**From the Individual to the Cultural Space Group**

**From the Individual to the Cultural Space Group**

DOI: 10.5772/intechopen.72357

#### Carole Tafforin Carole Tafforin Additional information is available at the end of the chapter

Additional information is available at the end of the chapter

http://dx.doi.org/10.5772/intechopen.72357

#### **Abstract**

From a behavioral point of view, human crews into Space will have to both live and work in physical environment (microgravity, 1/3 g, 1/6 g), confined environment (spatial restriction, social constraints, and sensorial privation), and isolated environment (familiar privation, cultural background, and remote communication) that involve a multisystem adaptive model on a long-duration process. Physiological, medical, psychological, sociological, anthropological, and ethological impacts have been emphasized in a wide panel of investigations. The current results are presented with a focus on relevant methods in ethology based on the observation, description, and quantification of (i) the individual behavior from short-term orbital missions; (ii) the social behavior during inter-planetary missions simulated in terrestrial environments; and (iii) the cultural behavior in considering manned missions on Moon, on Mars, and beyond. Global analysis highlights that the crewmembers going into Space will be definitively interactive men and women with personal experiences, social rules, and new cultural habits. They will have their individual identities and they will be a group entity for extended periods of time.

**Keywords:** space exploration, human behavior, adaptation, orbital mission, isolated and confined environments

### **1. Introduction**

When a human crew takes flight from Earth for the purpose of staying in Space, what could happen from an adaptive perspective? In the evolutionary history, the human being adopted the supine posture for walking. The possibility of movement of the individual then led to the evolution of kinds of socialities that resulted in cultural habits (**Figure 1**).

Firstly, just as gravity plays an essential role in terrestrial locomotion [1], microgravity is the new environmental factor that will lead to changes in sensory-motor activity. Secondly, the crew will be exposed to unusual environment factors as the space habitat will be isolated

© 2016 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons

Interplanetary missions are regarded as prime opportunities to highlight the psycho-physiological issues of man and woman under both microgravity and isolation and confinement conditions over very long durations. During these space travels, the crewmembers will have to adapt to a wide range of environmental factors such as weightlessness, social constraint, closed module, monotonic panorama, familial privation, and cultural diversity. They will also have to cope with the restrictions imposed by life-support system. The ethological works

From the Individual to the Cultural Space Group http://dx.doi.org/10.5772/intechopen.72357 33

In this complex network, the adaptation model to space environment (**Figure 3**) considers the individual as a whole with all the facets, concerning maladaptive reactions and adaptive strategies. It puts into action a "hard" system (*left facet of the model*), in terms of conservative regulation, which tends to recover the initial states of the sensorial mechanisms and the physiological mechanisms. For instance, deficits or variations in the environment induced by microgravity will generate, at the physiological level, a redistribution of fluids and electrolytes followed by a cardiovascular reaction leading to endocrinal and metabolic changes. At the sensorial level, the weightlessness will transfer the information from the inhibited vestibular function to the visual function, which will be reinforced. Consequently, a "soft" system (*middle facet*) will be activated, in terms of innovative regulation, to express new behavioral strategies by the adjustments or modifications of body orientations, postures, and movements. New motor learning will conduct to a new representation of the space environment (*upper facet*) involving

were particularly concerned with these interfaces [3, 4].

psychological functions, cognitive skills, sociability, and cultural ability.

**Figure 3.** Multisystem adaptive model in Space.

**Figure 1.** Evolutionary steps of human being on Earth.

and confined. Coping with monotony and facing up to autonomy thus becomes essential for adaptability. Furthermore, when moving out of space habitats during extra-vehicular activities (EVAs), such hostile environment is another factor to consider for survivability. Thirdly, all of these factors have to be taken into account in synergy with the temporal aspect of going far from Earth and for extended durations.

In sum, the human crew has to adapt to a new, unusual, and hostile environment for living and working in Space, and for extended periods of time. Many studies in ethology, i.e., the science of behavior, were performed in these extreme settings (**Figure 2**), in real situations (orbital missions), in simulations (parabolic flights and bed rests), during confinement experiments, and in analogue environments (polar stations). On the one hand, missions in orbital station or in space shuttle are new conditions of weightlessness; parabolic flights create the physical characteristics; bed rests simulate the physiological consequences. On the other hand, confined habitats are unusual conditions and South Pole stations or Artic expeditions are hostile environments analogous to space exploration missions.

Generation and applications of extraterrestrial environments on Earth [2] contribute to an exhaustive and global knowledge of what constitutes Space, from its physical characteristics to its behavioral aspects within the relationship between the individual and the environment.

**Figure 2.** New, unusual, and hostile environments on Earth.

Interplanetary missions are regarded as prime opportunities to highlight the psycho-physiological issues of man and woman under both microgravity and isolation and confinement conditions over very long durations. During these space travels, the crewmembers will have to adapt to a wide range of environmental factors such as weightlessness, social constraint, closed module, monotonic panorama, familial privation, and cultural diversity. They will also have to cope with the restrictions imposed by life-support system. The ethological works were particularly concerned with these interfaces [3, 4].

In this complex network, the adaptation model to space environment (**Figure 3**) considers the individual as a whole with all the facets, concerning maladaptive reactions and adaptive strategies. It puts into action a "hard" system (*left facet of the model*), in terms of conservative regulation, which tends to recover the initial states of the sensorial mechanisms and the physiological mechanisms. For instance, deficits or variations in the environment induced by microgravity will generate, at the physiological level, a redistribution of fluids and electrolytes followed by a cardiovascular reaction leading to endocrinal and metabolic changes. At the sensorial level, the weightlessness will transfer the information from the inhibited vestibular function to the visual function, which will be reinforced. Consequently, a "soft" system (*middle facet*) will be activated, in terms of innovative regulation, to express new behavioral strategies by the adjustments or modifications of body orientations, postures, and movements. New motor learning will conduct to a new representation of the space environment (*upper facet*) involving psychological functions, cognitive skills, sociability, and cultural ability.

**Figure 3.** Multisystem adaptive model in Space.

and confined. Coping with monotony and facing up to autonomy thus becomes essential for adaptability. Furthermore, when moving out of space habitats during extra-vehicular activities (EVAs), such hostile environment is another factor to consider for survivability. Thirdly, all of these factors have to be taken into account in synergy with the temporal aspect of going

In sum, the human crew has to adapt to a new, unusual, and hostile environment for living and working in Space, and for extended periods of time. Many studies in ethology, i.e., the science of behavior, were performed in these extreme settings (**Figure 2**), in real situations (orbital missions), in simulations (parabolic flights and bed rests), during confinement experiments, and in analogue environments (polar stations). On the one hand, missions in orbital station or in space shuttle are new conditions of weightlessness; parabolic flights create the physical characteristics; bed rests simulate the physiological consequences. On the other hand, confined habitats are unusual conditions and South Pole stations or Artic expeditions

Generation and applications of extraterrestrial environments on Earth [2] contribute to an exhaustive and global knowledge of what constitutes Space, from its physical characteristics to its behavioral aspects within the relationship between the individual and the environment.

far from Earth and for extended durations.

**Figure 2.** New, unusual, and hostile environments on Earth.

**Figure 1.** Evolutionary steps of human being on Earth.

32 Into Space - A Journey of How Humans Adapt and Live in Microgravity

are hostile environments analogous to space exploration missions.

Whether onboard the orbital Mir station or in the space shuttle where we analyzed video recordings, the results showed how humans in space elaborated a new world of perceptions and actions through the changes of body orientations. As an example of spationaut adapting to this new environment, after three days of space sickness induced by vestibular-ocular conflicts, we observed the occurrence of head-down orientations as main changes in the motor

From the Individual to the Cultural Space Group http://dx.doi.org/10.5772/intechopen.72357 35

Holistically, the physiological challenges facing man and woman going into Space have been well documented in books and chapters, with examples such as fundamentals of space physiology [7, 8] and space medicine [9, 10]. Exposure to microgravity and radiation has important physiological implications for the maintenance of medical health. Also, behavioral health is of prime importance to keep the missions operational. Psychology of space exploration is a new challenge for long-duration interplanetary flights and stays on planets far from Earth [11].

On the one hand, individuals' health status has to be optimum, with medical and physical requirements. The spationaut, with his/her physiology, has to regulate loss of weight, loss of bone, loss of muscle, loss of vision, and loss of proprioception. Microgravity effects are minimized with medical training before going into Space, special countermeasures on physical activity when staying in Space, and physical reconditioning when returning to Earth. Specific emphasis is placed on cardio-vascular responses by developing individual countermeasures [13] and on musculo-skeletal responses because there is an individual variability in spite of exercise regimes [14]. Emphasis is also placed on neuro-cognitive responses while maintaining a high level of performance [15] from body-disorientation to related stress in micrograv-

On the other hand, the individual's behavioral health should be positive with congruence and assertiveness requirements [16]. The spationaut, with his/her psychology, has to cope with loss of mental ability, loss of wide sociability, loss of close family contacts, loss of privacy, loss of large landscape, and a multitude of odors. Isolation and confinement effects are prevented with

Humans in Space might answer issues regarding psychological hurdles [12].

ity. That has an impact on the individual behavior in terms of behavioral health.

**Figure 5.** Head/body orientations in microgravity during a 7-day orbital flight.

activity (**Figure 5**).

**Figure 4.** Dynamics states of adaptation to Space.

Overall, the space traveler, fitted with his physiological luggage and sensorial luggage, equipped with his motor luggage and impacted by his sociocultural luggage, will follow an adaptive dynamics, day after day, month after month, year after year as evolving states of the individual behavior, the social behavior and the cultural behavior (**Figure 4**).

### **2. Individual behavior**

When experiencing for the first time, reduced gravity in parabolic flights, neophyte subjects were in confusing referential cues with inadequate body moving [5]. Their performance, described by the optimization of orientations in a three-dimensional space, improved over time. As they gradually develop harmonious coordination between sensory-motor and cognitive experience, spontaneous, preliminary, followed by integrative stages of adaptation underlie new relations between the body references and those of the physical environment. As a result, the individual behavior is characterized by a multidirectional motor activity.

Once in short-term orbital flights, the man or woman in space, i.e., the spationaut, has to perform domestic and professional tasks like those done under terrestrial gravity, whereas the "body tool" available to him/her has been placed in new conditions that require significant behavioral changes [6]. Microgravity has the most obvious effect of diversifying movements, postures, and orientations. The vertical position is thus no longer the only one possible. This means that in order to efficiently perform tasks, the individual has to invent new motor strategies that transform the quality of locomotion and manipulations with new orientation possibilities in weightlessness. In ethological studies, modifications of the motor behavior are treated as observable evidence of the human adaptation to space. In addition to the conservative physiological homeostasis, the quantitative description of what the moving individual is doing in microgravity is postulated as innovative regulation in the multisystem adaptive model.

Whether onboard the orbital Mir station or in the space shuttle where we analyzed video recordings, the results showed how humans in space elaborated a new world of perceptions and actions through the changes of body orientations. As an example of spationaut adapting to this new environment, after three days of space sickness induced by vestibular-ocular conflicts, we observed the occurrence of head-down orientations as main changes in the motor activity (**Figure 5**).

Holistically, the physiological challenges facing man and woman going into Space have been well documented in books and chapters, with examples such as fundamentals of space physiology [7, 8] and space medicine [9, 10]. Exposure to microgravity and radiation has important physiological implications for the maintenance of medical health. Also, behavioral health is of prime importance to keep the missions operational. Psychology of space exploration is a new challenge for long-duration interplanetary flights and stays on planets far from Earth [11]. Humans in Space might answer issues regarding psychological hurdles [12].

On the one hand, individuals' health status has to be optimum, with medical and physical requirements. The spationaut, with his/her physiology, has to regulate loss of weight, loss of bone, loss of muscle, loss of vision, and loss of proprioception. Microgravity effects are minimized with medical training before going into Space, special countermeasures on physical activity when staying in Space, and physical reconditioning when returning to Earth. Specific emphasis is placed on cardio-vascular responses by developing individual countermeasures [13] and on musculo-skeletal responses because there is an individual variability in spite of exercise regimes [14]. Emphasis is also placed on neuro-cognitive responses while maintaining a high level of performance [15] from body-disorientation to related stress in microgravity. That has an impact on the individual behavior in terms of behavioral health.

On the other hand, the individual's behavioral health should be positive with congruence and assertiveness requirements [16]. The spationaut, with his/her psychology, has to cope with loss of mental ability, loss of wide sociability, loss of close family contacts, loss of privacy, loss of large landscape, and a multitude of odors. Isolation and confinement effects are prevented with

**Figure 5.** Head/body orientations in microgravity during a 7-day orbital flight.

Overall, the space traveler, fitted with his physiological luggage and sensorial luggage, equipped with his motor luggage and impacted by his sociocultural luggage, will follow an adaptive dynamics, day after day, month after month, year after year as evolving states of the

When experiencing for the first time, reduced gravity in parabolic flights, neophyte subjects were in confusing referential cues with inadequate body moving [5]. Their performance, described by the optimization of orientations in a three-dimensional space, improved over time. As they gradually develop harmonious coordination between sensory-motor and cognitive experience, spontaneous, preliminary, followed by integrative stages of adaptation underlie new relations between the body references and those of the physical environment. As a result, the individual behavior is characterized by a multidirectional motor activity.

Once in short-term orbital flights, the man or woman in space, i.e., the spationaut, has to perform domestic and professional tasks like those done under terrestrial gravity, whereas the "body tool" available to him/her has been placed in new conditions that require significant behavioral changes [6]. Microgravity has the most obvious effect of diversifying movements, postures, and orientations. The vertical position is thus no longer the only one possible. This means that in order to efficiently perform tasks, the individual has to invent new motor strategies that transform the quality of locomotion and manipulations with new orientation possibilities in weightlessness. In ethological studies, modifications of the motor behavior are treated as observable evidence of the human adaptation to space. In addition to the conservative physiological homeostasis, the quantitative description of what the moving individual is doing in

microgravity is postulated as innovative regulation in the multisystem adaptive model.

individual behavior, the social behavior and the cultural behavior (**Figure 4**).

**2. Individual behavior**

**Figure 4.** Dynamics states of adaptation to Space.

34 Into Space - A Journey of How Humans Adapt and Live in Microgravity

ground support [17] as far as communication with Earth is possible. Relevant researches are conducted on personal value [18], personality trait [19], emotional state [20], communicative profile [21], and mental health, with the need of defining individual characteristics upon strong motivation [22]; in other words, all that has an impact on the individual behavior in ethological terms.

Good health, both medico-physiological and etho-psychological, is the key to quality of life and to successful work. The individual behavior in its optimal and positive meaning is the first link of the well-being and good-spirit of the crewmember within social contexts constrained by isolation and confinement once he/she has settled into Space.

### **3. Social behavior**

The isolated and the confined crewmember observed using the ethological approach has demonstrated that confinement generates stress manifestations versus isolation; that isolation enhances social relationships versus confinement, and that the crew adapted positively to both environments [23]. From the individual in orbital flight to a small group inside confinement chambers or inside polar stations, research works need continued sharpening on adaptation of the human being on Earth to the human being in Space, period by period [24].

communications, and between the sociometric parameter "popularity in leisure environment" and anxiety level. We also found significant positive correlations between the sociometric parameter "popularity in working environment" and interpersonal communications, and facial expressions; and between the sociometric parameter "popularity in leisure environment" and interpersonal communications, and facial expressions. This highlighted complementary viewpoints in the field of life sciences and social sciences: objective versus subjective, active versus discursive, exhaustive versus restrictive, and descriptive versus introspective [26].

From the Individual to the Cultural Space Group http://dx.doi.org/10.5772/intechopen.72357 37

Crew relations also play important roles in the success of missions where crewmembers stay one year and beyond in isolation and confinement. Wireless monitoring of interactive behaviors correlated with individual questionnaires, and video analyses of collective activities showed that the amount of time spent together during free time is highly associated with the

intensity of relationships [27].

