]. In 2015, out [40–44]. These results showed that sleep less than 6 h Flynn-Evans et al.  applied a mathematical model to during two consecutive nights could negatively affect cogni- estimate the timing of the circadian nadir among 21 tive performance, such as decreased response time, in- astronauts aboard ISS; crewmembers were studied an creased error, impaired working memory, and so on. average of 155 days each, 3248 days total. It was reported Moreover, the impaired performance would last within that the estimated circadian phase occurred outside the 1 week. If this condition was further extended, negative ef- sleep episode 19% of the time during the spaceflight. It fects on cognitive performance would be gradually accumu- can be seen that circadian rhythm disorder may be an im- lated which showed a much obvious dose-time portant cause of orbital sleep disturbance to astronauts. effectiveness relationship . Furthermore, the effect of In addition, human spaceflight practice had proved chronic sleep deprivation on performance was as similar as that astronauts experiencing a long-term spaceflight acute total sleep deprivation. Van Dongen et al. re- suffered more prominently from psychological and ported that 4–6 h of sleep for 14 consecutive nights was physiological problems. The adverse psychological reac- equivalent to 48 h or 24 h of sleep deprivation. Belenky et tion includes depression, anxiety, personality changes, and al. found that sleeping forlessthan6h in7consecu- intra-crew conflicts, the adverse physiological reaction in- tive nights caused impaired performance, hardly returned cludes cardiovascular deconditioning, muscle atrophy and to normal levels, even after 3 nights of sleep free. decrease of immune response and so on, which would In addition to performance impairment, other negative inevitably lead to some functional or organic disorders psychological and physiological health problems caused and diseases, such as space adaptation syndrome, pain, in- by lack of sleep have also attracted researchers. In 2009, fection and eye disease and so on. All those stress factors NASA reported that 36 h of sleep deprivation deterio- could cause sleep problems, which in turn could increase rated the emotional state of the participants including psychological/physical discomfort [4, 29]. energy level, arousal state, motivation and concentration . In 2010, Van der Helm et al.  found that 30 h Effects of lack of sleep on performance and mental and sleep deprivation resulted in that participants were un- physical health able to correctly identify two types of facial expressions, Many ground investigations showed that sleep insuffi- anger and pleasure. This may be an important reason ciency would affect human physical and mental health, for the social relation problems of crews in the long- and induce performance degradation [30–33]. A report term spaceflight. In 2014, Minkel et al.  reported that Wu et al. Military Medical Research (2018) 5:17 Page 4 of 12 one night of sleep deprivation could lead to the level of brain top-down control, while the stimulus driven atten- cortisol in a quiet state, and further increase when par- tion system was enhanced [52–55]. ticipants accepted social stress, and it may adversely affect the long-dated health. Effects on visual alertness Considering astronauts’ living environment including Continuous performance task test revealed that 72 h confinement, isolation, and other factors, some scholars confinement and isolation with sleep deprivation re- have carried out researches on the effects of sleep sulted in a significant decrease in visual alertness. The deprivation combined with restrictions. Chaumet et al. fMRI showed that, compared with pre-experiment, the  found that the tendency of adventure decreased in volunteers’ thalamic gray matter volume was signifi- the 36 h sleep deprivation, while the impulsiveness of cantly reduced, but the volume of hippocampus and that increased with normal sleep in the closed environ- the brain gray matter did not change after the experi- ment. Spitznagel et al.  reported that sleep ment, indicating that the decrease in visual alertness deprivation and cold exposure for 53 h had a superim- was associated with a decrease in gray matter volume posed effect on performance impairment. NASA had in the thalamus . completed a 45 d confined experiment named “Hera” experiment with four participants on July, 2017. During Effects on operational performance Hera, all crews were required to sleep 5 h per night of We found that 72 h sleep deprivation with isolation had 1 week, in the rest 2 days of which they could sleep 8 h negative effects on 3 levels of complexity and 3 types of for recovery. The purpose of this study was to investi- simulated space emergency operation performance. gate the effects of countermeasures on sleep deprivation However, highly complex operations and manual type under simulated spaceflight isolation . The results of operation performances remained relatively stable in our this research have not been reported yet. experiment, whereas low complex operations and two- Since 2006, our team has carried out a series of studies way discrimination type operations were significantly about the effects of 72 h sleep deprivation on human affected . This is similar