Articles in PresS. J Appl Physiol (February 4, 2016). doi:10.1152/japplphysiol.00928.2015 1 Analogs of Microgravity: space Research without Leaving the Planet-Highlighted Topic (Mini Review) 2 3 4 5 6 7 8 9 Effects of Isolation and Confinement on humans – Implications for manned space explorations Pagel JI1 and Choukèr A1 1 Stress and Immunology Lab, Department of Anesthesiology, Hospital of the University of Munich, Germany 16 17 18 Alexander Choukèr, Prof. Dr. Department of Anesthesiology University of Munich Marchioninistrasse 15 81377 Munich, Germany E-Mail to contact authors: [email protected]; [email protected] 19 20 Number of Figures: 0 21 Number of Tables: 2 22 Number of text pages: 18 23 Abstract: 174 24 Total words: 5180 25 Total characters with spaces: 35,070 26 27 28 Running title: Isolation and confinement in space analogue research 29 30 31 32 1 Copyright © 2016 by the American Physiological Society. Downloaded from http://jap.physiology.org/ by 10.220.32.247 on June 17, 2017 10 11 12 13 14 15 33 Abstract: 35 Human psychology and physiology are significantly altered by isolation and confinement. In light of 36 planned exploration class interplanetary missions, the related adverse effects on the human body 37 need to be explored and defined as they have a large impact on a mission’s success. Terrestrial space 38 analogues offer an excellent controlled environment to study some of these stressors during a space 39 mission in isolation without the complex environment of the International Space Station. Participants 40 subjected to these space analogue conditions can encounter typical symptoms ranging from 41 neurocognitive changes, fatigue, misaligned circadian rhythm, sleep disorders, altered stress 42 hormone levels and immune modulatory changes. This review focuses on both the psychological and 43 the physiological responses observed in participants of long-duration space-flight analogue studies, 44 such as Mars500 or Antarctic winter-over. They provide important insight into similarities and 45 differences encountered in each simulated setting. The identification of adverse effects from 46 confinement allows not only the crew to better prepare for, but also to design feasible 47 countermeasures that will help support space travelers during exploration class missions in the 48 future. 49 Key words: space analogue, stress, psychoneuroendocrinology, circadian rhythm, immunity 2 Downloaded from http://jap.physiology.org/ by 10.220.32.247 on June 17, 2017 34 1 Introduction 51 In the evolution of mankind, gregarious behavior such as hunting or living together in small groups 52 has been proven advantageous for survival. Sharing of specialized tasks and the division of labour 53 into different professions catering to the individuals’ talents have enabled the development of 54 multifaceted well-functioning modern societies. Isolation and exclusion from a social group as well as 55 confinement have been forms of punishment since the early ages and continue to be the case in 56 societies and prisons all over the world (9). Nevertheless, voluntary long-term confinement as a pair 57 or with a group of people can cause strains on individuals. Differences in nationality, cultural 58 background and character traits may induce severely altered stress levels and tension between the 59 confined subjects, which can result in various disease states. 60 Historic reports 61 During the initial winter assignment of the US Amundsen-Scott Station at the South Pole in 62 1956 under the framework of the International Geophysical Year (IGY), one of the team members 63 developed a severe case of paranoid schizophrenia. This endangered the crew as well as the mission 64 where he had to be sedated and confined for the rest of his stay (1, 53, 55). The arduous weather 65 conditions in Antarctica and the awareness of long-term confinement with a group of mostly 66 strangers can be quite challenging and stressful for the human mind (54). It is difficult to delineate 67 what the exact trigger was for that episode. At the time no provisions had been made to treat such a 68 patient and evacuation was impossible. Stuster wrote in his book “Bold endeavors” (53) that the 69 patient was confined to a “special room lined with matresses (…) to contain the sounds of psychotic 70 ravings”. The condition was clearly severe and long-term sedation was the only option the team had. 71 Based on reports from Nardini et al 1962 (31), this unexpected incident has led to routine psychiatric 72 screening as a part of the recruitment process for missions to Antarctica. What remains unknown, is 73 whether the individual had predispositions for developing such an episode due to prior mental health 74 or an entirely new manifestation. The individual did display abnormal behavior for a considerable 75 time period prior to the manifestation of the psychotic episode with signs of disorientation and 3 Downloaded from http://jap.physiology.org/ by 10.220.32.247 on June 17, 2017 50 disruptive behavior. One could also speculate that he felt isolated because he did not “fit” into the 77 team or that many different aspects of the situation reactivated a psychiatric condition he already 78 had. What became clear though is that a 12-month stay in Antarctica can trigger an acute spell of 79 psychosis, which makes psychiatric screening necessary. Such a screening is also applicable to the 80 multifactorial environment of spaceflight, where the human body is subjected to many physiological 81 and psychological stressors at the same time. Group tension and displacement of negative emotions 82 can easily arise between crew members in orbit as well as between crew members and mission 83 control personnel (23, 4). In this regard, the effects of extended stays in orbit and future 84 interplanetary missions where personnel are subjected to long-term isolation and confinement are of 85 great interest. 