**Figure 6.** Environmental and temporal factors simulated on Earth.

**Figure 7.** Social interactions in isolation during a 506-day Tara-Artic expedition.

The main results from the research showed three adaptive periods: initial, mid and final periods over a 28-day Isolation Study of the European Manned Space Infrastructure (ISEMSI) campaign; over a 60-day Experimental Campaign for European Manned Space Infrastructure (EXEMSI); and over a 135-day Human Behavior in Extended Spaceflight (HUBES) campaign. In these limited habitats, the personal distances decreased and the public distances increased among the crewmembers. We observed high values of social distances and body mobility from the initial period to the final period. An increasing spatial dispersion with decreasing social orientations was also noted among the crew at the midpoint of the medium-term simulations [25]. Over a 520-day Mars-500 experiment, the crew simulated how to live and work together like a real mission with a 250-day Earth-Mars travel, a 30-day Mars landing, and a 240-day Mars-Earth travel. The results showed that time had a major impact on the individual and interindividual behaviors in terms of personal actions, visual interactions, object interactions, body interactions, facial expressions, and collateral acts. The crewmembers followed phasic, periodic, and punctual behavioral changes in extended periods of time, as it was observed at the Antarctic Concordia station and during the Artic Tara expedition, to avoid monotony. Be it space simulators or analogue settings provided by these extraterrestrial environments on Earth for going into Space (**Figure 6**), the behavioral adaptation is mainly related to social interactions with an emphasis on visual interactions (**Figure 7**).

Along with physical and mental health, the social behavior in terms of nonverbal interactions and verbal communications has become of new interest to investigate interplanetary missions from the perspective of multidisciplinary approaches. For instance, correlation of etho-social and psycho-social data during the simulated Mars-500 interplanetary mission aimed at identifying crewmembers' behavioral profiles for better understanding Space groups of future explorations. We found significant negative correlations between anxiety and interpersonal

**Figure 6.** Environmental and temporal factors simulated on Earth.

ground support [17] as far as communication with Earth is possible. Relevant researches are conducted on personal value [18], personality trait [19], emotional state [20], communicative profile [21], and mental health, with the need of defining individual characteristics upon strong motivation [22]; in other words, all that has an impact on the individual behavior in ethological terms. Good health, both medico-physiological and etho-psychological, is the key to quality of life and to successful work. The individual behavior in its optimal and positive meaning is the first link of the well-being and good-spirit of the crewmember within social contexts con-

The isolated and the confined crewmember observed using the ethological approach has demonstrated that confinement generates stress manifestations versus isolation; that isolation enhances social relationships versus confinement, and that the crew adapted positively to both environments [23]. From the individual in orbital flight to a small group inside confinement chambers or inside polar stations, research works need continued sharpening on adaptation of the human being on Earth to the human being in Space, period by period [24]. The main results from the research showed three adaptive periods: initial, mid and final periods over a 28-day Isolation Study of the European Manned Space Infrastructure (ISEMSI) campaign; over a 60-day Experimental Campaign for European Manned Space Infrastructure (EXEMSI); and over a 135-day Human Behavior in Extended Spaceflight (HUBES) campaign. In these limited habitats, the personal distances decreased and the public distances increased among the crewmembers. We observed high values of social distances and body mobility from the initial period to the final period. An increasing spatial dispersion with decreasing social orientations was also noted among the crew at the midpoint of the medium-term simulations [25]. Over a 520-day Mars-500 experiment, the crew simulated how to live and work together like a real mission with a 250-day Earth-Mars travel, a 30-day Mars landing, and a 240-day Mars-Earth travel. The results showed that time had a major impact on the individual and interindividual behaviors in terms of personal actions, visual interactions, object interactions, body interactions, facial expressions, and collateral acts. The crewmembers followed phasic, periodic, and punctual behavioral changes in extended periods of time, as it was observed at the Antarctic Concordia station and during the Artic Tara expedition, to avoid monotony. Be it space simulators or analogue settings provided by these extraterrestrial environments on Earth for going into Space (**Figure 6**), the behavioral adaptation is mainly related to social

Along with physical and mental health, the social behavior in terms of nonverbal interactions and verbal communications has become of new interest to investigate interplanetary missions from the perspective of multidisciplinary approaches. For instance, correlation of etho-social and psycho-social data during the simulated Mars-500 interplanetary mission aimed at identifying crewmembers' behavioral profiles for better understanding Space groups of future explorations. We found significant negative correlations between anxiety and interpersonal

strained by isolation and confinement once he/she has settled into Space.

36 Into Space - A Journey of How Humans Adapt and Live in Microgravity

interactions with an emphasis on visual interactions (**Figure 7**).

**3. Social behavior**

communications, and between the sociometric parameter "popularity in leisure environment" and anxiety level. We also found significant positive correlations between the sociometric parameter "popularity in working environment" and interpersonal communications, and facial expressions; and between the sociometric parameter "popularity in leisure environment" and interpersonal communications, and facial expressions. This highlighted complementary viewpoints in the field of life sciences and social sciences: objective versus subjective, active versus discursive, exhaustive versus restrictive, and descriptive versus introspective [26].

Crew relations also play important roles in the success of missions where crewmembers stay one year and beyond in isolation and confinement. Wireless monitoring of interactive behaviors correlated with individual questionnaires, and video analyses of collective activities showed that the amount of time spent together during free time is highly associated with the intensity of relationships [27].

**Figure 7.** Social interactions in isolation during a 506-day Tara-Artic expedition.

Interpersonal and organizational issues were already raised within the first long-duration stays onboard the orbital Mir station and onboard the International Space Station (ISS). Negative effects included low crew cohesion, poor leadership skills, and crew tension resulting from environmental stress and related to crew heterogeneity [22]. However, positive effects of group experience inside space habitats need to be highlighted. For instance, from the human point of view, being in Space along with being in microgravity are unique opportunities for evidence of Earth observation as a whole. It is actually a salutogenic experience, as reported by the ISS inhabitants [28]. Despite constraints of social monotony, social isolation, and social confinement, the crewmember can create distance from the crew by widening the vision of the surrounding to a faraway environment. According to the classification of Hall [29], there is a shift from a social space to a public space (120–360 cm ad infinitum). Salutogenis means that individuals who adapt positively to an inhospitable or extreme environment can derive benefit from their experience [30]. One example of positive coping strategy in dealing with the stress of being in Space is seeking social support, which is defined as effort to obtain sympathy, help, information, or emotional support from other persons [31]. It is a component of social behavior.

cultural background and mission goal. On one side, the French group-member (FR1) spent the longest time at meal as it is customary in daily life activities in a given country or region. On the other side, the Russian-Italian-Chinese group (RUS, IT1, and CH1) spent the shortest time at meal as a specific fact attributed to Martian crew versus Orbital crew (RU1, RU2, and FR1). The latter stayed on the Mars-orbit, while the new space group simulated planet landing and staying. These results suggest that if individual differences could generate conflicts within the group members, cultural differences could enhance cohesion of the group, with cultural behavior viewed as positive way to live and work together very far from mother

**Subject RU1 RU2 RU3 FR1 IT1 CH1** Mean (minutes) 23 22 14 25 16 16 Standard deviation ±6 ±7 ±5 ±6 ±8 ±6

From the Individual to the Cultural Space Group http://dx.doi.org/10.5772/intechopen.72357 39

**Table 1.** Collective activity duration in confinement during a 520-day Mars-500 experiment.

Constructing micro-society models for cultural space groups is thus relevant from an anthropological perspective. The "notion of space" holds a major place in field studies and has an obvious relation with the notion of culture [37]. This approach takes into account spatial relations as a central variable that influences the cultural behavior and the underlying cognitive process. In the history of humanity, there has been a revolution in cognitive capabilities and in learning skills that brought *Homo sapiens* from real to virtual integration [38]. In the future of space exploration, there will be an evolution of the human adaptability to autonomy that will bring *Homo spatius* to virtual integration of the surrounding world, thus avoiding etiological factors of the environment (isolation, confinement, monotony, etc.). We know that cooperation was a behavioral response of survival in the ancient civilizations and ethnicities [36]; equivalent responses might occur in future micro-societies and on remote planets, from surviving to adapting and then evolving. Hence, it is of prime importance to consider the

Consider a manned mission on Moon, under hypogravity (1/6 g). Life-support system, rover exploration, navigation innovation, and basic technologies have resulted in the highest readiness for the development of planetary habitats in the conception of a Lunar village [39]. After having walked on the lunar surface, living, and working on the Moon need to be considered. With that aim, test beds were performed in analogue environments with an emphasis on field investigations at the Mars Desert Research Station (MDRS) that examined, for instance, communications in multilingual crews. The international and mixed-gender composition of small Euro-Moon-Mars crews properly simulated the very next isolated and confined groups who would land on the planet. Ethological studies on language skills showed that verbal communications and nonverbal interactions were influenced by cultural background such as the mother tongue [40]. Crew-members using nonnative languages compensate with interaction abilities. With the evolving of daily life habits in Space and over time, some will actively interact, others will actively communicate, and the whole will progress in a common cultural

Earth and for a very long time away from family links.

cultural values of the space group [4].

behavior.

For interplanetary missions, selection criteria should include social compatibility. Then training should enhance interpersonal skills, leading to the best way of psychosocial adaptation in Space [32]. The crew's effectiveness and safety will be thus enhanced. Interpersonal interactions have gained attention in studies conducted on different groups in analogue space stations referred to as Lunar Palace 1 [33]. Significant individual differences were identified, as well as crew structure was a determinant, even with mononational crewmembers. Results showed that group climate was a good state for a successful mission. However, intercultural interactions are new aims to emphasize. Culturally related differences in values and behavioral norms could influence cohesive group formation [34]. Multinational crews become cultural space groups on a long-duration process by sharing values from their individual experiences and perceptions of different terrestrial regions.

### **4. Cultural behavior**

Small groups of three to six members, mixed-gender and multicultural compositions would be core features of terrestrials gathered for deep space exploration. Such a group is a dynamic organization where all the forces are in equilibrium and regulated to obtain optimal efficiency structures [35]. The rules of adaptive dynamics of an isolated and confined crew could thus be compared to the laws governing self-organizing systems. These laws are based on the heterogeneity of their own elements. International composition is the first characteristic that may have an impact on the cultural behavior for building adaptive strategies. Also, gender composition is an element of heterogeneous organization and helps in mitigating the interpersonal conflicts for developing cooperative strategies [36]. This leads to new goals of investigations into intercultural relations with an emphasis on use of space, use of language, and use of time. The analysis of mean durations of collective activity, while free grouping at meal times during the Mars-500 experiment (**Table 1**), showed significant differences regarding


**Table 1.** Collective activity duration in confinement during a 520-day Mars-500 experiment.

Interpersonal and organizational issues were already raised within the first long-duration stays onboard the orbital Mir station and onboard the International Space Station (ISS). Negative effects included low crew cohesion, poor leadership skills, and crew tension resulting from environmental stress and related to crew heterogeneity [22]. However, positive effects of group experience inside space habitats need to be highlighted. For instance, from the human point of view, being in Space along with being in microgravity are unique opportunities for evidence of Earth observation as a whole. It is actually a salutogenic experience, as reported by the ISS inhabitants [28]. Despite constraints of social monotony, social isolation, and social confinement, the crewmember can create distance from the crew by widening the vision of the surrounding to a faraway environment. According to the classification of Hall [29], there is a shift from a social space to a public space (120–360 cm ad infinitum). Salutogenis means that individuals who adapt positively to an inhospitable or extreme environment can derive benefit from their experience [30]. One example of positive coping strategy in dealing with the stress of being in Space is seeking social support, which is defined as effort to obtain sympathy, help, information, or emotional support from other persons [31]. It

For interplanetary missions, selection criteria should include social compatibility. Then training should enhance interpersonal skills, leading to the best way of psychosocial adaptation in Space [32]. The crew's effectiveness and safety will be thus enhanced. Interpersonal interactions have gained attention in studies conducted on different groups in analogue space stations referred to as Lunar Palace 1 [33]. Significant individual differences were identified, as well as crew structure was a determinant, even with mononational crewmembers. Results showed that group climate was a good state for a successful mission. However, intercultural interactions are new aims to emphasize. Culturally related differences in values and behavioral norms could influence cohesive group formation [34]. Multinational crews become cultural space groups on a long-duration process by sharing values from their individual

Small groups of three to six members, mixed-gender and multicultural compositions would be core features of terrestrials gathered for deep space exploration. Such a group is a dynamic organization where all the forces are in equilibrium and regulated to obtain optimal efficiency structures [35]. The rules of adaptive dynamics of an isolated and confined crew could thus be compared to the laws governing self-organizing systems. These laws are based on the heterogeneity of their own elements. International composition is the first characteristic that may have an impact on the cultural behavior for building adaptive strategies. Also, gender composition is an element of heterogeneous organization and helps in mitigating the interpersonal conflicts for developing cooperative strategies [36]. This leads to new goals of investigations into intercultural relations with an emphasis on use of space, use of language, and use of time. The analysis of mean durations of collective activity, while free grouping at meal times during the Mars-500 experiment (**Table 1**), showed significant differences regarding

is a component of social behavior.

38 Into Space - A Journey of How Humans Adapt and Live in Microgravity

**4. Cultural behavior**

experiences and perceptions of different terrestrial regions.

cultural background and mission goal. On one side, the French group-member (FR1) spent the longest time at meal as it is customary in daily life activities in a given country or region. On the other side, the Russian-Italian-Chinese group (RUS, IT1, and CH1) spent the shortest time at meal as a specific fact attributed to Martian crew versus Orbital crew (RU1, RU2, and FR1). The latter stayed on the Mars-orbit, while the new space group simulated planet landing and staying. These results suggest that if individual differences could generate conflicts within the group members, cultural differences could enhance cohesion of the group, with cultural behavior viewed as positive way to live and work together very far from mother Earth and for a very long time away from family links.

Constructing micro-society models for cultural space groups is thus relevant from an anthropological perspective. The "notion of space" holds a major place in field studies and has an obvious relation with the notion of culture [37]. This approach takes into account spatial relations as a central variable that influences the cultural behavior and the underlying cognitive process. In the history of humanity, there has been a revolution in cognitive capabilities and in learning skills that brought *Homo sapiens* from real to virtual integration [38]. In the future of space exploration, there will be an evolution of the human adaptability to autonomy that will bring *Homo spatius* to virtual integration of the surrounding world, thus avoiding etiological factors of the environment (isolation, confinement, monotony, etc.). We know that cooperation was a behavioral response of survival in the ancient civilizations and ethnicities [36]; equivalent responses might occur in future micro-societies and on remote planets, from surviving to adapting and then evolving. Hence, it is of prime importance to consider the cultural values of the space group [4].

Consider a manned mission on Moon, under hypogravity (1/6 g). Life-support system, rover exploration, navigation innovation, and basic technologies have resulted in the highest readiness for the development of planetary habitats in the conception of a Lunar village [39]. After having walked on the lunar surface, living, and working on the Moon need to be considered. With that aim, test beds were performed in analogue environments with an emphasis on field investigations at the Mars Desert Research Station (MDRS) that examined, for instance, communications in multilingual crews. The international and mixed-gender composition of small Euro-Moon-Mars crews properly simulated the very next isolated and confined groups who would land on the planet. Ethological studies on language skills showed that verbal communications and nonverbal interactions were influenced by cultural background such as the mother tongue [40]. Crew-members using nonnative languages compensate with interaction abilities. With the evolving of daily life habits in Space and over time, some will actively interact, others will actively communicate, and the whole will progress in a common cultural behavior.

Consider a manned mission to Mars, under reduced gravity (1/3 g). In addition to key technologies and habitat designs, communication time to Earth is delayed by 20 min. Autonomy and auto-organization of the cultural space group become crucial. In case of lack of contact with mother Earth, in actual isolation, it is also crucial to break the monotony and to find new centers of interest within the group. A personal account of the Mars-500 experiment said that multiculture was seen as an advantage rather than a disadvantage because the crew attempted to understand each other and looked for new knowledge accumulated by every crewmember from their own living and working experiences [41]. It is important to take into account the need of rituals. In African villages, for instance, far from any civilization, there are small ethnic groups defined by their customary dwellings in small living places and in grouped huts to promote exchanges. Cultural behavior is associated with a region as well as a nation. In a Mars village, rituals of the inhabitants should be invented.

Considering the early humans, the evolutionary context began with the genus *Homo*. Originating in Africa, *Homo* dispersed widely across the terrestrial globe and was exposed to biological changes but more importantly influenced by culture, upon development of complex behaviors including advances in technology [42].

**Acknowledgements**

ethological studies.