to some previous reports, physiology, psychology, performance and countermea- and generally engaging in challenging and stimulating sures in confined and isolated environment. Although tasks can be used to compensate for the effects of sleep the situation of 72 h sleep deprivation in space had never deprivation stress through the compensatory mechanism been reported yet, the effect of sleeping 6 h per night in of the brain [30, 58, 59]. Although we also found that for consecutive beyond 2 months might be analogical. With the difficult manual rendezvous and docking operation, the consideration of further long-term spaceflight, for ex- the unitary isolation condition had no adverse effect on ample, the Mars mission could be more than 1 year, the the volunteers’ performance. However, the isolation situation of 72 h sleep deprivation could not be entirely coupled with sleep deprivation could significantly reduce ruled out. Furthermore, we could investigate the effects the docking success rate. The docking fuel consumption, of 24 h, 36 h and 48 h sleep deprivation within 72 h displacement deviation, pitch and yaw angle deviation schedule. It was also important for the success of the increased significantly, which seriously weakened the op- current spaceflight missions. The results of the re- eration performance of volunteers . This suggested search on the countermeasures will be briefly de- that sleep deprivation have a complex impact on space scribed in the next section. The following are the performance, and the characteristics of the operation it- main results of our previous works: self, such as the need of relying on the attention net- work, may be a very important factor. Effects on cognition The confined and isolated environment for 72 h with or Effects on emotion without sleep deprivation slowed perception, and the Chinese version of the State-Trait Anxiety Inventory, the effect of sleep deprivation was greater, but the perceived questionnaire Self-Rating Depression Scale, the Positive accuracy was not affected . Simple isolation for 72 h and Negative Affect Scale, and a brief Profile of Mood had no significant effect on working memory, prospect- States Cale (POMS) on mood changes were used in our ive memory and attention network. But in the late study on a laptop. We found that 72 h isolation had no period of the test which was 72 h confined isolation with obvious effect on individual emotion. But exposed to an sleep deprivation, the reaction time was prolonged, the isolation environment with 72 h sleep deprivation, anx- rate of accuracy decreased and the rate of leakage iety score and POMS score of emotional confusion of increased. The functional nuclear magnetic resonance volunteers increased significantly in the latter phase of imaging (fMRI) studies showed that for attentional tasks, the experiment while depression scores did not change confined isolation with sleep deprivation diminished the significantly. Notably, there was no significant change in endogenous attentional system in the brain and decreased the negative mood scores of the volunteers with 72 h Wu et al. Military Medical Research (2018) 5:17 Page 5 of 12 isolation and sleep deprivation, while the positive mood shift mode before the flight mission. NASA recommended score significantly decreased. The results above indicated that astronauts sleep 8 h or at least 6 h every day on orbit. that the psychological support strategy to promote the After work shift, sleep time can be prolonged by 1.5 h positive mood of astronauts might be a good method to than the day before. Furthermore, interesting works, deal with the sleep insufficiency in space [52, 53, 60]. enough time for rest and recreation should be arranged in the schedule to avoid sustained fatigue . Effects on reaction to emotional faces pictures Stuster et al.  reported that astronauts on ISS were Before and after 72 h confined isolation with sleep more inclined to take naps in daytime to improve their deprivation test, volunteers were arranged to browse emo- sleep quality in the middle and late stages of the flight tional faces pictures. The fMRI was performed after isola- missions. Some ground-based studies also supported the tion. The results showed that when volunteers viewed low viewpoint that fragmentary sleep or short nap in daytime intensity anger pictures after the experiment, they showed might contribute to alleviate the impairments of perform- activation of brain areas the same as high intensity anger ance caused by sleep deprivation at night [63, 64]. But after pictures, intimating that the threshold of negative emotion observing and analyzing the situation of a volunteer in was decreased and the sensitivity was increased. The find- Mars 500 simulation experiment, Basner et al. found ings were similar to the findings by van der Helm, further that self-selected naps in daytime may cause biological speculated that the lack of sleep may be an important rea- rhythm disorders during long-term missions and thus son for the tense relationship among members of the should be arranged and monitored carefully. It deserves group during long-term spaceflight . further discussion that whether taking naps in daytime could be a recommended countermeasure or not. Effects on physiological and biochemical parameters Some