86 87 Stress and stress prevention strategies 88 Although well-established stress prevention techniques like autogenic training can be acquired prior 89 to a mission, the participant’s ability to integrate and to interact with team members is key to the 90 development of favorable group dynamics and vital to the successful outcome of such a mission. 91 Stuster, who compared the characteristics of interplanetary missions to long-term naval expeditions, 92 identified the character traits necessary for successful adaptation to isolation and confinement such 93 as tolerance, emotional control or a sense of humor (52). As Selye stated in 1950: “Anything that 94 causes stress endangers life, unless it is met by adequate adaptive responses.”(3) The individual’s 95 genetically programmed and/or acquired adaptation mechanisms allow human beings to better cope 96 with stressful situations. But when do neuro-humoral or metabolic stress response systems, 97 specifically triggered by isolation and confinement, turn neuro-psychological strain into 98 pathophysiological symptoms? What are the favorable genetically primed or behavioral coping 99 strategies that provide some individuals with an advantage for overcoming such a situation? What 100 kind of countermeasures can be set in place to help the crew of exploration class missions in coping 101 with the adverse conditions? In other words, can confinement related stress be treated in a specific 4 Downloaded from http://jap.physiology.org/ by 10.220.32.247 on June 17, 2017 76 102 way? To answer these questions and to be able to design preventive measures, terrestrial space 103 analogues offer the unique opportunity to study single aspects of space travel separately without the 104 complex setting of actual spaceflight. The analogues offer i) a standardized high fidelity experimental setting such as the 106 experimental Mars500 mission simulation (in Moscow/Russia), or at the envihab facility 107 (Cologne/Germany) and ii) “real expedition” conditions such as in Antarctica. In addition, some 108 analogues allow simultaneous data collection from a larger number of subjects and the 109 implementation of a broader spectrum of methods. This mini review will look exemplarily at the 110 current data available from studies conducted in terrestrial space analogues with the focus on 111 isolation and confinement, and describe the psychological and physiological reactions and symptoms 112 observed in participants (see table 1). 113 114 2 Laboratory based spaceflight simulations 115 The 105 as well as the 520 day studies of the Mars500 programme, which was conducted jointly by 116 Roscosmos, the European (ESA) and the Chinese Space Agencies, were conducted at the refurbished 117 isolation facility located at the Institute of Biomedical Problems (IBMP) in Moscow, Russia. They 118 investigated the effects of long-term confinement in a group of six volunteers during a spaceflight 119 simulation to Mars. Although translation to a real Mars mission is limited (e.g. lack of microgravity or 120 exposure to radiation), this form of space analogue research allows an undisturbed view of the 121 effects of confinement on participants. 122 2.1 123 The facility was designed as a 550m3 habitat with four interconnected modules under artificial light 124 (50-300lx) (61). As a pilot study, Mars105 was conducted prior to Mars520 from March 31st to July 125 14th 2009. Mid-term isolation during Mars105 did not affect the participants’ overall health as much The factor of duration 5 Downloaded from http://jap.physiology.org/ by 10.220.32.247 on June 17, 2017 105 as during longer confinement in Mars520, which involved 520 days of confinement from June 3rd 127 2010 to November 4th 2011. There was no evidence of altered subjective psychological stress level, 128 hypothalamic–pituitary–adrenocortical axis (HPA) (glucocorticoid, catecholamine levels) activity, or 129 changed sleep patterns during Mars105 (16, 51). Autonomic heart rate variability (HRV) showed 130 increased amplitude oscillations at all frequencies and a reduced mean heart rate during the daytime 131 (increased wake parasympathetic activity) in contrast night time observations during sleep (61). 