**Author details**

Carole Tafforin

**References**

949-956

Ethospace, Toulouse, France

Address all correspondence to: ethospace@orange.fr

**Figure 8.** Adaptation scenario of the crews' behavior in Space.

October 2016; Guadalajara, Mexico. IAC-16.A1.2.6

behavior. Acta Astronautica. 2017;**139**:102-110

The author thanks the French Space Agency for its scientific and financial support in the entire

From the Individual to the Cultural Space Group http://dx.doi.org/10.5772/intechopen.72357 41

[1] Schlacht IL, Rittweger J, Foing B, Masali M, Daumer M, Cremasco MM. How measurements from hypogravity locomotion studies can inform the architectural design of planetery habitats. In: Proceedings of the 67th International Astronautical Conference;

[2] Beysens DA, Van Loon JWA. editors. Generation and Applications of Extra-Terrestrial

[3] Tafforin C, Thon B, Guell A, Campan R. Astronaut behavior in orbital flight situation: Preliminary ethological analysis. Aviation, Space and Environmental Medicine. 1989;**60**:

[4] Tafforin C, Giner Abati F. Cultural ethology as a new approach of interplanetary crew's

Environments on Earth. Aalborg, Denmark: River Publishers; 2015. 281 p

The discussion is open. Human nature would develop further with interplanetary humanization and Space colonization, beginning with physical evolution and extending over cultural evolution.

## **5. Conclusion**

In future research, the adaptation strategy of each spationaut and of the whole space group will be shown as a multisystem integration, from survivability factors (cardio-vascular deconditioning, hormone regulation, immune response, radiation reaction) to adaptability factors (motor behavior, cognitive demand, social interactions, verbal communications, cultural profiles, living habits). The main interest of transdisciplinary approaches is to investigate synergetic effects of the multiple determinants involved in human well-being, as positive facts, from the medical, physiological, psychological, sociological, anthropological, and ethological viewpoints. This would contribute in preventing negative environmental impacts on future interplanetary missions.

Once the space traveler reaches the Moon, Mars, or beyond, who will he or she be? They will definitively be an interactive man or woman, with their own social rules and cultural habits. He or she will have their individual identity and they will be as a group entity, by building the same language code and communication rules based on multinationalities.

From an individual behavior with new body orientations in microgravity, a social behavior with specific interactions and interindividual distances in confinement, to a cultural behavior with proper rules of communications within the space group after separation for a long time (**Figure 8**), we may draw an adaptive scenario of human crew in Space.

**Figure 8.** Adaptation scenario of the crews' behavior in Space.

### **Acknowledgements**

Consider a manned mission to Mars, under reduced gravity (1/3 g). In addition to key technologies and habitat designs, communication time to Earth is delayed by 20 min. Autonomy and auto-organization of the cultural space group become crucial. In case of lack of contact with mother Earth, in actual isolation, it is also crucial to break the monotony and to find new centers of interest within the group. A personal account of the Mars-500 experiment said that multiculture was seen as an advantage rather than a disadvantage because the crew attempted to understand each other and looked for new knowledge accumulated by every crewmember from their own living and working experiences [41]. It is important to take into account the need of rituals. In African villages, for instance, far from any civilization, there are small ethnic groups defined by their customary dwellings in small living places and in grouped huts to promote exchanges. Cultural behavior is associated with a region as well as a nation. In a Mars village, rituals of the

Considering the early humans, the evolutionary context began with the genus *Homo*. Originating in Africa, *Homo* dispersed widely across the terrestrial globe and was exposed to biological changes but more importantly influenced by culture, upon development of com-

The discussion is open. Human nature would develop further with interplanetary humanization and Space colonization, beginning with physical evolution and extending over cultural

In future research, the adaptation strategy of each spationaut and of the whole space group will be shown as a multisystem integration, from survivability factors (cardio-vascular deconditioning, hormone regulation, immune response, radiation reaction) to adaptability factors (motor behavior, cognitive demand, social interactions, verbal communications, cultural profiles, living habits). The main interest of transdisciplinary approaches is to investigate synergetic effects of the multiple determinants involved in human well-being, as positive facts, from the medical, physiological, psychological, sociological, anthropological, and ethological viewpoints. This would contribute in preventing negative environmental impacts on future

Once the space traveler reaches the Moon, Mars, or beyond, who will he or she be? They will definitively be an interactive man or woman, with their own social rules and cultural habits. He or she will have their individual identity and they will be as a group entity, by building the

From an individual behavior with new body orientations in microgravity, a social behavior with specific interactions and interindividual distances in confinement, to a cultural behavior with proper rules of communications within the space group after separation for a long time

same language code and communication rules based on multinationalities.

(**Figure 8**), we may draw an adaptive scenario of human crew in Space.

inhabitants should be invented.

evolution.

**5. Conclusion**

interplanetary missions.

plex behaviors including advances in technology [42].

40 Into Space - A Journey of How Humans Adapt and Live in Microgravity

The author thanks the French Space Agency for its scientific and financial support in the entire ethological studies.

### **Author details**

Carole Tafforin

Address all correspondence to: ethospace@orange.fr

Ethospace, Toulouse, France

### **References**


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**Chapter 4**

**Provisional chapter**

**Acute and Chronic Effects of Hypobaric Exposure upon**

**Acute and Chronic Effects of Hypobaric Exposure upon** 

Exposure to the hypobaric environment presents numerous physiological challenges to both aviators/pilots, mountain climbers and astronauts. Decompression sickness (DCS) is one of the most commonly experienced maladies and may present variably in protean fashion from mild symptoms such as the bends to severe neurological or pulmonary (i.e. chokes) symptomatology. Furthermore, exposure to extreme non-hypoxic hypobaric environments such as those experienced by our U-2 pilots, irrespective of clinical history of decompression sickness, incites development of white matter hyperintensity lesions that are diffuse in nature. Additionally, non-hypoxic hypobaric exposure also impacts white matter integrity independent of presence of white matter hyperintensities as measured by fractional anisotropy. Functionally, this translated into subtle but significantly lower neurocognitive test performance in U-2 pilots exposed to extreme non-hypoxic hypobaric conditions when compared to pilots without repeated exposure and correlated with degree of white matter lesion burden. In this chapter, we discuss results of our U-2 pilot studies along with published research on high-altitude climbers. We also review ongoing and future directional research and discuss operational implications due to our findings of non-hypoxic hypobaric exposure. Lastly, we examine the incidence of DCS in our astronaut population as well as the risks of performing extra-

> © 2016 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution,

© 2018 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use,

distribution, and reproduction in any medium, provided the original work is properly cited.

and reproduction in any medium, provided the original work is properly cited.

**Keywords:** decompression sickness, hypobaria, MRI, U-2 pilots, astronauts, extravehicular activity, white matter hyperintensities, fractional anisotropy, acute

DOI: 10.5772/intechopen.74231

**the Brain**

**Abstract**

**the Brain**

Paul Sherman and John Sladky

Paul Sherman and John Sladky

http://dx.doi.org/10.5772/intechopen.74231

vehicular activity (EVA).

mountain sickness, military free fall operations

Additional information is available at the end of the chapter

Additional information is available at the end of the chapter


#### **Acute and Chronic Effects of Hypobaric Exposure upon the Brain Acute and Chronic Effects of Hypobaric Exposure upon the Brain**

DOI: 10.5772/intechopen.74231

Paul Sherman and John Sladky Paul Sherman and John Sladky

Additional information is available at the end of the chapter Additional information is available at the end of the chapter

http://dx.doi.org/10.5772/intechopen.74231

#### **Abstract**

[36] Giner AF. Raices Biológicas del Comportamiento Agresivo en el Hombre. Salamanca,

[38] Harari YN. Sapiens. Une brève histoire d'humanité. Paris, France: Alban Michel; 2015.

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[41] Urbina D, Charles R. Symposium keynote: Enduring the isolation of interplanetary travel. A personal account of the Mars500 mission. Acta Astronautica. 2014;**93**:374-383

[42] Smith C. An adaptive paradigm for human space settlement. Acta Astronautica.

[37] Kokot W. Culture and space: Anthropological approaches. Ethnoscripts. 2007;**9**:10-23

Spain: Universidad de Salamanca; 2015

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Guadalajara, Mexico. IAC-16.A3.3.2

Journal of Anthropology. 2016;**12**:97-109

499 p

2016;**119**:207-217

Exposure to the hypobaric environment presents numerous physiological challenges to both aviators/pilots, mountain climbers and astronauts. Decompression sickness (DCS) is one of the most commonly experienced maladies and may present variably in protean fashion from mild symptoms such as the bends to severe neurological or pulmonary (i.e. chokes) symptomatology. Furthermore, exposure to extreme non-hypoxic hypobaric environments such as those experienced by our U-2 pilots, irrespective of clinical history of decompression sickness, incites development of white matter hyperintensity lesions that are diffuse in nature. Additionally, non-hypoxic hypobaric exposure also impacts white matter integrity independent of presence of white matter hyperintensities as measured by fractional anisotropy. Functionally, this translated into subtle but significantly lower neurocognitive test performance in U-2 pilots exposed to extreme non-hypoxic hypobaric conditions when compared to pilots without repeated exposure and correlated with degree of white matter lesion burden. In this chapter, we discuss results of our U-2 pilot studies along with published research on high-altitude climbers. We also review ongoing and future directional research and discuss operational implications due to our findings of non-hypoxic hypobaric exposure. Lastly, we examine the incidence of DCS in our astronaut population as well as the risks of performing extravehicular activity (EVA).

**Keywords:** decompression sickness, hypobaria, MRI, U-2 pilots, astronauts, extravehicular activity, white matter hyperintensities, fractional anisotropy, acute mountain sickness, military free fall operations

© 2016 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. © 2018 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

### **1. Introduction**

Normoxic hypobaric (low atmospheric pressure) exposure, such as experienced by U.S. Air Force (USAF) U-2 pilots, and inside safety personnel operating altitude chambers (low pressure chambers), is associated with increased subcortical white matter hyperintensity (WMH) burden [1, 2]. Astronauts conducting extravehicular activity (EVA), also known as "space walks," are exposed to a hypobaric environment similar to U-2 pilots. WMHs are regions of accumulation of extra-cellular water due to focal degradation of the myelin sheath [3], and the volume of WMHs is a non-specific marker of cerebral integrity sensitive to multiple etiologies [4]. Repetitive normoxic hypobaric exposure is associated with a decrease in axonal integrity as quantified by global decrease in Fractional Anisotropy (FA) using diffusion tensor imaging (DTI) technique in magnetic resonance imaging (MRI) [5]. Further, this decrease in axonal integrity and increased subcortical WMH burden are associated with a decrement in neurocognitive function [6]. A small convenience sample of astronaut brain MRI data suggests similar WMH change to U2 pilots [7], although the astronaut group was an average of 9 years older. The neuropathophysiological mechanism for decreased axonal integrity and formation of WMHs related to decompressive stress is poorly understood and ongoing human and animal studies are addressing this operational concern. The long-term ramifications of repeated hypobaric exposure are uncertain, but are relevant to current United States Air Force (USAF) military operations and deep space mission plans with frequent EVAs.

decompression. The current pressure suit is designed to automatically inflate in the event of any cabin decompression or bailout to maintain a physiological pressure equivalent of 35,000 feet (10,668 m) or less. U-2 pilots routinely fly operational sorties lasting 8–11 h every 3–4 days. This prolonged hypobaric exposure subjects U-2 pilots to high risk for decompression sickness (DCS). Altitude DCS generally occurs in individuals exposed to a cabin pressure equivalent to 18,000 feet (5486 m) or higher [15]. Pilots can voluntarily inflate the suit during flight to lower DCS risk or to reduce any DCS symptoms they are experiencing. To mitigate risk of DCS, U-2 pilots also undergo a standard denitrogenation ("prebreathing") procedure by breathing 100% oxygen for 60 min before flight. Prebreathing establishes an oxygen gradient to offload nitrogen from tissues to the blood, thereby decreasing nitrogen stored in the body. This prebreathe has been proven highly beneficial in reducing the incidence and delaying the onset of DCS [16]. In 2010 a 10-min exercise-enhanced pre-breathing (EEP) period was added to the standard 60-min resting prebreathe prior to any high-altitude sortie. This further enhances the denitrogenation process and, therefore, may further lower the risk of DCS for the U-2 pilot population [17]. During flight, the pilots breathe 100% oxygen provided by a

Acute and Chronic Effects of Hypobaric Exposure upon the Brain

http://dx.doi.org/10.5772/intechopen.74231

47

Low-pressure chamber inside safety monitors undergo routine exposure to 25,000 feet (7620 m) for approximately 30 min per training flight, with total time above 18,000 feet (5246 m) not exceeding 60 min. Exposure frequency is variable but generally not more often than every third day, although occasionally mission demands require every other day exposure. The flight profile includes a 30-min denitrogenation period on 100% oxygen and the monitor remains on oxygen (never experiences hypoxia) for the duration of the flight (see

Altitude chamber inside observers experience a similar hypobaric environment to U-2 pilots

Following the creation of the first vacuum pump circa 1670, Robert Boyle first noted the formation of numerous gas bubbles in his animals exposed to the reduced atmospheric pressures of the pump [18]. However, it was not until 1862 when the first human episode of DCS was recorded by Paul Bert in his hot air balloon. Bert documented his experience of transient left arm flaccid paralysis that occurred following rapid ascent (305 m/min) to 29,000 feet (8838 m) which resolved following his return to surface [19]. Both hypobaric and hyperbaric exposures can result in decompression sickness (DCS) and neurologic DCS (NDCS). Each of these dysbaric environmental exposures share similar clinical and pathophysiological features, but there are inherent differences to both. One of the fundamental differences is the time of onset; in a hypobaric environment (aviators and astronauts), the symptoms occur during the exposure to a low atmospheric pressure. Conversely, following hyperbaric exposure (divers), the symptoms typically occur after the exposure with majority occurring within 24 h. Furthermore, the pathophysiology is felt to be different as arterial gas embolism occurs primarily during hyperbaric exposure and rarely during hypobaric exposure. Furthermore, the spinal cord is more

at a much shorter duration and without increased radiation exposure risk.

separate dedicated life support system.

**2.1. DCS physiology**

**Figure 1** below, Air Force Instruction [AFI] 11-403).

WMHs have also been demonstrated in high-altitude mountain climbers [8, 9]. Extreme mountain climbers have demonstrated transient white matter volume change and diffusion tensor imaging (DTI) changes [10, 11]. WMHs have also been demonstrated in other dysbaric environments such as occupational and recreational diving [12, 13]. Results of a meta-analysis of experienced, healthy divers, without a history of neurological DCS, suggest that repeated hyperbaric exposure increases the prevalence of WMHs [14]. Divers included military, commercial and recreational divers, caisson workers, and hyperbaric chamber attendants. It is unknown if WMHs associated with diving or altitude exposure behave in a similar fashion.

### **2. Background**

The U-2S Dragon Lady is a high-altitude military reconnaissance aircraft capable of flying at altitudes over 70,000 feet (21,336 m) for up to 15 h. The U-2 has performed high altitude reconnaissance operations for nearly 60 years and remains heavily utilized by the USAF today. The cabin pressurization system exposes U-2 pilots to cabin pressures equivalent to 29,500 feet (8992 m), approximately the altitude on the summit of Mount Everest. The aircraft was designed with a partially pressurized cabin to save weight and thereby increase attainable altitude. Pilots are required to wear a full pressure suit in case of unexpected cabin decompression. The current pressure suit is designed to automatically inflate in the event of any cabin decompression or bailout to maintain a physiological pressure equivalent of 35,000 feet (10,668 m) or less. U-2 pilots routinely fly operational sorties lasting 8–11 h every 3–4 days. This prolonged hypobaric exposure subjects U-2 pilots to high risk for decompression sickness (DCS). Altitude DCS generally occurs in individuals exposed to a cabin pressure equivalent to 18,000 feet (5486 m) or higher [15]. Pilots can voluntarily inflate the suit during flight to lower DCS risk or to reduce any DCS symptoms they are experiencing. To mitigate risk of DCS, U-2 pilots also undergo a standard denitrogenation ("prebreathing") procedure by breathing 100% oxygen for 60 min before flight. Prebreathing establishes an oxygen gradient to offload nitrogen from tissues to the blood, thereby decreasing nitrogen stored in the body. This prebreathe has been proven highly beneficial in reducing the incidence and delaying the onset of DCS [16]. In 2010 a 10-min exercise-enhanced pre-breathing (EEP) period was added to the standard 60-min resting prebreathe prior to any high-altitude sortie. This further enhances the denitrogenation process and, therefore, may further lower the risk of DCS for the U-2 pilot population [17]. During flight, the pilots breathe 100% oxygen provided by a separate dedicated life support system.