other ground-based studies indicated that it may During the period of 72 h isolation and sleep be helpful to have sleep extension before or after sleep deprivation, the heart rate and body temperature of vol- restriction. Banks et al.  carried out an experiment, unteers showed a trend of high in the day and low at in which 159 participants had been given 0–10 h recov- night, and the circadian rhythm of systolic and diastolic ery sleep after undergoing 4 h of nocturnal time in bed blood pressure was not obvious. After the experiment, every night for 5 consecutive days. They found that neu- the levels of growth hormone, cortisol, and dopamine in robehavioral functions were improved with recovery serum significantly increased, while melatonin slightly sleep time and have obvious quantity-effect relationship. decreased, compared with pre-experiment. These results By observing the task performance of 24 subjects who suggested that closed isolation with sleep deprivation af- had underwent seven sleep restriction nights (3 h in fects the biological rhythms of volunteers and increases bed) after seven adequate sleep nights (7–10 h in bed), their excitability (data not shown). The changes of corti- Rupp et al.  found that although sleep extension sol of blood in the experiment were similar to those of before sleep restriction didn’t affect reaction time, it im- Minkel et al. . proved cognitive function. Our research indicated that reasonable collocation and Countermeasures for sleep disturbance in spaceflight time assignment of different complexities and types of Improve sleep environment tasks could be used in designing work-rest schedule to Creating a good environment in the space cabin is bene- prevent the negative effects of sleep deprivation on per- ficial to ensure the sleep quality and sleep time thus to formance . The astronauts of Shenzhou-9 and -10 meet the performance and health needs of the crew. missions in China suggested that sleep time arrangement Comparing with the relatively primitive sleep conditions on orbit should be personalized to a certain extent and in short-term shuttle flights, ISS has improved the habit- giving astronauts some autonomy could improve sleep ability in ambient temperature, wind speed, noise, and efficacy. Currently, NASA is studying how to modify carbon dioxide levels in addition to comfortable sleeping flight schedules to allow for adequate sleep and time off bags, restraints to prevent floating, and private sleep on a case-by-case basis. At the same time, a scheduling quarters to minimize interruptions. This process is con- dashboard is under development to track behavioral tinuously developed with obvious progress. However, health and mission stressors and to enable early stage much more efforts need to be invested, especially in the detection and mitigation [2, 68]. The schedules with new noise control [2, 11, 27, 61, 62]. countermeasures will be verified and objectively evalu- ated in future spaceflight. Design reasonable on-orbit work-rest schedules A detailed on-orbit work-rest schedule should be designed Pharmacologic interventions according to launching and landing time, crew numbers, Sleep medication is the most prevalent countermeasure time critical events, load demands, mission objectives, and during spaceflight. Barger et al.  and Whitmire et al. Wu et al. Military Medical Research (2018) 5:17 Page 6 of 12  reported that more than 70% of both shuttle and 2017, Chinese researchers reported that doses of Ginseno- ISS astronauts use sleep medications during the flight side Rh1 could prevent cognitive impairment caused by missions, which hastened the approach of sleep but did sleep deprivation in mice, and the effect was similar to not bring longer sleep duration. Dijk et al.  con- that of modafinil . This suggested that some active in- ducted a rigorous controlled trial during space shuttle gredients of Traditional Chinese Medicine (TCM) are po- flights. They found that melatonin significantly improved tential irritants with further exploration value. sleep latency compared to placebo, but there was no dif- More work needs to be done to study the efficacy, side ference in other sleep parameters. The sleep medications effects, and method of administration of sleeping medi- frequently used in space include zolpidem, zaleplon, cation on orbit, so as to screen and develop individual- continuous release zolpidem, flurazepam etc. The sleep ized sleep medications and stimulants with high safety. medications occasionally used include temazepam, eszo- piclone, melatonin, quetiapine fumarate etc. [7, 16, 61]. Light treatment Three sleep medications were provided on orbit in As an effective stimulus to regulate human circadian China space laboratory mission. They were triazolam, rhythm, neuroendocrine and neurobehavioral response, zolpidem and diphenhydramine, in which diphenhydra- light could be used to treat sleep disorders and maintain mine was also effective for motion sickness. health of individuals in intercontinental flight, shift work Numerous ground-based studies on shift work staff and spaceflight [79, 80]. demonstrated that zolpidem improved sleep quality and The human circadian pacemaker is most sensitive to increased sleep duration, but decreased mood on the fol- short-wavelength blue light