132 Although no acute inflammation or elevated plasma cytokine levels were detected, distinct effectors 133 of innate immunity were found to be inconsistently deregulated. Granulocyte mediated H2O2 134 production and shedding of the cell adhesion molecule CD62L were both found to be increased in the 135 volunteers (51). Many studies drew the conclusion that Mars105 did not impose a very strong stress 136 stimulus on participants and the observed effects were therefore limited (16, 51). By contrast, when 137 volunteers were confined for 520-days, the neuroendocrine stress responses were significantly 138 altered. The responses of the endocannabinoid system were partly affected (67) and the level of 139 salivary cortisol and catecholamines as markers for HPA activity were found to be increased during 140 isolation (22, 63, 64, 67). Accordingly, a decrease in cortical activity of α- and ß-waves can be 141 correlated with the sensory deprivation and monotony encountered during isolation (22). Physical 142 activity decreased during isolation and resulted in impaired neuromuscular performance mainly in 143 the lower limbs (7). Moreover, the circadian heart rate and HRV were significantly disrupted and 144 circadian misalignment was observed due to the lack of natural daylight (62). A well-balanced 145 day/night cycle, however, with adequate sleep/rest and activity phases properly synchronized to the 146 circadian rhythm is critical for keeping the crew healthy (5, 6, 9). During long-term confinement, the 147 percentage of sleep and rest phases increased, sleep quality and sleep-wake periodicity were 148 disrupted resulting in a decreased performance of participants (5, 6), which was paralleled by 149 reduced positive emotion ratings (67). The influence on the immune system includes a higher 150 percentage of lymphocytes (∼ 50%), an increase of CD3+T cells with a stable ratio of CD4+ helper T 151 cells/ CD8+ cytotoxic T cells and CD19+ B cells (64). IFN-γ and TNF-α secretion after stimulation with 6 Downloaded from http://jap.physiology.org/ by 10.220.32.247 on June 17, 2017 126 152 Epstein-Barr-Virus (EBV) antigen, a measure for adaptive immune response towards viral antigens, 153 was altered (14, 64). 154 2.2 155 Certain crew members are more prone to suffer from disease or psychological strains than others. 156 This can be due to distinct character traits, emotional instability or a genetic predisposition (36). 157 Interestingly, some of the Mars520 participants showed stronger shifts in the sleep-wake cycle than 158 others. Common genetic variations rendering individuals prone to sleep restriction and sleep cycle 159 disruption have already been suggested. Their use as predictive biomarkers would help to identify 160 vulnerable astronauts prior to a mission, where one can implement adequate countermeasures such 161 as supported rhythm alignment with the use of an artificial external zeitgeber (19). Moreover, crew 162 members with prior experience in spaceflight mission under difficult circumstances are beneficial in 163 critical situations. An astronaut who stays on the ISS for the first time will find it more difficult to 164 adjust to the conditions and will therefore have a different experience than someone who has been 165 there before and the same is true for confinement in space analogues. 166 2.3 167 The Simulation of Flight of the International Crew on the Space Station (SFINCSS-99) isolation study 168 was also conducted at the IBMP from July 1999 to April 2000. The first group consisted of four 169 Russian males who were confined for 240 days in a 100m3 combined working and sleeping room. The 170 second group comprised of 4 males and spent 110 days in a 200m3 area with separated dorms for 171 every subject. It was shown, that acute psychic stress, as measured by a self-evaluation 172 questionnaire, did not occur in participants neither during the 110-day nor during the 240-day 173 confinement (7). The innate immune system, however, was consistently activated as measured by 174 enhanced expression of ß2 integrins and elevated amounts of circulating granulocytes. Interestingly, 175 the return from confinement back to normal surroundings exerted the strongest immunological 176 changes in the subjects (7). This more pronounced effect on immunity might be due to the restricted The effect of the individual crew member 7 Downloaded from http://jap.physiology.org/ by 10.220.32.247 on June 17, 2017 The effect of available free space 177 free space availability for participants (200m3/100m3 versus 550m3 during the Mars studies). The 178 restricted space allowed little chance to retreat from the group during tense and stressful situations. 179 2.4 180 Confinement simulation under such high fidelity conditions is not only a platform to test the effects 181 of space flight during the mission, but also provides excellent conditions to investigate the effects of 182 environmental re-exposition, such as the return to Earth, when landing on another planet or 183 destination in space (65). Moreover, post-mission observation periods can include another 184 evaluation of the physiological system and serve as an acute insult to the organism in testing for 185 persisting effects of such prolonged confinement. 