Low-pressure chamber inside safety monitors undergo routine exposure to 25,000 feet (7620 m) for approximately 30 min per training flight, with total time above 18,000 feet (5246 m) not exceeding 60 min. Exposure frequency is variable but generally not more often than every third day, although occasionally mission demands require every other day exposure. The flight profile includes a 30-min denitrogenation period on 100% oxygen and the monitor remains on oxygen (never experiences hypoxia) for the duration of the flight (see **Figure 1** below, Air Force Instruction [AFI] 11-403).

Altitude chamber inside observers experience a similar hypobaric environment to U-2 pilots at a much shorter duration and without increased radiation exposure risk.

#### **2.1. DCS physiology**

**1. Introduction**

46 Into Space - A Journey of How Humans Adapt and Live in Microgravity

sion plans with frequent EVAs.

behave in a similar fashion.

**2. Background**

Normoxic hypobaric (low atmospheric pressure) exposure, such as experienced by U.S. Air Force (USAF) U-2 pilots, and inside safety personnel operating altitude chambers (low pressure chambers), is associated with increased subcortical white matter hyperintensity (WMH) burden [1, 2]. Astronauts conducting extravehicular activity (EVA), also known as "space walks," are exposed to a hypobaric environment similar to U-2 pilots. WMHs are regions of accumulation of extra-cellular water due to focal degradation of the myelin sheath [3], and the volume of WMHs is a non-specific marker of cerebral integrity sensitive to multiple etiologies [4]. Repetitive normoxic hypobaric exposure is associated with a decrease in axonal integrity as quantified by global decrease in Fractional Anisotropy (FA) using diffusion tensor imaging (DTI) technique in magnetic resonance imaging (MRI) [5]. Further, this decrease in axonal integrity and increased subcortical WMH burden are associated with a decrement in neurocognitive function [6]. A small convenience sample of astronaut brain MRI data suggests similar WMH change to U2 pilots [7], although the astronaut group was an average of 9 years older. The neuropathophysiological mechanism for decreased axonal integrity and formation of WMHs related to decompressive stress is poorly understood and ongoing human and animal studies are addressing this operational concern. The long-term ramifications of repeated hypobaric exposure are uncertain, but are relevant to current United States Air Force (USAF) military operations and deep space mis-

WMHs have also been demonstrated in high-altitude mountain climbers [8, 9]. Extreme mountain climbers have demonstrated transient white matter volume change and diffusion tensor imaging (DTI) changes [10, 11]. WMHs have also been demonstrated in other dysbaric environments such as occupational and recreational diving [12, 13]. Results of a meta-analysis of experienced, healthy divers, without a history of neurological DCS, suggest that repeated hyperbaric exposure increases the prevalence of WMHs [14]. Divers included military, commercial and recreational divers, caisson workers, and hyperbaric chamber attendants. It is unknown if WMHs associated with diving or altitude exposure

The U-2S Dragon Lady is a high-altitude military reconnaissance aircraft capable of flying at altitudes over 70,000 feet (21,336 m) for up to 15 h. The U-2 has performed high altitude reconnaissance operations for nearly 60 years and remains heavily utilized by the USAF today. The cabin pressurization system exposes U-2 pilots to cabin pressures equivalent to 29,500 feet (8992 m), approximately the altitude on the summit of Mount Everest. The aircraft was designed with a partially pressurized cabin to save weight and thereby increase attainable altitude. Pilots are required to wear a full pressure suit in case of unexpected cabin Following the creation of the first vacuum pump circa 1670, Robert Boyle first noted the formation of numerous gas bubbles in his animals exposed to the reduced atmospheric pressures of the pump [18]. However, it was not until 1862 when the first human episode of DCS was recorded by Paul Bert in his hot air balloon. Bert documented his experience of transient left arm flaccid paralysis that occurred following rapid ascent (305 m/min) to 29,000 feet (8838 m) which resolved following his return to surface [19]. Both hypobaric and hyperbaric exposures can result in decompression sickness (DCS) and neurologic DCS (NDCS). Each of these dysbaric environmental exposures share similar clinical and pathophysiological features, but there are inherent differences to both. One of the fundamental differences is the time of onset; in a hypobaric environment (aviators and astronauts), the symptoms occur during the exposure to a low atmospheric pressure. Conversely, following hyperbaric exposure (divers), the symptoms typically occur after the exposure with majority occurring within 24 h. Furthermore, the pathophysiology is felt to be different as arterial gas embolism occurs primarily during hyperbaric exposure and rarely during hypobaric exposure. Furthermore, the spinal cord is more

second condition is the development of a gas bubble from the presence of bubble nuclei from the supersaturated tissue. This typically occurs when the decompression rate of the ambient pressure exceeds the rate of inert gas wash-out from the tissues. During diving, caisson work or operation in a compressed air tunnel, supersaturation results due to increase in inert gas partial pressure in the tissues as a direct result of inspiring the air at high pressures. Hypobaric conditions such as aviation or extravehicular activity (EVA) in space predispose to supersaturation of pre-existing dissolved nitrogen at sea level (~570 mm Hg) which can then form bubbles when exposed to reduced barometric pressure. Gas supersaturation in the tissue can be mitigated with phase transition. The issue with DCS is when a gas space arises due to partial or complete desaturation of a pocket of supersaturated tissue. This sets up a pressure difference or "deformation pressure" within the tissue [22]. It is the pressure difference and not necessarily the volume of gas involved which causes the pain observed in

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Formation of bubbles can result in direct mechanical, embolic and even biochemical effects and the results can range from trivial to fatal. The bubbles can result in mechanical distortion of tissues resulting in pain or may occlude vascular structures resulting in stroke-like signs and symptoms. There are three potential sources of microemboli: (1) micro-bubbles of gas; presumably nitrogen; (2) small thrombi secondary to platelet activation and deposition; (3) microparticles. Other effects also include endothelial injury resulting in leakage of plasma and increased leukocyte endothelial adhesion. The classic symptoms of DCS including joint pain, paresthesias and skin changes are thought to be secondary to either direct pressure of the gas bubble on the tissue itself, blockage of small arteriolar vessels, and/or interaction with serological proteins [20]. While echo imaging has shown the presence of venous gas emboli in tissues [23], the presence of arterial gas emboli is quite uncommon, reported in only 6 of more than 1500 altitude chamber exposure cases [24]. Occlusion of small cerebral vessels by activated platelets due to accelerated coagulation in the presence of venous nitrogen gas bubbles was demonstrated in both medium and large-sized arteries in mice after DCS and therefore remains another possibility for the development

Signs and symptoms of decompression (DCS) are protean and range from mild to severe including death. Historically DCS has classically been divided into arterial embolism, Type I, Type II and skin bends. However, due to inconsistencies in applying this classification system, it has largely been replaced by the all-inclusive term decompression illness (DCI) and based on system involvement. For consistency, we will keep with the prior classification system. Type 1 is typically referred to as "pain only" DCS symptoms or the "bends" with localized pain in the joints (lower extremities; particularly knee involvement) and may be accompanied by cutaneous manifestations (pruritus and mottling) and constitutional symptoms. Type II symptoms are systemic and more severe and generally involve both the central nervous

pain-only DCS.

of WMH [25].

**2.2. Signs and symptoms of DCS**

**Figure 1.** AFI 11-403; Nov 30, 2012. Initial altitude chamber flight profile with rapid decompression.

preferentially affected and vulnerable during hyperbaric exposure [20]. Arterial gas embolism (AGE) arises as expanding gas ruptures alveolar capillaries allowing the entry of alveolar gas into the arterial circulation. Venous gas emboli (VGE) in small quantities are common in diving but are typically asymptomatic as they are effectively filtered by the lung. However, VGE is not a desired condition and in large quantities can cause cough, dyspnea, substernal chest pain, pulmonary edema (referred to as the "chokes") and further cardiorespiratory distress. The presence of a patent foramen ovale (PFO) or other right-to-left shunt can cause the VGE to enter the arterial circulation. The incidence of PFO is approximately 25% in the general population [21].

There are two conditions requisite for development of DCS. The first requires the supersaturation of an inert gas in the surrounding tissue. Supersaturation is defined simply as the partial pressure of the inert gas is greater than the surrounding ambient pressure. The second condition is the development of a gas bubble from the presence of bubble nuclei from the supersaturated tissue. This typically occurs when the decompression rate of the ambient pressure exceeds the rate of inert gas wash-out from the tissues. During diving, caisson work or operation in a compressed air tunnel, supersaturation results due to increase in inert gas partial pressure in the tissues as a direct result of inspiring the air at high pressures. Hypobaric conditions such as aviation or extravehicular activity (EVA) in space predispose to supersaturation of pre-existing dissolved nitrogen at sea level (~570 mm Hg) which can then form bubbles when exposed to reduced barometric pressure. Gas supersaturation in the tissue can be mitigated with phase transition. The issue with DCS is when a gas space arises due to partial or complete desaturation of a pocket of supersaturated tissue. This sets up a pressure difference or "deformation pressure" within the tissue [22]. It is the pressure difference and not necessarily the volume of gas involved which causes the pain observed in pain-only DCS.

Formation of bubbles can result in direct mechanical, embolic and even biochemical effects and the results can range from trivial to fatal. The bubbles can result in mechanical distortion of tissues resulting in pain or may occlude vascular structures resulting in stroke-like signs and symptoms. There are three potential sources of microemboli: (1) micro-bubbles of gas; presumably nitrogen; (2) small thrombi secondary to platelet activation and deposition; (3) microparticles. Other effects also include endothelial injury resulting in leakage of plasma and increased leukocyte endothelial adhesion. The classic symptoms of DCS including joint pain, paresthesias and skin changes are thought to be secondary to either direct pressure of the gas bubble on the tissue itself, blockage of small arteriolar vessels, and/or interaction with serological proteins [20]. While echo imaging has shown the presence of venous gas emboli in tissues [23], the presence of arterial gas emboli is quite uncommon, reported in only 6 of more than 1500 altitude chamber exposure cases [24]. Occlusion of small cerebral vessels by activated platelets due to accelerated coagulation in the presence of venous nitrogen gas bubbles was demonstrated in both medium and large-sized arteries in mice after DCS and therefore remains another possibility for the development of WMH [25].

#### **2.2. Signs and symptoms of DCS**

preferentially affected and vulnerable during hyperbaric exposure [20]. Arterial gas embolism (AGE) arises as expanding gas ruptures alveolar capillaries allowing the entry of alveolar gas into the arterial circulation. Venous gas emboli (VGE) in small quantities are common in diving but are typically asymptomatic as they are effectively filtered by the lung. However, VGE is not a desired condition and in large quantities can cause cough, dyspnea, substernal chest pain, pulmonary edema (referred to as the "chokes") and further cardiorespiratory distress. The presence of a patent foramen ovale (PFO) or other right-to-left shunt can cause the VGE to enter the arterial circulation. The incidence of PFO is approximately 25% in the

**Figure 1.** AFI 11-403; Nov 30, 2012. Initial altitude chamber flight profile with rapid decompression.

48 Into Space - A Journey of How Humans Adapt and Live in Microgravity

There are two conditions requisite for development of DCS. The first requires the supersaturation of an inert gas in the surrounding tissue. Supersaturation is defined simply as the partial pressure of the inert gas is greater than the surrounding ambient pressure. The

general population [21].

Signs and symptoms of decompression (DCS) are protean and range from mild to severe including death. Historically DCS has classically been divided into arterial embolism, Type I, Type II and skin bends. However, due to inconsistencies in applying this classification system, it has largely been replaced by the all-inclusive term decompression illness (DCI) and based on system involvement. For consistency, we will keep with the prior classification system. Type 1 is typically referred to as "pain only" DCS symptoms or the "bends" with localized pain in the joints (lower extremities; particularly knee involvement) and may be accompanied by cutaneous manifestations (pruritus and mottling) and constitutional symptoms. Type II symptoms are systemic and more severe and generally involve both the central nervous system and cardiopulmonary systems (see **Table 1** below). Skin bends refer to the marbled appearance of the skin whereas the characteristic rash of livedo reticularis (cutis marmorata) is a more severe form of skin bends and is nearly pathognomonic for decompression sickness in the appropriate clinical context [26]. In one prospective study that looked at 447 cases of DCS over an 11 year period at the Armstrong Laboratory, the most collective symptom was musculoskeletal in 83% of the cases of which knee pain was the most common. This was followed by paresthesias in 10.8%, chokes in 2.7%, cutaneous lesions in 2.2% and neurological deficits in 0.5% [27]. Neurological decompression sickness (NCDS) resulting from hypobaric exposure typically involves the brain more than spinal cord and may range from mild symptoms such as slowed thought processes to severe including confusion, aphasia, unresponsiveness and

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The USAF U-2 pilots are at considerable risk of development of DCS due to the extreme altitudes and long duration sorties. The risk of DCS is dependent on both the rapidity of ascent as well as the duration of exposure to altitude (typically defined as >18,000 feet) in a hypobaric environment. In a 1996 survey of 416 active/retired U-2 pilots (60% response rate), more than 75% of the pilots attested to DCS symptoms such as joint pain or skin manifestations. 12% of those surveyed cited at least one episode that was severe enough to abort or alter the profile of their mission [29]. The risk of DCS per flight increased from 0.076% pre-2006 to 0.23% during the 2006–2010 operation years [30]. Furthermore, 44% of episodes were diagnosed as NDCS including 5 life-threatening cases with symptoms ranging from mild, such as complaints of slowed thought processes to severe, including anomia, confusion, unresponsiveness, and cognitive decline. Neuropsychiatric symptoms persisted in 6 pilots which may represent permanent injury. This upsurge in NDCS was felt to be a consequence of more frequent and longer periods of flight/hypobaric exposure

Astronauts are also at risk for the development of DCS. Before the very first EVA (extravehicular activity) occurred, NASA realized that DCS was a risk to be mitigated. Earth-normal atmospheric pressure at sea level is 760 mm Hg (14.7 psia or 1ATA). The current NASA space-suit referred to as the EMU (extravehicular mobility unit) operates at 4.3 psia or 222 mm Hg above the vacuum of space whereas the Russian Orlan space-suit operates at 5.8 psia. Increasing the space-suit pressure or reducing cabin inert pressure are the two ways to reduce the pressure gradient differential between environments to help minimize risk of DCS. However, increasing suit pressure typically results in reduced operational capacity by the astronaut due to increased fatigue, reduced dexterity and mobility [26]. DCS is a known risk during EVA but complete elimination of DCS is practically impossible. Therefore, mitigation plans between USAF, United States Navy (USN), NASA and the academic research community were undertaken to define "acceptable risk." The current definition implemented by the International Space Station (ISS) protocols is the following: (1) DCS < 15%; (2) Grade IV VGE < 20%; (3) No

However, despite the above concerns of DCS, there have been no recorded cases of DCS among astronauts and cosmonauts during EVA's working in pressurized space-suits between 3.7 and 5.8 psia. This is in stark contrast to both Russian and American altitude chamber technicians who report symptoms or signs of DCS ~ 20–40% of the time [26, 31]. There are three possible explanations for this disparity: (1) Potential bias not to report symptoms; (2)

even permanent cognitive decline [28].

**2.3. Incidence of DCS in U-2 pilots**

for the pilots [28].

type II DCS.

**2.4. Incidence of DCS in astronauts**


**Table 1.** DCS signs and symptoms.

by paresthesias in 10.8%, chokes in 2.7%, cutaneous lesions in 2.2% and neurological deficits in 0.5% [27]. Neurological decompression sickness (NCDS) resulting from hypobaric exposure typically involves the brain more than spinal cord and may range from mild symptoms such as slowed thought processes to severe including confusion, aphasia, unresponsiveness and even permanent cognitive decline [28].