ranging from 460 to 480 nm lowing day, which requires attention [69, 70]. Unlike . Through human experiment, West et al.  dem- other sleep-inducing hypnotics, melatonin is used pri- onstrated that the suppression of lower intensity blue marily to shift the circadian rhythm. Some studies light to melatonin is greater compared with broad showed that melatonin modestly improved sleep effi- spectrum bright light at night, and that blue irradiances ciency during circadian misaligned sleep episodes rela- above 20 μW/cm significantly suppressed melatonin in tive to placebo [71, 72]. By animal experiments, Wang et a dose-response manner, with higher irradiances eliciting al.  from China Astronaut Research and Training greater suppression. Given that melatonin suppression is Center has proved that midazolam nasal gel spray pos- associated with improved alertness and performance, a sesses obvious sedative and hypnotic effects and by nasal study by Rahman et al.  demonstrates that lower in- administration it is easy to use with rapid effect and high tensity blue light has better feasibility than the broad bioavailability. Midazolam nasal gel spray is expected to spectrum bright light. be used in the flight because of its shorter T max and A research manifested that the human visual system had higher bioavailability. peak sensitivity to green light of approximately 555 nm. Stimulant could be used in flight when an astronaut Green light is capable of eliciting melatonin suppression, needs to overcome drowsiness and stay awake. In the re- which is similar to blue light, but the effect of green light cords of Apollo 7 mission, the sleep condition of an is temporary . These findings suggested that it may be astronaut was too bad that he fell asleep on duty and possible to use a combination of green light and blue light had to take 5 mg amphetamine to stay awake. In post- to optimize light-induced circadian phase shifting. Zeitzer flight interviews, Whitmire et al.  found that 75% of et al.  found that light flashes of 2 milliseconds given the astronauts had used caffeine or modafinil as stimu- every 30 s were sufficient to cause a phase shift of approxi- lants during their missions. In China space laboratory mately 30 min. It means that using millisecond flashes of mission, caffeine was also provided on orbit. light to promote sleep or wakefulness in space could re- Ground-based researches indicated that caffeine im- duce energy consumption. proved the decline of alert, cognition and operation per- In 1990, on NASA’s Space Transport System-35 mis- formance caused by sleep deprivation, particularly for sion, crewmembers were exposed to timed, bright white emergent situations where extended wakefulness or where fluorescent light at 10,000 lx during their preflight, quar- a rapid transition from sleep to wake is required [74, 75]. antine period at Johnson Space Center. This intervention By comparing the effectiveness of caffeine, modafinil and successfully realigned crewmembers’ melatonin rhythm dextroamphetaminein different sleep deprivation trials, with their required sleep-wake cycle . Subsequent Killgore et al. [76, 77] found that all the three stimulants space shuttle missions employed the program that in- significantly improved performance compared to placebo. cluded a preflight light therapy regimen. In the Payload In this case although caffeine resulted the fastest, it was Operations Control Center at Marshall Space Center, a associated with the most negative side-effect. Dextroam- study was done testing the utility of bright light treat- phetamine had the longest latency to improve and caused ment of NASA ground crew who worked on shifted disrupted recovery sleep. Modafinil had no side effects. In schedules. 18 ground crew personnel were divided into Wu et al. Military Medical Research (2018) 5:17 Page 7 of 12 an experimental group and received schedules for bright made psychological self-adjustment and received profes- white fluorescent light exposure at 10,000 lx, with sunlight sional psychological support. All the measures helped the avoidance. The control study participants underwent no volunteer greatly to maintain positive mood and to deal treatment. The results showed that the experimental group with sleep issues (unpublished information). In addition, had better sleep, performance, and physical and emotional in the 72 h sleep deprivation experiment, our team found well-being . During the Phoenix Mars Lander mission, that comprehensive psychological intervention including NASA conducted a research to test the effectiveness of a improving self-confidence, active resource integration and lighting countermeasure to synchronize the circadian sys- so on, which can effectively reduce the negative effect of tem of operational ground personnel supporting the 3- sleep deprivation on mood state and alleviate the decline month mission, living on a Mars sol (24.6 h) at mission of operation performance . control. A portable light box containing arrays of blue LEDs was placed on the desk of the participants to provide a Crew selection and training photic time cue to facilitate circadian adjustment to the Due to individual difference as well as the great potential longer day length. The circadian rhythm of the urinary me- and plasticity in physiology and psychology, the selection tabolite of melatonin, 6-sulphatoxymelatonin (aMT6s), was and training of crew can be taken as an important meas- used to assess circadian period. The results demonstrated ure to cope with the sleep issues in spaceflight. that 87% of participants were able to adapt to the Mars sol In the 72 h sleep deprivation experiment, our team . It seems that lighting countermeasures are necessary found that a few volunteers experienced significant cog- for both astronauts and ground crew in long-term space- nitive and performance decrements and extreme bad flight missions. emotion (unpublished information). Rupp et al.  