6 months after completion of their mission, the 186 Mars520 volunteers were subjected to acute stress during a parabolic flight campaign to compare 187 the stress burden of these previously confined subjects to healthy and unaffected volunteers. After 188 the exposure to 30 parabolas with repeated 1 G, 1.8 G and 0G phases, salivary cortisol levels and 189 urinary excretion of epinephrine were increased compared to pre-flight (63). Interestingly, in 190 comparison to the control group, cortisol levels were much higher in the Mars520 group indicating 191 that a chronic stress burden leads to a priming effect with pre-activated HPA. Post-operational long-term effects 193 3 Antarctica, a testbed for real exploration type isolation conditions 194 Expeditions to reach Antarctica were a heroic endeavor in the 19th century that fascinated people 195 and Roald Amundsen eventually reached the South Pole on 14 December 1911. Today, the extreme 196 inhospitable environment has not lost its fascination and is host to international research facilities 197 such as the French-Italian Concordia Station at Dome C located 3.233m above sea level on the 198 Antarctica Plateau. Concordia is one of the inland all year research stations together with the Russian 199 Vostok Station and the US Amundsen-Scott South Pole Station and is situated 1,100km inland from 8 Downloaded from http://jap.physiology.org/ by 10.220.32.247 on June 17, 2017 192 200 the coastal-based French research station Dumont D’Urville. Other research facilities situated at the 201 coast include the German Neumayer- III and the British Halley IV research stations. 202 3.1 203 Pre-selection of suitable expedition volunteers, with regard to psychological and physiological health, 204 is a difficult task (36, 54). Palinkas and Suedfeld defined three critical personal character traits for 205 successful polar missions: task ability, emotional stability, and social compatibility (36). Although 206 volunteers are thoroughly screened, a 5.2% incidence of DSM (Diagnostic and Statistical Manual of 207 Mental Disorders) IV validated disorders were detected in participants after return with mood 208 disorders being the most common diagnoses (30.2%), followed by adjustment disorders (27.9%), 209 sleep-related disorders (20.9%), and substance-related disorders (9.3%) (33). The 1-year incidence 210 values of DSM IV classified disorders in the general public of the USA evaluated in the National 211 Epidemiologic Survey on Alcohol and Related Conditions (NESARC) were lower: major depressive 212 disorder (1.51%), generalized anxiety disorder (1.12%), bipolar I disorder (0.53%) and drug 213 dependence (0.32%). (20). Nevertheless, the results of the NESARC survey are evidently not directly 214 comparable due to study design, group size and composition. Being encapsulated with the thought of 215 “nowhere to go”, surrounded by a vast ice covered landscape and spending a winter with a 3-month 216 lasting complete darkness put full year inhabitants under extreme psycho-social strain, which has 217 been recognized already during the first winter-over crew in the 1950s (31, 53, 55). Psychological 218 adaptation to this extreme setting is a multifactorial process (32). Typical symptoms that participants 219 of polar expeditions report are fatigue, headaches, gastrointestinal problems, sleeping difficulties, 220 impaired cognition such as a state of spontaneous fugue also called “the Antarctic stare” (35), 221 depressed mood or tension towards crew members (21, 27, 30). The psychosocial effects of the 222 Antarctic environment are noted to be of seasonal nature. The characteristic stare is accompanied 223 with motionlessness and speechlessness, lasting 1 to 90 minutes, has been reported in the majority 224 of winter–over crew members after the onset of winter and ended shortly before the return of 225 daylight (37). Furthermore, this behavior correlates to reports of depression. Though this is not a Psychological strain of an extreme environment Downloaded from http://jap.physiology.org/ by 10.220.32.247 on June 17, 2017 9 proper classified condition according to the DSM IV, the combined state of sleeping disorder, 227 cognition impairment, negative affect and tension towards crew members is referred to as the 228 winter-over syndrome, which becomes aggravating in the second half of an expedition. This 229 characteristic time-course is completely independent of the duration of the expedition and referred 230 to as the third quarter phenomenon (34, 36). The polar triiodothyronine syndrome (T3 syndrome) 231 comprises of subclinical seasonal changes of thyroid gland function including lower levels of the 232 effector hormone T3 (hypothyroidism) and elevated levels of thyreotropin-stimulating hormone 233 (TSH) (39, 41). These changes, though subclinical in nature, significantly correlate with cognitive 234 performance and mood alterations as evidenced by the Profile Of Mood States (POMS) questionnaire 235 (40). Changes in the HPA axis were also detected. Supplements of levothyroxine and exposure to 236 bright light (10,000 lux) during winter had beneficial effects on the observed mood alterations 237 (35,40). During the early adaptation phase (1 month) of the Concordia winter-over crew in 2008, 238 cortisol levels and stress questionnaires did not report higher stress levels. However, 24h urinary 239 catecholamine excretion was significantly increased (13). 