#### **2.3. Incidence of DCS in U-2 pilots**

**DCS classification Signs and symptoms Location of bubbles**

ing descent or even hours later

• Mottling (mild)

• Headache

abdomen • Ascending paralysis • Bowel/bladder incontinence

• Dry cough

• Pitting edema

Skin bends: cutis marmorata • Livedo reticularis rash

• Pain may often occur at altitude but may occur dur-

system and cardiopulmonary systems (see **Table 1** below). Skin bends refer to the marbled appearance of the skin whereas the characteristic rash of livedo reticularis (cutis marmorata) is a more severe form of skin bends and is nearly pathognomonic for decompression sickness in the appropriate clinical context [26]. In one prospective study that looked at 447 cases of DCS over an 11 year period at the Armstrong Laboratory, the most collective symptom was musculoskeletal in 83% of the cases of which knee pain was the most common. This was followed

• Formication (feeling of ants crawling on skin)

• Dysthesias and paresthesias around lower chest • Constriction pain/pressure around chest or

• Visual changes: diplopia, scotomas

• Seizures, vertigo, unconsciousness

• Fasciculations or muscle twitching

• Dyspnea (shortness of breath)

• Pain worsened with breathing • Deep burning chest pain

• Paresthesias/numbness

Large joints: • Elbows • Hips • Wrists • Shoulders

Skin

Brain

Spinal cord

Peripheral nerves

Lungs

Skin

**Type I:** "Pain-only"

"Bends" • Localized deep joint pain

50 Into Space - A Journey of How Humans Adapt and Live in Microgravity

Neurological • Confusion/memory loss

Mild skin changes • Pruritus

**Type II:** More severe systemic

Cardiopulmonary: aka

**Table 1.** DCS signs and symptoms.

"Chokes"

involvement

The USAF U-2 pilots are at considerable risk of development of DCS due to the extreme altitudes and long duration sorties. The risk of DCS is dependent on both the rapidity of ascent as well as the duration of exposure to altitude (typically defined as >18,000 feet) in a hypobaric environment. In a 1996 survey of 416 active/retired U-2 pilots (60% response rate), more than 75% of the pilots attested to DCS symptoms such as joint pain or skin manifestations. 12% of those surveyed cited at least one episode that was severe enough to abort or alter the profile of their mission [29]. The risk of DCS per flight increased from 0.076% pre-2006 to 0.23% during the 2006–2010 operation years [30]. Furthermore, 44% of episodes were diagnosed as NDCS including 5 life-threatening cases with symptoms ranging from mild, such as complaints of slowed thought processes to severe, including anomia, confusion, unresponsiveness, and cognitive decline. Neuropsychiatric symptoms persisted in 6 pilots which may represent permanent injury. This upsurge in NDCS was felt to be a consequence of more frequent and longer periods of flight/hypobaric exposure for the pilots [28].

#### **2.4. Incidence of DCS in astronauts**

Astronauts are also at risk for the development of DCS. Before the very first EVA (extravehicular activity) occurred, NASA realized that DCS was a risk to be mitigated. Earth-normal atmospheric pressure at sea level is 760 mm Hg (14.7 psia or 1ATA). The current NASA space-suit referred to as the EMU (extravehicular mobility unit) operates at 4.3 psia or 222 mm Hg above the vacuum of space whereas the Russian Orlan space-suit operates at 5.8 psia. Increasing the space-suit pressure or reducing cabin inert pressure are the two ways to reduce the pressure gradient differential between environments to help minimize risk of DCS. However, increasing suit pressure typically results in reduced operational capacity by the astronaut due to increased fatigue, reduced dexterity and mobility [26]. DCS is a known risk during EVA but complete elimination of DCS is practically impossible. Therefore, mitigation plans between USAF, United States Navy (USN), NASA and the academic research community were undertaken to define "acceptable risk." The current definition implemented by the International Space Station (ISS) protocols is the following: (1) DCS < 15%; (2) Grade IV VGE < 20%; (3) No type II DCS.

However, despite the above concerns of DCS, there have been no recorded cases of DCS among astronauts and cosmonauts during EVA's working in pressurized space-suits between 3.7 and 5.8 psia. This is in stark contrast to both Russian and American altitude chamber technicians who report symptoms or signs of DCS ~ 20–40% of the time [26, 31]. There are three possible explanations for this disparity: (1) Potential bias not to report symptoms; (2) Masked DCS symptoms; (3) Potential operational and gravitational benefits of the spaceflight environment.

element. The primary difference is the presence of hypoxia in AMS and HACE. AMS generally occurs above 2500 m and has been defined by the Lake Louise Consensus Group as the presence of a headache with one or more of the following: gastrointestinal symptoms (nausea, vomiting, anorexia), insomnia, dizziness and lassitude or fatigue [35]. Determining factors include the rate of ascent, altitude reached, altitude at which a person sleeps and individual physiology. Most consider HACE to be a clinical and pathophysiologic extension of AMS. HACE is an encephalopathy, characterized by disturbances of consciousness that may progress to coma, ataxic gait, increased intracranial pressure and retinal hemorrhages.

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A growing body of evidence suggests that is not only hypoxia, but hypobaria that contributes to the development of AMS [36–40]. The underlying pathophysiology of AMS remains poorly understood. Hypoxia-induced cerebral vasodilatation or its effectors, such as nitric oxide, may produce the headache, possibly via the trigeminovascular system or by causing mild cerebral edema [41–43]. Whether this edema is cytotoxic (intracellular), vasogenic (extracellular), or both remains controversial. However, MRI has demonstrated reversible abnormalities in HACE, such as areas of increased T2 and fluid-attenuated inversion recovery signal intensity within the splenium of the corpus callosum (white matter structure), with associated increased apparent diffusion coefficient (ADC) values consistent with increased water diffusivity. These findings are indicative of vasogenic edema. Hemodynamic factors such as sustained vasodilation, impaired cerebral autoregulation and elevated capillary pressure may contribute to vasogenic edema [44–47]. Hypoxia-induced biochemical alteration of the blood brain barrier may also be important. Current high altitude human research demonstrates increased cerebral blood flow after a single hypoxic hypobaric exposure to 7620 m for occupational training which persists at 72 h. These findings will be described in detail later

Central nervous system MRI changes demonstrated in AMS have similarity with recently published astronaut data. These include intracranial fluid redistribution, increased intracranial pressure in microgravity, and brain structural plasticity changes from pre-to-post space-

Our original U-2 pilot brain MRI evaluations were performed on a Siemens (Siemens AG, Erlangen, Germany) Magnetom Tim Trio 3-Tesla scanner at the Research Imaging Institute (RII), University of Texas Health Science Center San Antonio (UTHSCSA), with a 12-channel phased array coil. All subsequent human and animal MRI data has been acquired on the same Siemens Magnetom Verio 3-Tesla scanner at Wilford Hall Ambulatory Surgical Center (WHASC), Joint Base San Antonio, Texas using a 32-channel phased array coil. This includes all imaging on control/normal subjects and low-pressure chamber inside safety monitors. Both scanners are operated under quality control and assurance guidelines in accordance

Three-dimensional imaging parameters were for T1 magnetization prepared rapid acquisition gradient echo (MPRAGE), repetition time (TR) = 2200 ms, echo time (TE) = 2.85 ms, isotropic resolution = 0.80 mm, and for fluid-attenuated inversion recovery (FLAIR), TR = 4500 ms,

**2.6. Brain magnetic resonance imaging (MRI) techniques**

with recommendations by the American College of Radiology.

in this chapter.

flight [48–50].

Regarding the bias not to report, an EVA is considered the pinnacle of any astronaut's career and the willingness to divulge mild DCS symptoms such as pain that was not operationally limiting would be nominal. It is important to note that NASA's current policy states that any DCS symptom incurred by a crewmember or test subject who participate in hypobaric or hyperbaric operations needs to be reported [26]. It is known that under-reporting of DCS symptoms occurred in the U-2 pilot population as reporting of DCS symptoms during hypobaric operational training could lead to disqualification. This was discussed earlier in Bendrick's article on 275 U-2 pilots of whom 75% reported DCS symptoms via an anonymous questionnaire at least once in their career but rarely reported it to their Flight Surgeon [29]. Interestingly, Webb et al. in 1996 published an article citing an incidence of DCS in 77% of test-subjects undergoing the 60 min U-2 pre-breathing protocol [32]. This again highlights the disparity between operational vs. research reports of DCS and underscores that for numerous reasons, astronauts and pilots are not inclined to report every slight discomfort they experience.

However, in addition to under-reporting bias, there are valid reasons why mild symptoms of DCS may be masked during an EVA. Astronauts frequently take aspirin prior to any EVA to pre-emptively mitigate any aches or pain. In addition, the actual operation of the EMU spacesuit that the astronaut dons can be painful. It would be near difficult for an astronaut to discern pain from "pain-only" DCS vs. the natural discomfort incurred from working within the confines of the EMU. Furthermore, as most "pain-only" DCS symptoms resolve following re-pressurization after completion of the EVA, there is no driving force for astronauts to report [26].

Furthermore, it is distinctly possible that DCS has not occurred during an EVA. There is a stark contrast between a test subject wearing an O<sup>2</sup> mask in a shirt-sleeve training environment at 1-G and an astronaut maneuvering in an uncomfortable spacesuit in micro-G environment, surrounded by 100% O2. One aspect to reduced incidence of DCS is simply due to limited motion in the both the Orlan (Russian) and EMU (American) spacesuits. Another possible explanation is the longer pre-breathing exposure during EVA's compared to those tested in a chamber along with exposure to a micro-gravity (μG) environment. The latter situation is unique in that during adaptation to a μG condition, there are substantial fluid shifts from the legs to the torso and head with a net reduction in total body water. As a response to these fluid shifts, denitrogenation may be more efficient and accelerate nitrogen wash-out from the tissues [33]. Furthermore, astronauts are physically active during their prebreathe protocols and it is well documented that exercise during prebreathe enhances N2 washout from the tissues [34].

#### **2.5. Acute mountain sickness**

A review of clinical and MRI findings in acute mountain sickness (AMS) and high altitude cerebral edema (HACE) demonstrates parallels to recent findings in our U-2 pilots and lowpressure chamber inside safety monitors, with the hypobaric environment as the common element. The primary difference is the presence of hypoxia in AMS and HACE. AMS generally occurs above 2500 m and has been defined by the Lake Louise Consensus Group as the presence of a headache with one or more of the following: gastrointestinal symptoms (nausea, vomiting, anorexia), insomnia, dizziness and lassitude or fatigue [35]. Determining factors include the rate of ascent, altitude reached, altitude at which a person sleeps and individual physiology. Most consider HACE to be a clinical and pathophysiologic extension of AMS. HACE is an encephalopathy, characterized by disturbances of consciousness that may progress to coma, ataxic gait, increased intracranial pressure and retinal hemorrhages.

A growing body of evidence suggests that is not only hypoxia, but hypobaria that contributes to the development of AMS [36–40]. The underlying pathophysiology of AMS remains poorly understood. Hypoxia-induced cerebral vasodilatation or its effectors, such as nitric oxide, may produce the headache, possibly via the trigeminovascular system or by causing mild cerebral edema [41–43]. Whether this edema is cytotoxic (intracellular), vasogenic (extracellular), or both remains controversial. However, MRI has demonstrated reversible abnormalities in HACE, such as areas of increased T2 and fluid-attenuated inversion recovery signal intensity within the splenium of the corpus callosum (white matter structure), with associated increased apparent diffusion coefficient (ADC) values consistent with increased water diffusivity. These findings are indicative of vasogenic edema. Hemodynamic factors such as sustained vasodilation, impaired cerebral autoregulation and elevated capillary pressure may contribute to vasogenic edema [44–47]. Hypoxia-induced biochemical alteration of the blood brain barrier may also be important. Current high altitude human research demonstrates increased cerebral blood flow after a single hypoxic hypobaric exposure to 7620 m for occupational training which persists at 72 h. These findings will be described in detail later in this chapter.

Central nervous system MRI changes demonstrated in AMS have similarity with recently published astronaut data. These include intracranial fluid redistribution, increased intracranial pressure in microgravity, and brain structural plasticity changes from pre-to-post spaceflight [48–50].

#### **2.6. Brain magnetic resonance imaging (MRI) techniques**

Masked DCS symptoms; (3) Potential operational and gravitational benefits of the spaceflight

Regarding the bias not to report, an EVA is considered the pinnacle of any astronaut's career and the willingness to divulge mild DCS symptoms such as pain that was not operationally limiting would be nominal. It is important to note that NASA's current policy states that any DCS symptom incurred by a crewmember or test subject who participate in hypobaric or hyperbaric operations needs to be reported [26]. It is known that under-reporting of DCS symptoms occurred in the U-2 pilot population as reporting of DCS symptoms during hypobaric operational training could lead to disqualification. This was discussed earlier in Bendrick's article on 275 U-2 pilots of whom 75% reported DCS symptoms via an anonymous questionnaire at least once in their career but rarely reported it to their Flight Surgeon [29]. Interestingly, Webb et al. in 1996 published an article citing an incidence of DCS in 77% of test-subjects undergoing the 60 min U-2 pre-breathing protocol [32]. This again highlights the disparity between operational vs. research reports of DCS and underscores that for numerous reasons, astronauts and pilots are not inclined to report every slight discomfort they

However, in addition to under-reporting bias, there are valid reasons why mild symptoms of DCS may be masked during an EVA. Astronauts frequently take aspirin prior to any EVA to pre-emptively mitigate any aches or pain. In addition, the actual operation of the EMU spacesuit that the astronaut dons can be painful. It would be near difficult for an astronaut to discern pain from "pain-only" DCS vs. the natural discomfort incurred from working within the confines of the EMU. Furthermore, as most "pain-only" DCS symptoms resolve following re-pressurization after completion of the EVA, there is no driving force for astronauts to

Furthermore, it is distinctly possible that DCS has not occurred during an EVA. There is a

ment at 1-G and an astronaut maneuvering in an uncomfortable spacesuit in micro-G environment, surrounded by 100% O2. One aspect to reduced incidence of DCS is simply due to limited motion in the both the Orlan (Russian) and EMU (American) spacesuits. Another possible explanation is the longer pre-breathing exposure during EVA's compared to those tested in a chamber along with exposure to a micro-gravity (μG) environment. The latter situation is unique in that during adaptation to a μG condition, there are substantial fluid shifts from the legs to the torso and head with a net reduction in total body water. As a response to these fluid shifts, denitrogenation may be more efficient and accelerate nitrogen wash-out from the tissues [33]. Furthermore, astronauts are physically active during their prebreathe

protocols and it is well documented that exercise during prebreathe enhances N2

A review of clinical and MRI findings in acute mountain sickness (AMS) and high altitude cerebral edema (HACE) demonstrates parallels to recent findings in our U-2 pilots and lowpressure chamber inside safety monitors, with the hypobaric environment as the common

mask in a shirt-sleeve training environ-

washout

stark contrast between a test subject wearing an O<sup>2</sup>

52 Into Space - A Journey of How Humans Adapt and Live in Microgravity

environment.

experience.

report [26].

from the tissues [34].

**2.5. Acute mountain sickness**

Our original U-2 pilot brain MRI evaluations were performed on a Siemens (Siemens AG, Erlangen, Germany) Magnetom Tim Trio 3-Tesla scanner at the Research Imaging Institute (RII), University of Texas Health Science Center San Antonio (UTHSCSA), with a 12-channel phased array coil. All subsequent human and animal MRI data has been acquired on the same Siemens Magnetom Verio 3-Tesla scanner at Wilford Hall Ambulatory Surgical Center (WHASC), Joint Base San Antonio, Texas using a 32-channel phased array coil. This includes all imaging on control/normal subjects and low-pressure chamber inside safety monitors. Both scanners are operated under quality control and assurance guidelines in accordance with recommendations by the American College of Radiology.

Three-dimensional imaging parameters were for T1 magnetization prepared rapid acquisition gradient echo (MPRAGE), repetition time (TR) = 2200 ms, echo time (TE) = 2.85 ms, isotropic resolution = 0.80 mm, and for fluid-attenuated inversion recovery (FLAIR), TR = 4500 ms, TE = 11 ms, isotropic resolution = 1.00 mm. FLAIR image processing was previously reported [2, 51–54]. WMH regions were coded as ependymal regions, contiguous with CSF structures, and as subcortical regions as previously described [57]. WMHs were quantified in number (count) and total volume.