The lighting facilities on board ISS had been changed found that the subjects with poor PVT performance and from General Luminaire Assemblies to Solid-State Light- emotional display were more likely to be affected by ing Assembly (SSLA) at the end of 2016. This was an sleep restriction. Recent studies have found that certain important step in the development of light therapy from genetic polymorphisms are associated with vulnerability ground research into space practice. Three different to sleep loss. Groeger et al.  and Vandewalle et al.  5/5 LEDs were used for the ISS SSLAs: a broadband LED reported that the subjects with PER3 genotype variant composed of a highly converted green phosphor that had poorer ability to complete tasks and had vulnerability emitted white light, a blue LED that emitted narrow in response to sleep deprivation and rhythm disorder 4/4 band blue-appearing light with a peak emission of compared with those carrying the PER3 variant. An et 468 nm, and a red LED with a peak emission near al. reported that the main genotype of PER3 in Han 4/4 626 nm. This new lighting system provides three set- Chinese is PER3 . The genotype frequency of Han 4/4 tings: general illumination mode, phase shift/alertness Chinese was 78.33% for PER3 (twice the frequency of mode, and pre-sleep mode. Based on operational tasks Caucasians, African Americans and Italian), 1.67% for 5/5 being performed or crewmember preference, further PER3 (1/10–1/6 the frequency of Caucasians, African lighting control was possible in each setting via a dim- Americans and Italian) . In addition, Goel et al.  mer switch to meet the visual demand and as lighting found that the COMT Val158Met polymorphism may be countermeasures against sleep disorder and circadian a genetic marker for predicting individual differences in rhythm disorder in ISS [62, 80]. We look forward to new sleep homeostasis. These results suggest that the sleep encouraging research achievements to be reported. deprivation experiment and genotype identification can be used to screen those of vulnerability in response to sleep Psychological support deprivation and rhythm disorder, so as to ensure the Appropriate psychological support or intervention could astronauts who carry out missions on orbit have better be helpful for astronauts to cope with the problems in adaptability to environment and assignment. Further falling asleep and poor sleep quality, and it has good research is necessary in this field. effects on relieving fatigue, promoting rest and sleep Around 2013, our team conducted training for some [61, 62, 89]. With measures such as sleep cognitive be- Chinese astronauts on adaptability to sleep deprivation havioral intervention, direct or indirect psychological sup- in a closed isolation environment for 72 h. The astro- port to the astronauts had good effects, which started nauts were divided into three groups and were given from space station missions of the US and Russia and had space food during the period. They completed a number been used in Shenzhou-9, − 10 and − 11 missions. Before of tests and simulated space operations. In 2015, the Mars 500 experiment, training of mood regulation skills, adaptability training was carried out for 6 oceanauts on sleep-promoting skills and leisure time management con- “Jiaolong” manned deep-sea submersible for 36 h by our sciousness were conducted on the Chinese volunteer by team. Good effects had been achieved from the training, our team. During Mars 500 experiment, the volunteer mainly reflected in three aspects. The first, emotion, Wu et al. Military Medical Research (2018) 5:17 Page 8 of 12 cognition and operation performance of the trainees were significantly better than that of ordinary healthy volunteers, which showed the role of selection and train- ing. Secondly, the characteristics of the psychological and physiological responses of each trainee in the special environment were recorded and will provide important basis for specific psychological support and training and medical safety in the future. Thirdly, the trainees had fully experienced the reactions in the special environ- ment, mastered the coping methods and improved their tolerance (unpublished information). TCM and other measures In the experiment of sleep deprivation in narrow and Fig. 1 The practice of Tai Chi during Shenzhou-10 mission sealed environment, our team studied the effect of Tai Chi training on mood and EEG spectrum power. The study showed that Tai Chi training could improve mood Fig. 2 Frame diagram of on-orbit sleep problems of astronauts and countermeasures. In human space flight, sleep time and quality on orbit are apparently