240 3.2 241 The environmental conditions in spaceflight and the analogues can be described as hypobaric 242 hypoxic. Therefore decreased mean oxygen saturation levels (85.7 and 88.7%, at 1 week and 1 243 month, respectively) as well as elevated hemoglobin and platelet levels were detected. Plasma 244 adenosine, a measure for hypoxia related immune alterations, was slightly increased at 1 week and 245 accordingly, a leukocyte subpopulation shift towards granulocytes was detected alongside impaired 246 PMNL activation and H2O2 production (13). Innate immune modulations at the mucosal barrier 247 revealed seasonal changes in immunoglobulin (Ig) A and IgM levels, where maximal immune 248 suppression inversely correlated with altered psycho-social stress at a time-point after 4 months (18). 249 Unfortunately, acute stress symptoms or hormone levels were not investigated. In a different study, 250 anti-inflammatory cytokines (IL-10 and IL-1RA) were found to be decreased whereas pro- 251 inflammatory IFN-γ was elevated (44). The observed immune changes demonstrate a shift towards a Environmental triggers of the immune system 10 Downloaded from http://jap.physiology.org/ by 10.220.32.247 on June 17, 2017 226 252 pro-inflammatory type 1 CD4+ T helper cell (TH1) dominant phenotype (45) and are in line with the 253 previously observed EBV-viral reactivation study (29, 58). Interestingly, body weight supplementation 254 of vitamin D has shown to reduce the shedding of EBV into saliva (47,69). 255 3.3 256 The decline of cognitive performance is one of the key issues during long-term spaceflight. Its decline 257 during spaceflight due to monotony or increased sense of stress could lead to devastating outcomes. 258 Frequently reported symptoms of cognition impairment include memory loss, difficulties 259 concentrating, increased reaction time and disturbance of vigilance (30,40). The previously 260 mentioned fugue states and even an increased susceptibility to suggestion belong to the canon of 261 symptoms (3, 36). The dimension of cognitive impairment during Antarctic winter-over is yet to be 262 elucidated. A couple of studies were unable to measure such a decline and this seems to depend on 263 testing format, the composition of crew members and the course of the mission (1, 28,40). Abeln et 264 al., for example, used commercially available games to test cognitive tasks such as visuoperceptual 265 speed, reaction time, arithmetics and object recall. However, likely due to a training effect, no 266 alterations in cognition were detectable (1). Other studies showed that the motivation of subject was 267 key to good performance values (12). Due to inconsistent use of testing formats and variable subject 268 composition as well as limited study size, it is difficult to compare study results and to detect discrete 269 changes. 270 3.4 271 New research increasingly focuses on advanced imaging techniques to quantify neurocognitive 272 alterations and the brain’s ability to quickly adapt to altered stimuli (neuroplasticity) in confined 273 situations such as long-term spaceflight. Advanced magnet resonance imaging (MRI) techniques such 274 as Diffusion Tensor imaging (DTI) (15) allow for the visualization of diffusion changes in target 275 neurofiber tracts, which enables direct measurement of the distinct changes due to neuroplasticity 276 (11). With the use of DTI and whole brain voxel-based analysis, it has been shown that patients Impairment of cognition 11 Downloaded from http://jap.physiology.org/ by 10.220.32.247 on June 17, 2017 New strategies for the evaluation of neurocognitive performance suffering from bipolar I disorder exhibit distinct white matter changes when compared to healthy 278 controls (4). Studies using DTI in space and Antarctic winter-over crews are still ongoing (17, 26,60) 279 and results of these studies are highly anticipated. Functional MRI (fMRI) comprises of MRI imaging 280 and a simultaneous functional performance of the test subject. The person investigated is first 281 examined in a resting state and then asked to mentally visualize activities (e.g. imagining running, 282 walking etc.). Recently published data examining a single astronaut before and after a 6-months 283 flight in space revealed alterations in vestibular and motor-related regions. The observed 284 dysfunctions were clinically correlated with vestibular ataxia and reduced motor control abilities. 285 Interestingly, these dysfunctions likely originate from the cortex, rather than from deconditioned 286 gravity sensing organs as previously suggested (59). The application of these MRI methods will 287 greatly advance our knowledge on the neurocognitive effects in terrestrial analogue and spaceflight 288 studies. The immune modulatory changes together with the severe psychosocial stress render 289 Antarctica as one of the most interesting space analogues available. Aside from all the predominant 290 negative effects, it is worth mentioning that many volunteers return with positive memories of their 291 expedition to Antarctica. A stay at Antarctica for a short time or for winter-over is for many a once in 292 a lifetime challenge and adventure, not to mention a worthwhile undertaking. 