**2.7. White matter integrity in high altitude pilots exposed to hypobaria**

in neuropsychiatric and neurological disorders [80].

The number and volume of WMH regions are sensitive markers of cerebral health, commonly used to study the extent of the cerebral injury [71]. Healthy cerebral white matter tracts are myelinated with compounds containing long-chain fatty acids with very short T2-relaxation time and thus appear dark on T2-weighted images. Local edema, often associated with degradation of the myelin sheath, results in localized accumulation of extracellular water, which leads to an increased signal intensity on a T2-weighted image. HWM lesions also form in normal aging, where they begin to occur during mid adulthood (fourth-fifth decade of life). In both normal subjects and patients who suffered brain injury, the number and volume of HWM lesions are correlated with a decline in cerebral integrity [72], reduction in cerebral white matter and gray matter volumes [73, 74], cerebral blood flow [75], and cerebral glucose metabolism [76]. Increasing numbers and volumes of HWM regions have also been linked to cognitive declines, particularly in executive functioning [77], processing speed [78], and general cognitive status [79], and were correlated with the severity of neurocognitive deficits

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The etiology of HWM is nonspecific and is commonly associated with cerebral ischemia and disruptions of cerebral circulation [81]. Histopathological findings indicate there are two distinct types of HWM lesions: subcortical and ependymal. Subcortical HWM regions are more closely associated with ischemic factors [3]. In contrast, periventricular ependymal HWM lesions are thought to be of non-ischemic origin and potentially produced by pulse-wave encephalopathy [55, 82, 83]. This condition refers to the microtears in the ependymal lining

Our initial study evaluated 50 U-2 pilots (avg. age 37.4 ± 5.2 year), 12 (avg. age 38.9 ± 6.1 year) of whom had suffered neurological decompression sickness (NDCS) [86]. The NDCS pilots demonstrated a significantly higher total WMH lesion volume (*p* = 0.026) compared to the non-NDCS pilots, but not a significant increase in total lesion count (*p* = 0.120). Analysis of the lesion by type (subcortical vs. ependymal) did not demonstrate a significant difference between NDCS pilots and non-NDCS pilots (*p* = 0.059). Examination of regional measurements revealed pilots who experienced NDCS had significantly higher number and volume of insular subcortical lesions (*p* = 0.020 and *p* = 0.018, respectively). No difference was noted in the presence of mild hypertension or mild hyperlipidemia. No difference was noted with total flight hours or average high-flight hours per month between the two groups. No pilot had a history of significant head injury, significant scuba diving history, episode of decompression illness associated with diving, or high-altitude exposure other than that associated with USAF flight duties. The initial hypothesis for the elevation of WMH volume in pilots that suffered NDCS was hypobaric-related gas microemboli (<30 μm) which may have led to loss of permeability or occlusion of small cerebral vessels and subsequent immune mediated gliosis (**Figure 2**).

What was noteworthy was the prevalence of WMHs in high altitude pilots that had not suffered NDCS, mandating comparison of high altitude pilots to a normal control group.

Subsequent MRI evaluation was performed on 105 total high-altitude U-2 pilots (U2P; mean age 37.7), 83 low pressure chamber aerospace physiology inside observers (AOP; mean age

caused by the pulsatile movements of ventricular cerebrospinal fluid (CSF) [83–85].

Calibration MRI data was performed in 46 patients (CAL) on both the RII and WHASC scanners for the cross comparison and analysis of advanced imaging sequences such as diffusion imaging [5]. The calibration for the average FA values in subjects imaged on both scanners showed excellent correlation (*r* = 0.85), with coefficients of variation were similar to what has been previously reported [56, 57].

High angular resolution diffusion imaging (HARDI) was utilized for diffusion tensor imaging (DTI) and fractional anisotropy (FA) assessment as previously reported [51, 58]. Briefly, DTI data were collected using a single-shot echo-planar, single refocusing spin-echo, T2-weighted sequence with a spatial resolution of 1.7 × 1.7 × 3.0 mm with sequence parameters of TE/TR = 87/8000 ms, We chose the ENIGMA-DTI analysis protocol [59] because it can effectively overcome the impact of the punctate WMH lesions on FA values compared to simple averaging of FA values within a region of interest, effectively limiting analysis of FA values to that of the normal-appearing WM. DTI is a quantitative MRI technique that has an advantage over T2-weighted fluid attenuated inversion recovery (FLAIR) imaging because it can ascertain subtle WM damage in normal-appearing WM prior to development of WMH lesions [60]. FA is a widely used quantitative measure of WM microstructure, extracted from DTI [61]. FA is an important biomarker in clinical studies as it can sensitively track WM changes in neurological and psychiatric diseases [57, 62, 63] and in normal development and aging [64].

Two additional advanced sequence techniques were used in our current hypobaric research: pseudo-continuous arterial spin labeling (pCASL) and proton magnetic resonance spectroscopy (MRS). pCASL technique is a noninvasive method for calculation of estimate cerebral blood flow which does not require intravenous contrast injection. MRS demonstrates quantifiable neurometabolite concentrations regions of interest, both gray and white matter. pCASL imaging data for gray and white matter were collected using gradient-echo echo-planar imaging with TE/TR = 16/4000 ms as previously reported [51]. Further, pCASL data were processed using the pipeline described elsewhere [65]. Perfusion-weighted images were calculated based on the methods described by others [67, 68].

Proton magnetic resonance spectroscopy (MRS) data were acquired from voxels placed in frontal white matter (FWM) and the anterior cingulate cortex (ACC). For the frontal white matter region, short TE and long TE data were acquired using point resolved spectroscopy localization (TR = 1500 ms, short TE = 30, long TE = 135 ms, number of signals averaged (NEX) = 256, volume of interest (VOI) ~ 3.4 cm<sup>3</sup> ). Data were acquired in both hemispheres and averaged together. For the anterior cingulate, the same short TE point resolved spectroscopy localization parameters were used with a voxel size of 6 cm3 . Standard neurometabolites were evaluated using available software and methods as previously reported [69, 70] We have demonstrated a high degree of consistency across structural and physiological measurements with brain MRI [51].

#### **2.7. White matter integrity in high altitude pilots exposed to hypobaria**

TE = 11 ms, isotropic resolution = 1.00 mm. FLAIR image processing was previously reported [2, 51–54]. WMH regions were coded as ependymal regions, contiguous with CSF structures, and as subcortical regions as previously described [57]. WMHs were quantified in number

Calibration MRI data was performed in 46 patients (CAL) on both the RII and WHASC scanners for the cross comparison and analysis of advanced imaging sequences such as diffusion imaging [5]. The calibration for the average FA values in subjects imaged on both scanners showed excellent correlation (*r* = 0.85), with coefficients of variation were similar to what has

High angular resolution diffusion imaging (HARDI) was utilized for diffusion tensor imaging (DTI) and fractional anisotropy (FA) assessment as previously reported [51, 58]. Briefly, DTI data were collected using a single-shot echo-planar, single refocusing spin-echo, T2-weighted sequence with a spatial resolution of 1.7 × 1.7 × 3.0 mm with sequence parameters of TE/TR = 87/8000 ms, We chose the ENIGMA-DTI analysis protocol [59] because it can effectively overcome the impact of the punctate WMH lesions on FA values compared to simple averaging of FA values within a region of interest, effectively limiting analysis of FA values to that of the normal-appearing WM. DTI is a quantitative MRI technique that has an advantage over T2-weighted fluid attenuated inversion recovery (FLAIR) imaging because it can ascertain subtle WM damage in normal-appearing WM prior to development of WMH lesions [60]. FA is a widely used quantitative measure of WM microstructure, extracted from DTI [61]. FA is an important biomarker in clinical studies as it can sensitively track WM changes in neurological and psychiatric diseases [57, 62, 63] and in normal development and

Two additional advanced sequence techniques were used in our current hypobaric research: pseudo-continuous arterial spin labeling (pCASL) and proton magnetic resonance spectroscopy (MRS). pCASL technique is a noninvasive method for calculation of estimate cerebral blood flow which does not require intravenous contrast injection. MRS demonstrates quantifiable neurometabolite concentrations regions of interest, both gray and white matter. pCASL imaging data for gray and white matter were collected using gradient-echo echo-planar imaging with TE/TR = 16/4000 ms as previously reported [51]. Further, pCASL data were processed using the pipeline described elsewhere [65]. Perfusion-weighted images were calculated based

Proton magnetic resonance spectroscopy (MRS) data were acquired from voxels placed in frontal white matter (FWM) and the anterior cingulate cortex (ACC). For the frontal white matter region, short TE and long TE data were acquired using point resolved spectroscopy localization (TR = 1500 ms, short TE = 30, long TE = 135 ms, number of signals averaged

averaged together. For the anterior cingulate, the same short TE point resolved spectroscopy

evaluated using available software and methods as previously reported [69, 70] We have demonstrated a high degree of consistency across structural and physiological measurements with

). Data were acquired in both hemispheres and

. Standard neurometabolites were

(count) and total volume.

aging [64].

brain MRI [51].

been previously reported [56, 57].

54 Into Space - A Journey of How Humans Adapt and Live in Microgravity

on the methods described by others [67, 68].

(NEX) = 256, volume of interest (VOI) ~ 3.4 cm<sup>3</sup>

localization parameters were used with a voxel size of 6 cm3

The number and volume of WMH regions are sensitive markers of cerebral health, commonly used to study the extent of the cerebral injury [71]. Healthy cerebral white matter tracts are myelinated with compounds containing long-chain fatty acids with very short T2-relaxation time and thus appear dark on T2-weighted images. Local edema, often associated with degradation of the myelin sheath, results in localized accumulation of extracellular water, which leads to an increased signal intensity on a T2-weighted image. HWM lesions also form in normal aging, where they begin to occur during mid adulthood (fourth-fifth decade of life). In both normal subjects and patients who suffered brain injury, the number and volume of HWM lesions are correlated with a decline in cerebral integrity [72], reduction in cerebral white matter and gray matter volumes [73, 74], cerebral blood flow [75], and cerebral glucose metabolism [76]. Increasing numbers and volumes of HWM regions have also been linked to cognitive declines, particularly in executive functioning [77], processing speed [78], and general cognitive status [79], and were correlated with the severity of neurocognitive deficits in neuropsychiatric and neurological disorders [80].

The etiology of HWM is nonspecific and is commonly associated with cerebral ischemia and disruptions of cerebral circulation [81]. Histopathological findings indicate there are two distinct types of HWM lesions: subcortical and ependymal. Subcortical HWM regions are more closely associated with ischemic factors [3]. In contrast, periventricular ependymal HWM lesions are thought to be of non-ischemic origin and potentially produced by pulse-wave encephalopathy [55, 82, 83]. This condition refers to the microtears in the ependymal lining caused by the pulsatile movements of ventricular cerebrospinal fluid (CSF) [83–85].

Our initial study evaluated 50 U-2 pilots (avg. age 37.4 ± 5.2 year), 12 (avg. age 38.9 ± 6.1 year) of whom had suffered neurological decompression sickness (NDCS) [86]. The NDCS pilots demonstrated a significantly higher total WMH lesion volume (*p* = 0.026) compared to the non-NDCS pilots, but not a significant increase in total lesion count (*p* = 0.120). Analysis of the lesion by type (subcortical vs. ependymal) did not demonstrate a significant difference between NDCS pilots and non-NDCS pilots (*p* = 0.059). Examination of regional measurements revealed pilots who experienced NDCS had significantly higher number and volume of insular subcortical lesions (*p* = 0.020 and *p* = 0.018, respectively). No difference was noted in the presence of mild hypertension or mild hyperlipidemia. No difference was noted with total flight hours or average high-flight hours per month between the two groups. No pilot had a history of significant head injury, significant scuba diving history, episode of decompression illness associated with diving, or high-altitude exposure other than that associated with USAF flight duties. The initial hypothesis for the elevation of WMH volume in pilots that suffered NDCS was hypobaric-related gas microemboli (<30 μm) which may have led to loss of permeability or occlusion of small cerebral vessels and subsequent immune mediated gliosis (**Figure 2**).

What was noteworthy was the prevalence of WMHs in high altitude pilots that had not suffered NDCS, mandating comparison of high altitude pilots to a normal control group.

Subsequent MRI evaluation was performed on 105 total high-altitude U-2 pilots (U2P; mean age 37.7), 83 low pressure chamber aerospace physiology inside observers (AOP; mean age

AOP and U2P total hours of hypobaric exposure versus WMH volume/count was not significant (WMH volume/count, r250.002/r250.009, respectively). The total hours of exposure were not significantly associated with WMH presence in either group. Likewise, the Spearman correlation coefficient between 2 measures of WMH burden and age were positive but not

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Regional analysis revealed that frontal lobe lesions constituted the largest fraction of both volume and number of WMH loci in both U-2 pilots (50 and 56% for volume and number, respectively) and normative controls (69 and 70% for volume and number, respectively). This is presumably because higher metabolic demand and cerebral blood flow. Pilots had a higher volume (*p* < 0.03) of WMH in the frontal, insula, limbic, sublobar, and temporal regions and a higher number (*p* < 0.01) of WMH in the insula, limbic, temporal, and sublobar regions. WMH were normally uniformly distributed throughout the brain in U2P than in controls and did not

The relationship between hypobaric exposure and WMH is complex. We observed no significant correlations between WMH measurements and the total number or hours of hypobaric exposure. This suggests that other factors may modulate the hypobaria-related WMH change, including hyperoxemic pre-exposure nitrogen degassing, exposure duration, level of physical and mental activity during exposure, frequency of exposure episodes, and amount of rest between exposures, as well as other yet unknown environmental and genetic susceptibility risk factors. Injury secondary to microemboli, of nitrogen gas, platelet-based thrombi or mic-

Diffusion tensor imaging (DTI) and FA findings in U2P were noteworthy for demonstrating effects suggesting a global process, affecting normal appearing white matter, not just subcortical white matter damage, presumably secondary to repetitive hypobaric exposure. Wholebrain average FA values for all pilots were significantly lower than in controls (KS *p* < 0.001; GLM *p* < 0.001). After Bonferroni correction of *p*-values, we observed two regional findings: pilots had significantly decreased FA values for the sagittal striatum (*p* < 0.001), while pilots had significantly higher FA values for fronto-occipital fibers (*p* = 0.003). Functionally, the striatum coordinates multiple aspects of cognition, including motor and action-planning, decisionmaking, motivation, reinforcement, and reward perception. The fronto-occipital tract integrates auditory and visual association cortices with the prefrontal cortex. Other FA tracts were not

We separated the pilots into lower two-thirds (U2PL)/upper one-third (U2P-U) based on WMH burden (U2P-L/U2P-H). There was no significant difference in WMH burden between U2P-L and controls (CTRL) (WMH volume/count *p* = 0.17/0.52, respectively), while there was a significant difference between U2P-H/U2P-L (*p* < 0.001/, 0.001) and U2P-H/CTRL (*p* < 0.001/<0.001). Comparing FA values of U2P-H and U2P-L to CTRL demonstrated significantly lower FA values in both pilot groups for whole brain average FA (*p* < 0.001/*p* < 0.001, respectively, U2P-H/ U2P-L) and sagittal stratum (*p* = 0.005/*p* = 0.01). Comparing mean values of U2P-H to U2P-L demonstrated a nonsignificant trend toward lower FA values in U2P-H than U2P-L for whole-

brain average FA and all tracts except fronto-occipital where U2P-H = U2P-L).

significant (all r<sup>2</sup> < 0.03; all *p* > 0.10).

roparticles, remain a potential source of this injury.

increase with age.

significantly different.