decreased. This figure presents six kinds of causes, some effects of sleep deficiency on performance and mental and physical health, and seven kinds of countermeasures for sleep disturbance in spaceflight. The symbol of ‘↓’ means decreased or impaired Wu et al. Military Medical Research (2018) 5:17 Page 9 of 12 and reduce the low frequency activity of the EEG signals, to be further researched. Among them, drug screening indicating that this training has obvious antagonism on and the development of new preparations should be at- sleep deprivation . We speculate that Tai Chi training tached with special importance. As a new technology, also helps to hasten sleep and keep deep sleep. In light treatment is being used and tested on ISS, which Shenzhou-10 and -11 missions of China, some astronauts should also be considered in the design and construction practiced Tai chi and initially proved its feasibility in of Chinese space station. Specific selection and training microgravity (Fig. 1). The effects of Tai Chi as a potential of crew, especially gene selection, as a potential method, countermeasure for sleep problems need to be seriously needs to be further tested and verified. Some promising investigated and proved. measures such as TCM and transcranial magnetic/elec- The methods commonly used in TCM, such as acu- tric stimulation have not yet been applied in flight. More point stimulation, acupuncture and massage, as well as ground-based researches and preparations should be transcranial magnetic/electric stimulation and eating carried out, and the on-orbit tests need to be conducted food which helps for sleep or wakefulness, were proved as soon as possible. to be effective on promoting sleep, staying alert or im- proving cognition in the ground-based research [97–99]. Conclusions These potential methods are expected to be further eval- The research on sleep problems is becoming a new fron- uated and possibly applied in Chinese space station. tier of aerospace medicine. The effects of spaceflight on sleep and the countermeasures need to be further stud- Summary and prospect ied. The research achievements in this field will not only We summarized on-orbit sleep problem of astronauts ensure the safety, health and performance of astronauts and countermeasures as Fig. 2. in space, but also benefit people living on earth. In spaceflight, sleep insufficiency and worse sleep qual- Abbreviations ity are common problems for astronauts. The main fMRI: Functional nuclear magnetic resonance imaging; ISS: International causes of sleep disturbance in spaceflight include the space station; NASA: National Aeronautics and Space Administration; POMS: Profile of Mood States Scale; REM: Rapid eye movement; SSLA: Solid- confined cabin, the adjustment of work-rest schedule, state lighting assembly; SWS: Slow-wave sleep; TCM: Traditional Chinese the unreasonable working arrangement, the impaired Medicine sleep homostatic regulation, the circadian rhythm desyn- Acknowledgements chrony, the psychological/physical discomfort, etc. Fewer The authors are grateful to Xiao-Lu Jing, Xue-Yong Liu, Hai-Bo Qin, Jun on-orbit studies about the effects of sleep on behavioral Wang, Shuang Zhao, Bing-Mu Xin, Qiong Xie and Zhi-Jun Xiao for supplying performance and lots of ground-based studies on the ef- technical and translation assistance. fects of sleep deprivation (restriction) indicated that Funding sleep loss would cause the decline of cognition and oper- This work was supported by the Manned Spaceflight Program of China, ation performance. But the effects are complex and it the Advanced Space Medio-Engineering Research Project of China (2014SY54A0001). might be related to the factors such as the type of cogni- tive and operation work. In addition, sleep deprivation Availability of data and materials also affects mood state and the secretion of some hor- All the relevant data and materials are presented in this article. mones such as cortisol, thus bringing potential hazard to Authors’ contributions health. Therefore, sleep disturbance is an important risk BW is composer of this article, the other authors YW, XRW, DL, DX, FW factor in medium and long term manned spaceflight, espe- participated in material collection and the article polish. All authors have read and approved the final manuscript. cially in interstellar travel. Next, researches about the effects of sleep on immune function, hormone secretion, Ethics approval and consent to participate gastrointestinal function and cardiovascular health should Not applicable. be conducted; further study about the effects of sleep dis- Consent for publication turbance on behavioral performance and group dynamics Written informed consent was obtained from the person for publication of on-orbit need to be carried out. this review and any accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal. The countermeasures against sleep problems in space- flight include improving sleep environment, designing Competing interests reasonable on-orbit work-rest schedule, pharmacologic The authors declare that they have no competing interests. interventions, light treatment, psychological support, Received: 17 December 2017 Accepted: 10 May 2018 crew selection and training, TCM and so on. 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