293 294 295 296 297 298 4 Short term confinement in underwater habitats: bridging science to operational 299 needs 300 Human beings can experience Isolation and confinement not only in prepared laboratory settings or 301 specialized research facilities, they encounter it everyday. A naval expedition or sailing trip where 12 Downloaded from http://jap.physiology.org/ by 10.220.32.247 on June 17, 2017 277 one is confined to a vessel with others and exposed to the force of nature, very closely resembles an 303 interplanetary mission (53). The vastness of the ocean does provide some sensory input (daylight, 304 animals, colors) but when diving, these sensory inputs are eradicated. Saturation divers live and work 305 in underwater-pressurized habitats. The nature of this remote and extreme environment makes 306 underwater habitats an excellent facility for space analogue research. The Aquarius Reef Base is an 307 underwater sea laboratory currently owned by the Florida International University (FIU) and located 308 in the Florida Keys National Marine Sanctuary at an operating depth of 47 feet and operating 309 pressure of 2.5 Atos. NASA Extreme Environment Mission Operations (NEEMO) trains astronauts in 310 this unique underwater setting during 10 -14 space analogue missions. Astronauts are subjected to 311 isolation and confinement in an extreme environment based station, daily 5-9 hour dives simulating 312 extra vehicular activity (EVA), and circadian-rhythm misalignment due to a lack of natural 313 synchronizers (10,50). 314 In a pilot study investigating 6 male astronauts in the context of innate immune alterations 315 before, during and after hyperbaric hyperoxia, no psychoneuroendocrine changes were detected. 316 Blood analysis revealed leukocytosis, granulocytosis, monocytosis and lymphocytopenia during the 317 dive. Whereas pro-inflammatory cytokines such as IL-2, IL-6, IL-8, TNF-α and IFN-γ remain 318 unchanged. An increased expression of the adhesion molecule CD11b and shedding of CD62L on 319 PMNLs were also detected. Moreover, PMNL related H2O2 production exhibited an increased 320 sensitivity to adenosine (50). These results illustrate an inflammatory high alert state with increased 321 sensitivity towards possible stimuli. Similar systemic proinflammatory states and increased oxidative 322 stress were also observed after a short dive (56). Well known inflammatory markers of red blood cell 323 metabolism, the total body iron stores (serum ferritin) (46) and toxic labile iron forms (non- 324 transferrin-bound iron), were increased in the participants (2, 8). Blood homocysteine levels went up 325 while the activity of superoxide dismutase (SOD) deteriorated , suggesting oxidative stress during the 326 dive (68). 327 Though NEEMO is a very special setting with hyperbaric hyperoxic conditions, it shows that 13 Downloaded from http://jap.physiology.org/ by 10.220.32.247 on June 17, 2017 302 even a 14-day exposure to such a harsh environment can cause changes in immunity and antioxidant 329 levels in the body. The long-term effects remain unknown, since a prolonged observation was not a 330 part of the protocol. Clearly as human beings, we are not adapted to these living conditions but these 331 would be the conditions on other planets such as Mars. Even if we were to build an artificial habitat 332 with tolerable atmospheric conditions, we have to be aware of the fact that our body will still react 333 to the non-Earth environments. Correspondingly, our immune system will most likely encounter 334 altered and more virulent strains of Earth pathogens or perhaps completely novel foreign pathogens 335 in space. This means astronauts are faced with adverse conditions with an impaired immune 336 response, making medical support and optimizations all the more important in space flight. 337 338 5 Analogue environment for future space exploration 339 The evolution of human kind is still ongoing. On our journey to another planet we would have to rely 340 on the sharing of responsibilities among crew members similar to the early ages when we 341 transformed from hunter-gatherers into ancient civilized societies. The extensive program of 342 cosmonaut and astronaut training allows these candidates to experience some aspects of space 343 travel in a relatively secure setting on Earth. Evidently, an intensive and exhaustive training for 344 astronauts is crucial for the success of a mission but can only be as good as the scientific foundations 345 it is based on. Program designers and scientists have to define what risks and dangers astronauts 346 might encounter and to better prepare them: future manned exploration to the moon, asteroids and 347 to Mars can be best practiced when the facilities appropriately simulate outer space conditions. This 348 will become increasingly more critical since the Earth bound analogues will be a function of the 349 mission scopes, mission length and overall boundary/budgetary estimates of such future exploration 350 class missions. The selection of an analogue mission scenario must meet two criteria: it must be a 351 