**Figure 2.** Axial FLAIR images demonstrating multiple subcortical WMHs in a U-2 pilot, without NDCS.

36.5) and 148 age and health matched advanced/doctorate degree control subjects (CTRL; mean age 34.6) [1, 2, 5, 6]. All study subjects were active duty members of the US Armed Forces. All participants were between the ages of 26 and 50 years, were healthy at time of study without any history of central neurologic or psychiatric disease, and had undergone a routine annual medical examination within 12 months prior to study. All participants at the time of testing met USAF Flying Class II neurological standards [87]. Briefly, exclusionary criteria for Flying Class II include a history of any of the following: head trauma with any loss of consciousness or amnesia; migraine headache; psychiatric or psychological disease requiring any medication or hospitalization; hypertension (HTN) requiring more than a single angiotensin-converting enzyme inhibitor (ACE-I) for control; hyperlipidemia (HLD) requiring more than a single statin for control; diabetes or glucose intolerance; ischemic cardiac disease; any neurological disease including infection, seizure, or stroke; any medical condition associated with neurological injury; or substance or drug abuse or dependence. All AOP had experienced >50 occupational exposures to >25,000 feet altitude. Two (2.4%) of AOP and 16 (15%) of U2P reported mission-related symptoms of NDCS. All U2P and AOP undergo standardized hypoxic hypobaric chamber exposure as part of routine aircrew qualification training every 5 years; these exposures are of 30- to 60-min duration with hypoxia relieved via 100% oxygen aviator mask with the onset of physiological symptoms. Fourteen CTRL had experienced a single episode of aircrew hypoxic hypobaric chamber exposure as part of initial flight surgeon qualification training. No subject experienced NDCS related to this periodic aircrew chamber training.

Group-wise analysis demonstrated that both AOP and U2P, two groups occupationally exposed to nonhypoxic hypobaria, had significantly elevated WMH volume/count compared to CTRL. Although the WMH volume/count were higher in U2P than in AOP, neither was statistically significant. Comparable results were obtained in group-wise analysis after excluding any subject with HTN or HLD (14 CTRL, 10 AOP and 20 U2P) and after excluding AOP or U2P who had experienced NDCS. Equivalency of U2P to AOP WMH volume was noted on the Kolmogorov–Smirnov test (p50.388). The Jonckheere–Terpstra test demonstrated CTRL < PHY\_U2P on WMH volume (p50.024) and count (p50.012); AOP < U2P was not significant (*p* > 0.10). The Spearman correlation coefficients between WMH volume/count and age and hours of hypobaric exposure were positive but not significant. Linear regression of combined AOP and U2P total hours of hypobaric exposure versus WMH volume/count was not significant (WMH volume/count, r250.002/r250.009, respectively). The total hours of exposure were not significantly associated with WMH presence in either group. Likewise, the Spearman correlation coefficient between 2 measures of WMH burden and age were positive but not significant (all r<sup>2</sup> < 0.03; all *p* > 0.10).

Regional analysis revealed that frontal lobe lesions constituted the largest fraction of both volume and number of WMH loci in both U-2 pilots (50 and 56% for volume and number, respectively) and normative controls (69 and 70% for volume and number, respectively). This is presumably because higher metabolic demand and cerebral blood flow. Pilots had a higher volume (*p* < 0.03) of WMH in the frontal, insula, limbic, sublobar, and temporal regions and a higher number (*p* < 0.01) of WMH in the insula, limbic, temporal, and sublobar regions. WMH were normally uniformly distributed throughout the brain in U2P than in controls and did not increase with age.

36.5) and 148 age and health matched advanced/doctorate degree control subjects (CTRL; mean age 34.6) [1, 2, 5, 6]. All study subjects were active duty members of the US Armed Forces. All participants were between the ages of 26 and 50 years, were healthy at time of study without any history of central neurologic or psychiatric disease, and had undergone a routine annual medical examination within 12 months prior to study. All participants at the time of testing met USAF Flying Class II neurological standards [87]. Briefly, exclusionary criteria for Flying Class II include a history of any of the following: head trauma with any loss of consciousness or amnesia; migraine headache; psychiatric or psychological disease requiring any medication or hospitalization; hypertension (HTN) requiring more than a single angiotensin-converting enzyme inhibitor (ACE-I) for control; hyperlipidemia (HLD) requiring more than a single statin for control; diabetes or glucose intolerance; ischemic cardiac disease; any neurological disease including infection, seizure, or stroke; any medical condition associated with neurological injury; or substance or drug abuse or dependence. All AOP had experienced >50 occupational exposures to >25,000 feet altitude. Two (2.4%) of AOP and 16 (15%) of U2P reported mission-related symptoms of NDCS. All U2P and AOP undergo standardized hypoxic hypobaric chamber exposure as part of routine aircrew qualification training every 5 years; these exposures are of 30- to 60-min duration with hypoxia relieved via 100% oxygen aviator mask with the onset of physiological symptoms. Fourteen CTRL had experienced a single episode of aircrew hypoxic hypobaric chamber exposure as part of initial flight surgeon qualification training. No subject experienced NDCS related to this periodic aircrew chamber training.

**Figure 2.** Axial FLAIR images demonstrating multiple subcortical WMHs in a U-2 pilot, without NDCS.

56 Into Space - A Journey of How Humans Adapt and Live in Microgravity

Group-wise analysis demonstrated that both AOP and U2P, two groups occupationally exposed to nonhypoxic hypobaria, had significantly elevated WMH volume/count compared to CTRL. Although the WMH volume/count were higher in U2P than in AOP, neither was statistically significant. Comparable results were obtained in group-wise analysis after excluding any subject with HTN or HLD (14 CTRL, 10 AOP and 20 U2P) and after excluding AOP or U2P who had experienced NDCS. Equivalency of U2P to AOP WMH volume was noted on the Kolmogorov–Smirnov test (p50.388). The Jonckheere–Terpstra test demonstrated CTRL < PHY\_U2P on WMH volume (p50.024) and count (p50.012); AOP < U2P was not significant (*p* > 0.10). The Spearman correlation coefficients between WMH volume/count and age and hours of hypobaric exposure were positive but not significant. Linear regression of combined The relationship between hypobaric exposure and WMH is complex. We observed no significant correlations between WMH measurements and the total number or hours of hypobaric exposure. This suggests that other factors may modulate the hypobaria-related WMH change, including hyperoxemic pre-exposure nitrogen degassing, exposure duration, level of physical and mental activity during exposure, frequency of exposure episodes, and amount of rest between exposures, as well as other yet unknown environmental and genetic susceptibility risk factors. Injury secondary to microemboli, of nitrogen gas, platelet-based thrombi or microparticles, remain a potential source of this injury.

Diffusion tensor imaging (DTI) and FA findings in U2P were noteworthy for demonstrating effects suggesting a global process, affecting normal appearing white matter, not just subcortical white matter damage, presumably secondary to repetitive hypobaric exposure. Wholebrain average FA values for all pilots were significantly lower than in controls (KS *p* < 0.001; GLM *p* < 0.001). After Bonferroni correction of *p*-values, we observed two regional findings: pilots had significantly decreased FA values for the sagittal striatum (*p* < 0.001), while pilots had significantly higher FA values for fronto-occipital fibers (*p* = 0.003). Functionally, the striatum coordinates multiple aspects of cognition, including motor and action-planning, decisionmaking, motivation, reinforcement, and reward perception. The fronto-occipital tract integrates auditory and visual association cortices with the prefrontal cortex. Other FA tracts were not significantly different.

We separated the pilots into lower two-thirds (U2PL)/upper one-third (U2P-U) based on WMH burden (U2P-L/U2P-H). There was no significant difference in WMH burden between U2P-L and controls (CTRL) (WMH volume/count *p* = 0.17/0.52, respectively), while there was a significant difference between U2P-H/U2P-L (*p* < 0.001/, 0.001) and U2P-H/CTRL (*p* < 0.001/<0.001). Comparing FA values of U2P-H and U2P-L to CTRL demonstrated significantly lower FA values in both pilot groups for whole brain average FA (*p* < 0.001/*p* < 0.001, respectively, U2P-H/ U2P-L) and sagittal stratum (*p* = 0.005/*p* = 0.01). Comparing mean values of U2P-H to U2P-L demonstrated a nonsignificant trend toward lower FA values in U2P-H than U2P-L for wholebrain average FA and all tracts except fronto-occipital where U2P-H = U2P-L).

Lower average FA findings are consistent with a diffuse disruption in white matter integrity. This finding trended with higher WMH burden previously described. Reduced sagittal striatum FA has been shown to be genetically associated with processing speed deficits in two independent cohorts [88]. We observed a decrease in processing speed in U2P compared to a USAF pilot cohort control [11] and this may suggest the reduced sagittal stratum FA in U-2 pilots may explain this decrease in processing speed. Additionally, USAF pilots are uniquely high-functioning individuals with exceptional visual-spatial abilities [89], which may account for the higher FA values in the fronto-occipital fibers in U-2 pilots, reflecting this associative cognitive ability, and provide an anatomical basis for the superior spatial performance noted in all USAF pilots. Historically, the pathophysiological theory of hypobaric related brain damage has been arterial gas emboli, but there are other recent studies which also suggest a more diffuse process [23, 90]. It is improbable that gas emboli alone could produce the diffuse disruption of axonal integrity demonstrated by our MRI findings. Our studies provide support for other potential pathophysiological explanations, including neuroinflammation and microparticle damage [91, 92].

**2.9. Current research and future directions**

and MRS.

cognitive proficiency.

Current human research is focused upon occupational exposure in military environments, specifically the serologic, neurometabolite and brain MRI changes after a single exposure to low pressure chamber altitude training (training profile as per AFI 11–403 above). Study volunteers are active duty members who have recently completed basic military training and are completing an aircrew fundamentals course prior to additional training for aircrew duties (AFC). AFC students experience hypoxia symptoms for 3–5 min to meet the training objective. An additional active duty age-matched control group (CTRL) group was also recruited. Brain MRI technique is similar to technique previously described; all performed on the same WHASC Siemens 3-Tesla scanner, with discussion of pCASL

IPS: information processing speed; IPA: information processing accuracy; GCF: general cognitive function; GCA: general

**MicroCog category U-2 pilots (n = 93) Air Force pilots (n = 80)** *p***-Value, t-test (2-tailed)**

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Attention/mental control 104.4 ± 9.3 103.8 ± 10.8 0.696 Reasoning Calculation 99.4 ± 12.5 106.5 ± 10.9 <0.001 Memory 105.5 ± 12.5 110.9 ± 13.7 0.007 Spatial Processing 109.1 ± 9.4 109.1 ± 9.4 0.989 Reaction Time 107.3 ± 6.7 104.8 ± 9.2 0.047 IPS 103.6 ± 12.5 106.5 ± 10.5 0.100 IPA 102.1 ± 9.8 105.8 ± 10.0 0.016 GCF 103.5 ± 10.0 108.5 ± 10.6 0.002 GCP 105.4 ± 9.4 108.6 ± 10.2 0.037

**Table 2.** Microcognitive testing results in U-2 pilots compared to Air Force pilot controls.

Preliminary evaluation of pCASL and MRS techniques has been performed on 96 AFC trainees and 68 healthy CTRL subjects. MRI evaluation was obtained 24 h before, 24 h after, and 72 h after low pressure chamber exposure and at the same time intervals for CTRL without the hypobaric exposure. A GAM which controlled for age and gender differences was used to the compare the two groups. There is a statistically significant increase in cerebral blood flow (CBF) in white matter in the AFC group (*p* < 0.001). The difference is dependent upon age as a covariable, although there is no significant difference in age between the two groups (*p* > 0.10). It is possible that this might reflect a difference in central nervous system maturation. Increased CBF persists on the 72-h post exposure MRI and it is unknown how long CBF remains elevated. Findings reflect an increased metabolic demand upon the brain and suggest a transient injury from a single exposure to hypobaria. There was a significant difference in most neurometabolites within the ACC and in GSH within the FWM in aircrew personnel with hypobaric exposure as compared to controls. These differences may be representative of changes at a cellular level in response to,

#### **2.8. Neurocognitive changes**

WMH are also relevant surrogates for cerebral activity in neurological disorders and also normal aging. As stated earlier, these WMH have also been linked to cortical and subcortical functions particularly executive function, processing speed, overall cognition along with motor/gait function [76–78]. Therefore, we compared neurocognitive performance in U-2 pilots with repeated hypobaric exposure to pilots without repeated hypobaric exposure and also assessed whether cognitive performance correlated with severity of WMH burden. All participants were between the ages of 26–47 years old and had to meet Flying Class II standards and could not have any prior history of neurological or psychiatric disease. 106 U-2 pilots were compared against 83 active duty (AD) pilots who were also matched for age at time of cognitive testing. Computer-based Multi-Dimension Aptitude Battery-II (MAB-II) and Assessment of Cognitive Function (MicroCog) assessments were utilized. MAB-II yields an overall evaluation of neurocognitive ability based on the Wechsler Adult Intelligence Scale and generates three intelligence quotient (IQ) scores: full-scale IQ, verbal IQ and performance IQ. The MicroCog is a separate computer-based cognitive assessment that comprises18 subsets resulting in 9 index scores. The MicroCog was specifically chosen to provide more accurate information regarding reaction time and processing speed, both critical functions to any active aviator. While there were no significant differences between U-2 and AF pilots on the MAB-II testing, there were subtle but significant differences on the Micro-Cog assessment. Specifically, U-2 pilots scored significantly in the following domains (see **Table 2**): reasoning/ calculation (*p* < 0.001), memory (*p* = 0.007), information processing accuracy (*p* = 0.016), and general cognitive functioning (*p* = 0.002). Furthermore, within the U-2 pilot population, significantly lower scores on reasoning/calculation, memory, general cognitive functioning and proficiency were observed in those pilots with higher WMH burden [6]. However, it is relevant to note that despite the differences in the U-2 pilots, their overall neurocognitive performance continues to remain commensurate with age and cohort-specific normative data tempering concerns for any immediate clinical significance. The long-term sequela is unknown.


IPS: information processing speed; IPA: information processing accuracy; GCF: general cognitive function; GCA: general cognitive proficiency.

**Table 2.** Microcognitive testing results in U-2 pilots compared to Air Force pilot controls.

#### **2.9. Current research and future directions**

Lower average FA findings are consistent with a diffuse disruption in white matter integrity. This finding trended with higher WMH burden previously described. Reduced sagittal striatum FA has been shown to be genetically associated with processing speed deficits in two independent cohorts [88]. We observed a decrease in processing speed in U2P compared to a USAF pilot cohort control [11] and this may suggest the reduced sagittal stratum FA in U-2 pilots may explain this decrease in processing speed. Additionally, USAF pilots are uniquely high-functioning individuals with exceptional visual-spatial abilities [89], which may account for the higher FA values in the fronto-occipital fibers in U-2 pilots, reflecting this associative cognitive ability, and provide an anatomical basis for the superior spatial performance noted in all USAF pilots. Historically, the pathophysiological theory of hypobaric related brain damage has been arterial gas emboli, but there are other recent studies which also suggest a more diffuse process [23, 90]. It is improbable that gas emboli alone could produce the diffuse disruption of axonal integrity demonstrated by our MRI findings. Our studies provide support for other potential pathophysiological explanations, including neuroinflammation and

WMH are also relevant surrogates for cerebral activity in neurological disorders and also normal aging. As stated earlier, these WMH have also been linked to cortical and subcortical functions particularly executive function, processing speed, overall cognition along with motor/gait function [76–78]. Therefore, we compared neurocognitive performance in U-2 pilots with repeated hypobaric exposure to pilots without repeated hypobaric exposure and also assessed whether cognitive performance correlated with severity of WMH burden. All participants were between the ages of 26–47 years old and had to meet Flying Class II standards and could not have any prior history of neurological or psychiatric disease. 106 U-2 pilots were compared against 83 active duty (AD) pilots who were also matched for age at time of cognitive testing. Computer-based Multi-Dimension Aptitude Battery-II (MAB-II) and Assessment of Cognitive Function (MicroCog) assessments were utilized. MAB-II yields an overall evaluation of neurocognitive ability based on the Wechsler Adult Intelligence Scale and generates three intelligence quotient (IQ) scores: full-scale IQ, verbal IQ and performance IQ. The MicroCog is a separate computer-based cognitive assessment that comprises18 subsets resulting in 9 index scores. The MicroCog was specifically chosen to provide more accurate information regarding reaction time and processing speed, both critical functions to any active aviator. While there were no significant differences between U-2 and AF pilots on the MAB-II testing, there were subtle but significant differences on the Micro-Cog assessment. Specifically, U-2 pilots scored significantly in the following domains (see **Table 2**): reasoning/ calculation (*p* < 0.001), memory (*p* = 0.007), information processing accuracy (*p* = 0.016), and general cognitive functioning (*p* = 0.002). Furthermore, within the U-2 pilot population, significantly lower scores on reasoning/calculation, memory, general cognitive functioning and proficiency were observed in those pilots with higher WMH burden [6]. However, it is relevant to note that despite the differences in the U-2 pilots, their overall neurocognitive performance continues to remain commensurate with age and cohort-specific normative data tempering

concerns for any immediate clinical significance. The long-term sequela is unknown.

microparticle damage [91, 92].