high fidelity simulation which enables in-depth exploration of space flight related stressors on a large 352 number of subjects and be representative of the missions anticipated in the next 10-25 years. In the 14 Downloaded from http://jap.physiology.org/ by 10.220.32.247 on June 17, 2017 328 post ISS era, several vehicles and missions are in the planning and pre-planning stages, ranging from 354 free flyers in various Earth (or even lunar) orbits or beyond. These projects include the Chinese Space 355 Station CSS, “landing”-docking scenarios on asteroids, expeditions to the moon or with prolonged 356 presence as a stepping stone for future Mars missions. The aim is for these plans to be realized by 357 2050. These conditions and scopes are highly variable, the analogues must address the effects of 358 various group sizes, gender composition, limited living space in the spacecraft vs. more spacious 359 habitats at the lunar or planetary destination. Also, the effect of life support systems (regeneration, 360 green houses) must be considered alongside the effects of the atmospheres. The latter is generally 361 speaking a hypobaric and hypoxic condition to facilitate extra-habitat/vehicular activities, but 362 imposes fire hazards and technical constraints (57). 363 Depending on the scopes and in particular, the confinement facilities , high fidelity mid- to long-term 364 simulations with variable crew sizes of three and more crew members can be accommodated, for 365 example, in Russia. The Human Exploration Research Analog (HERA) facility and NEEMO, will support 366 research especially on operational issues, crew composition and day to day life in habitats. When 367 environmental or additional life support systems are to be tested with measurements on human 368 organ homeostasis, the newly built and recently operational envihab facility (25) or the Olympic sport 369 center in Planica (48) are favorable candidates. When a non-artificial habitat is to be tested, 370 Antarctica seems to serve as the most hostile and mission relevant environment at either hypoxic 371 (e.g. the French/Italian Concordia-, the US Amundsen–Scott South Pole- or the Russian Vostok- 372 Station), or normoxic conditions (e.g. at the British Halley VI or Neumayer III). 373 Already to date, given the broad portfolio of space analogues available for research, scientists have 374 been gathering data from very unique and interesting environmental settings on Earth. But each and 375 every analogue has its own characteristics, which has been described in this review (See table 2). 376 15 Downloaded from http://jap.physiology.org/ by 10.220.32.247 on June 17, 2017 353 377 6 Space analogues as training facilities 379 Analogue studies provide valuable insight for two parties, on the one hand to the scientific 380 community by extending our knowledge in the field, on the other hand to Cosmonauts and 381 Astronauts as they gain experience while taking part in mission simulations. As such, complete 382 mission simulations are highly valuable tools. The ESA CAVES program (Cooperative Adventure for 383 Valuing and Exercising human behavior and performance Skills) is a training opportunity where 384 astronauts participate in a cave exploration with the goal of encountering new life forms and to train 385 teamworking skills (49). The nature of the strange and uncommon environments inhabited by often 386 novel organisms surviving off of elements like manganese or sulfur, without light and in a potentially 387 life threatening setting offers a training scenario for space missions (8, 49). Similarly to the effects 388 observed during the Mars confinement studies, the reunion with daylight after leaving the darkness 389 and seclusion of the cave is a highly emotional experience for participants. With regard to an 390 expedition to Mars, extraterrestrial caves are being discussed as a possible first natural form of 391 habitat on Mars (8). Expanding this approach of priming the crew to space like conditions and 392 especially to prolonged confinement and isolation, a “mission” to Antarctica before Mars can 393 certainly be worthwhile preparation. 394 395 7 Coping strategies and countermeasures in space analogues 396 Current strategies to ameliorate the effects of isolation and confinement in space or Antarctica 397 involve first and foremost the careful selection of candidates for group compatibility, social skills as 398 well as psychological and physical health (31). Once mission bound, maintenance of crew health is a 399 better strategy than therapy. Providing good nutrition and dietary supplements can prevent disease. 400 This could involve previously mentioned levothyroxine (35) or Vitamin D (69) supplements. 401 Furthermore, physical exercise was found to be beneficial for a balanced mood in Antarctica (1) and 16 Downloaded from http://jap.physiology.org/ by 10.220.32.247 on June 17, 2017 378 402 during Mars500 (42). Sleeping disorders and disruption of the circadian cycle can be reduced at least 403 in part with the use of an artificial zeitgeber e.g. 10,000 lux bright white light (35). Core social coping 404 strategies involve team building exercises, team activities or entertainment and access to 405 communication such as “support from home”. Current research stations in Antarctica are capable of 406 providing access to the Internet or telephone. Social bonding between fellow crew members 407 especially for long-term confinement missions is best achieved prior to the mission, if possible. 408 Training in space analogue facilities can be a platform to achieve this goal. 409 8 Conclusion and outlook 411 Isolation and confinement can put the human body under a large amount of psycho-neuro-endocrine 412 duress, which results in measurable pathophysiologic symptoms. Terrestrial space analogues offer a 413 very good setting for scientists to study these effects and to provide international space agencies 414 with the information they need to select, prepare and to protect astronauts in short spaceflight and 415 in particular, long-term exploration class missions. Experiments in analogue environments offer 416 unique conditions to explore the nature of human adaptation and to allow high fidelity investigations 417 in a clinical context. As such, standardized conditions of confinement (e.g. MARS500, envihab, 418 PlanHab and other in the US and in China) can be advantageous in their application as a metabolic 419 chamber for nutritional and metabolic studies (38, 66) or as a hypoxic environment for disease 420 studies in human organs. 421 Despite the scientific advancements thus far, exploration class interplanetary missions are a 422 bold endeavor not for the faint of heart. They require not only brave and experienced crew members 423 but also a huge amount of resources including further technical developments, medical scientific 424 research and strong psychological support. These investments into further investigations will not 425 only be required for safe manned space exploration but will no doubt serve to benefit life on Earth. 426 17 Downloaded from http://jap.physiology.org/ by 10.220.32.247 on June 17, 2017 410 427 428 Acknowledgements: The authors are very grateful to the support from Anne Guo (MD, Department 429 of Anaesthesiology, Munich, Germany) for language editing of this manuscript. The authors are 430 supported by grants (Nr 50WB0919, 50WB1317) from the German Ministry of Technology and 431 Energy (BMWi) as handled by DLR. 432 Downloaded from http://jap.physiology.org/ by 10.220.32.247 on June 17, 2017 18 9 References 434 435 436 437 438 439 440 441 442 443 444 445 446 447 448 449 450 451 452 453 454 455 456 457 458 459 460 461 462 463 464 465 466 467 468 469 470 471 472 473 474 475 476 477 478 479 480 481 482 1. Abeln V, MacDonald-Nethercott E, Piacentini MF, Meeusen R, Kleinert J, Strueder HK, and Schneider S. 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J Nutr 141: 692-697, 2011. 22 Downloaded from http://jap.physiology.org/ by 10.220.32.247 on June 17, 2017 587 588 589 590 591 592 593 594 595 596 597 598 599 600 601 602 603 604 605 606 607 608 609 610 611 612 613 614 615 616 617 618 619 620 621 622 623 624 625 626 627 628 629 630 631 632 633 634 no psychoneuroendocrine effects observed Psychological Effects Mars520 study • high inter-individual differences in the behavioral responses • symptoms of depression • reduced positive emotion ratings Antarctica (Concordia) • cognitive impairment • mood alterations (depression) • tension towards crew members • sleeping disorder • state of spontaneous fugue • third quarter phenomenon Downloaded from http://jap.physiology.org/ by 10.220.32.247 on June 17, 2017 Mars105 study • signs of sensory deprivation and monotony (decrease in α and ß waves) • heart rate and HRV significantly disrupted • sleep quality and sleep-wake periodicity • impaired neuromuscular performancecircadian heart rate and HRV significantly disrupted • salivary cortisol and urinary catecholamine secretion increased, the endocannabinoid 2arachidonoylglycerol (2-AG) decreased • lymphocytosis with an increase of CD3+T cells • IFN-γ and TNF-α secretion after stimulation with Epstein-Barr-Virus (EBV) antigen were altered • post-mission parabolic flight campaign: salivary cortisol levels and urinary excretion of epinephrine were increased compared to preflight and unlike the control group • pro-inflammatory type 1 CD4+ T helper cell (TH1) pronounced phenotype • impaired PMNL activation and reduced capacity to produce H2O2 • EBV-viral reactivation • polar T3 syndrome • elevated 24h urinary catecholamine excretion • elevated hemoglobin and platelets • elevated Plasma adenosine Downloaded from http://jap.physiology.org/ by 10.220.32.247 on June 17, 2017 Physiological effects • increased HRV • increased wake parasympathetic activity • inconsistent immune changes • increased shedding of the cell adhesion molecule CD62L • Granulocyte mediated H2O2 production elevated Downloaded from http://jap.physiology.org/ by 10.220.32.247 on June 17, 2017 no major psychoneuroendocrine effects observed NEEMO • leukocytosis • granulocytosis • monocytosis • lymphocytopenia • inflammatory alert state • increased total body iron stores • increased oxidative stress Downloaded from http://jap.physiology.org/ by 10.220.32.247 on June 17, 2017
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