58 Into Space - A Journey of How Humans Adapt and Live in Microgravity

**2.8. Neurocognitive changes**

Current human research is focused upon occupational exposure in military environments, specifically the serologic, neurometabolite and brain MRI changes after a single exposure to low pressure chamber altitude training (training profile as per AFI 11–403 above). Study volunteers are active duty members who have recently completed basic military training and are completing an aircrew fundamentals course prior to additional training for aircrew duties (AFC). AFC students experience hypoxia symptoms for 3–5 min to meet the training objective. An additional active duty age-matched control group (CTRL) group was also recruited. Brain MRI technique is similar to technique previously described; all performed on the same WHASC Siemens 3-Tesla scanner, with discussion of pCASL and MRS.

Preliminary evaluation of pCASL and MRS techniques has been performed on 96 AFC trainees and 68 healthy CTRL subjects. MRI evaluation was obtained 24 h before, 24 h after, and 72 h after low pressure chamber exposure and at the same time intervals for CTRL without the hypobaric exposure. A GAM which controlled for age and gender differences was used to the compare the two groups. There is a statistically significant increase in cerebral blood flow (CBF) in white matter in the AFC group (*p* < 0.001). The difference is dependent upon age as a covariable, although there is no significant difference in age between the two groups (*p* > 0.10). It is possible that this might reflect a difference in central nervous system maturation. Increased CBF persists on the 72-h post exposure MRI and it is unknown how long CBF remains elevated. Findings reflect an increased metabolic demand upon the brain and suggest a transient injury from a single exposure to hypobaria. There was a significant difference in most neurometabolites within the ACC and in GSH within the FWM in aircrew personnel with hypobaric exposure as compared to controls. These differences may be representative of changes at a cellular level in response to, or preceding, changes in blood flow to these regions versus age-related differences or differing WMH between the two groups. This remains a subject of ongoing evaluation.

2D and Doppler echocardiography. Following exposure, the 10 parachutists then engaged in ground level moderate exercise consisting of a 4 km/h. march on a treadmill while carrying a Bergen weighing 40 lbs. While the study sample was small, there was no evidence of VGE or DCS during the altitude profile of the study and no evidence for resurgence of VGE or exercise intolerance during the ground profile of the study [96]. These findings corroborated Webb's work in 2002 that indicated that exercise at ground level would not trigger a resurgence of

Acute and Chronic Effects of Hypobaric Exposure upon the Brain

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As discussed earlier in the chapter under DCS subsection, there have been no reported cases of DCS during EVA. This concern has been mitigated using various strategies such as implementation of a lower pressure high oxygen environment utilized in the Gemini, Apollo space missions and Skylab space station coupled with single 4-h pre-launch oxygen prebreathe. This resting 4 h-in-suit prebreathe protocol [98] has been utilized six times during space-flight without reported incidents of DCS. Other protocols included the "Camp-Out" protocol (last used on May 6, 2011) which involved exposure to a mildly hypoxic environment requiring a single 40–75 min in-suit prebreathe, along with several exercise-enhanced protocols. The two most common of the exercise prebreathe protocols include the "cycle ergometer with vibration isolation and stabilization" (CEVIS) and "in-suit light exercise (ISLE) protocols. These were developed to help minimize scheduling constraints of EVA's following delivery of the International Space Station (ISS) *Quest* airlock in 2001. The theory behind these protocols is that since denitrogenation is a perfusion-limited process, the implementation of exercise into the prebreathe protocol may facilitate denitrogenation. The CEVIS protocol uses a short but intense prebreathe exercise protocol (10 min duration) utilizing cycle ergometry with escalating workload peaking at 75% VO2 max. After completion of exercise, the astronaut then prebreathes 100% oxygen for the next 50 min followed by depressurization to 10.2 psia in the ISS airlock over 30 min. It is during this depressurization that the spacesuit is donned. As of May 6, 2016, the CEVIS protocol has been utilized 52 times with no reported signs or symptoms of DCS. In contrast to the CEVIS protocol, ISLE prebreathe protocol replaces the bouts of short, intense exercise with longer period of mild exercise in the EMU (spacesuit). While it shares many steps with the CEVIS exercise protocol it does differ in that only 40 min are spent prebreathing followed by 20 min depressurization to 10.2 psia. Once the suit is donned, mild exercise consisting of arm and leg circular motions are performed over 4 min followed by 1-min rest period. This cycle continues for total duration of 50 min achieving a VO2 max of 6.8% (compared to 75% in the CEVIS protocol). This is followed by an additional 50 min prebreathe of 100% oxygen culminating in a final depressurization of the airlock to vacuum. The ISLE protocol has been used over 40 times since May 6, 2016 without any occurrences of DCS

These complex prebreathing protocols were designed to meet operational demands but in doing so have left knowledge gaps regarding DCS risk factors particularly in space. These include risk of bubble formation in space, micronuclei generation, implications of tissue saturation across different gas and pressure environments, and nitrogen elimination in space. Furthermore, there are numerous physiological factors to consider such as age, body habitus,

VGE or DCS symptoms following a 2-h exposure at an altitude of 35,000 feet [97].

**2.11. Extravehicular activity (EVA)**

is currently the prime protocol used by the ISS [26].

#### **2.10. Military free fall operations**

U-2 pilots are not the only group at risk of DCS during operational movements or exercises. This would include our high-altitude high-opening (HAHO) and high-altitude low opening (HALO) parachutists. Due to improvements in both parachutes and life-support systems, military parachutists are now able to drop from altitudes in excess of 25,000 feet. These higher altitudes carry an increased risk of DCS. Furthermore, slow descent (HAHO operations), colder temperatures (ambient temperature at 35,000 feet is approximately −56°C), and even moderate exercise at altitude [93] increase the risk of VGE. Another practical issue is that the presence of any facial hair can impair the seal of the oxygen mask over the parachutist's face rendering prebreathing ineffective. All parachutists engaged in military free fall (MFF) must undergo strict prebreathing protocol as outlined by Air Force Instruction (AFI) 11-409 (See **Table 3** below) [94].

Furthermore, in an effort to reduce the physical demands and risk of DCS on MFF parachutists, the following military protocol was issued: (1) MFF parachutists may not conduct more than two jumps between 13,000 and 17,999 feet in a 24-h period; (2) Conduct no more than one oxygen jump above 18,000 feet in a 24-h period; (3) not conduct MFF operations within 24 h of making a non-oxygen dive and (4) not wear dark goggles on MFF operations that require prebreathing to facilitate viewing of the eyes of the jumpers by the jumpmaster to ensure they are not experiencing physiological difficulties [95]. Despite such extensive and potentially mitigating protocols there is little information in the literature regarding the actual incidence of DCS affecting parachutists engaged in HAHO or HALO operations. One small study of 10 experienced parachutists underwent blinded exposure in a hypobaric chamber to both 17,500 and 35,000 feet respectively separated by 48 h. Participants underwent 60 min 100% O<sup>2</sup> prebreathe, and then decompressed to respective altitude over 7 min where they remained for 15 min followed by slow descent over 35 min. They were suspended to reduplicate the effects of the harnesses on blood flow in the lower limbs. VGE detection was accomplished by precordial


a Supplemental oxygen: parachutists/jumpers may perform unpressurized operations between 10,000 and 13,000 feet without supplemental oxygen not exceed 30 min. For unpressurized flight above 13,000 feet or exceeding the 30-min envelope between 10,000 and 13,000 feet, a continuous supply of supplemental oxygen will be used.

2D and Doppler echocardiography. Following exposure, the 10 parachutists then engaged in ground level moderate exercise consisting of a 4 km/h. march on a treadmill while carrying a Bergen weighing 40 lbs. While the study sample was small, there was no evidence of VGE or DCS during the altitude profile of the study and no evidence for resurgence of VGE or exercise intolerance during the ground profile of the study [96]. These findings corroborated Webb's work in 2002 that indicated that exercise at ground level would not trigger a resurgence of VGE or DCS symptoms following a 2-h exposure at an altitude of 35,000 feet [97].

#### **2.11. Extravehicular activity (EVA)**

or preceding, changes in blood flow to these regions versus age-related differences or differing WMH between the two groups. This remains a subject of ongoing evaluation.

U-2 pilots are not the only group at risk of DCS during operational movements or exercises. This would include our high-altitude high-opening (HAHO) and high-altitude low opening (HALO) parachutists. Due to improvements in both parachutes and life-support systems, military parachutists are now able to drop from altitudes in excess of 25,000 feet. These higher altitudes carry an increased risk of DCS. Furthermore, slow descent (HAHO operations), colder temperatures (ambient temperature at 35,000 feet is approximately −56°C), and even moderate exercise at altitude [93] increase the risk of VGE. Another practical issue is that the presence of any facial hair can impair the seal of the oxygen mask over the parachutist's face rendering prebreathing ineffective. All parachutists engaged in military free fall (MFF) must undergo strict prebreathing protocol as outlined by Air Force Instruction (AFI) 11-409 (See

Furthermore, in an effort to reduce the physical demands and risk of DCS on MFF parachutists, the following military protocol was issued: (1) MFF parachutists may not conduct more than two jumps between 13,000 and 17,999 feet in a 24-h period; (2) Conduct no more than one oxygen jump above 18,000 feet in a 24-h period; (3) not conduct MFF operations within 24 h of making a non-oxygen dive and (4) not wear dark goggles on MFF operations that require prebreathing to facilitate viewing of the eyes of the jumpers by the jumpmaster to ensure they are not experiencing physiological difficulties [95]. Despite such extensive and potentially mitigating protocols there is little information in the literature regarding the actual incidence of DCS affecting parachutists engaged in HAHO or HALO operations. One small study of 10 experienced parachutists underwent blinded exposure in a hypobaric chamber to both 17,500 and

35,000 feet respectively separated by 48 h. Participants underwent 60 min 100% O<sup>2</sup>

and then decompressed to respective altitude over 7 min where they remained for 15 min followed by slow descent over 35 min. They were suspended to reduplicate the effects of the harnesses on blood flow in the lower limbs. VGE detection was accomplished by precordial

Supplemental oxygen: parachutists/jumpers may perform unpressurized operations between 10,000 and 13,000 feet without supplemental oxygen not exceed 30 min. For unpressurized flight above 13,000 feet or exceeding the 30-min

envelope between 10,000 and 13,000 feet, a continuous supply of supplemental oxygen will be used.

**Altitude Oxygen requirement Pre-breathe time Maximum** 10,000–12,999 feet Aircrew: supplemental jumpers: see below<sup>a</sup> N/A Unlimited 13,000–19,999 feet Supplemental N/A Unlimited 20,000–24,999 feet 100% O<sup>2</sup> 30 min 110 min 25,000–29,999 feet 100% O<sup>2</sup> 30 min 60 min 30,000–34,999 feet 100% O<sup>2</sup> 45 min 30 min 35,000 feet or greater 100% O<sup>2</sup> 75 min 30 min

prebreathe,

**2.10. Military free fall operations**

60 Into Space - A Journey of How Humans Adapt and Live in Microgravity

**Table 3** below) [94].

a

**Table 3.** AFI 11-109.

As discussed earlier in the chapter under DCS subsection, there have been no reported cases of DCS during EVA. This concern has been mitigated using various strategies such as implementation of a lower pressure high oxygen environment utilized in the Gemini, Apollo space missions and Skylab space station coupled with single 4-h pre-launch oxygen prebreathe. This resting 4 h-in-suit prebreathe protocol [98] has been utilized six times during space-flight without reported incidents of DCS. Other protocols included the "Camp-Out" protocol (last used on May 6, 2011) which involved exposure to a mildly hypoxic environment requiring a single 40–75 min in-suit prebreathe, along with several exercise-enhanced protocols. The two most common of the exercise prebreathe protocols include the "cycle ergometer with vibration isolation and stabilization" (CEVIS) and "in-suit light exercise (ISLE) protocols. These were developed to help minimize scheduling constraints of EVA's following delivery of the International Space Station (ISS) *Quest* airlock in 2001. The theory behind these protocols is that since denitrogenation is a perfusion-limited process, the implementation of exercise into the prebreathe protocol may facilitate denitrogenation. The CEVIS protocol uses a short but intense prebreathe exercise protocol (10 min duration) utilizing cycle ergometry with escalating workload peaking at 75% VO2 max. After completion of exercise, the astronaut then prebreathes 100% oxygen for the next 50 min followed by depressurization to 10.2 psia in the ISS airlock over 30 min. It is during this depressurization that the spacesuit is donned. As of May 6, 2016, the CEVIS protocol has been utilized 52 times with no reported signs or symptoms of DCS. In contrast to the CEVIS protocol, ISLE prebreathe protocol replaces the bouts of short, intense exercise with longer period of mild exercise in the EMU (spacesuit). While it shares many steps with the CEVIS exercise protocol it does differ in that only 40 min are spent prebreathing followed by 20 min depressurization to 10.2 psia. Once the suit is donned, mild exercise consisting of arm and leg circular motions are performed over 4 min followed by 1-min rest period. This cycle continues for total duration of 50 min achieving a VO2 max of 6.8% (compared to 75% in the CEVIS protocol). This is followed by an additional 50 min prebreathe of 100% oxygen culminating in a final depressurization of the airlock to vacuum. The ISLE protocol has been used over 40 times since May 6, 2016 without any occurrences of DCS is currently the prime protocol used by the ISS [26].

These complex prebreathing protocols were designed to meet operational demands but in doing so have left knowledge gaps regarding DCS risk factors particularly in space. These include risk of bubble formation in space, micronuclei generation, implications of tissue saturation across different gas and pressure environments, and nitrogen elimination in space. Furthermore, there are numerous physiological factors to consider such as age, body habitus, aerobic conditioning, presence of PFO, gender, hydration status and even timing of menstrual cycle that can influence the development of DCS in a hypobaric environment or vacuum such as space. The relative risk and importance of these physiologic risk factors in the genesis of DCS is unknown until a multivariate analysis such as logistic regression or survival analysis is undertaken. Lastly, these DCS risk-mitigation protocols will not likely be sufficient or applicable to future space exploration missions that utilize suitports, variable pressure suits, and require the ability to rapidly deorbit for medical therapy. Historically EVA has been a single event in a flight day. However, the standard operational concept for future exploration missions is the possibility of multiple EVA's in 1 day or performing a single EVA several days in a row. Development of the Exploration Atmosphere coupled with use of suitports is going to push the boundaries of EVA operations and the subsequent potential risk of DCS is unknown [26].

**Conflict of interest**

**Author details**

**References**

Paul Sherman\* and John Sladky

Dayton, Ohio, United States

2012;**33**(1):9-20

2014;**83**(7):638-645

e1-168.e6

Performance. 2016;**87**(12):983-988

Neither Dr. Sherman nor Dr. Sladky report any conflicts of interest.

\*Address all correspondence to: paul.m.sherman3.civ@mail.mil

711th Human Performance Wing, United States Air Force School of Aerospace Medicine,

Acute and Chronic Effects of Hypobaric Exposure upon the Brain

http://dx.doi.org/10.5772/intechopen.74231

63

[1] McGuire S, Sherman P, Profenna L, Grogan P, Sladky J, et al. White matter hyperintensi-

[2] McGuire SA, Sherman PM, Wijtenburg SA, Rowland LM, Grogan PM, et al. White matter hyperintensities and hypobaric exposure. Annals of Neurology. 2014;**76**(5):719-726 [3] Fazekas F, Kleinert R, Offenbacher H, Schmidt R, Kleinert G, et al. Pathologic correlates of incidental MRI white matter signal hyperintensities. Neurology. 1993;**43**(9):1683-1689 [4] Kochunov P, Williamson DE, Lancaster J, Fox P, Cornell J, et al. Fractional anisotropy of water diffusion in cerebral white matter across the lifespan. Neurobiology of Aging.

[5] McGuire SA, Boone GR, Sherman PM, Tate DF, Wood JD, et al. White matter integrity in high-altitude pilots exposed to hypobaria. Aerospace Medicine and Human

[6] McGuire SA, Tate DF, Wood J, Sladky JH, McDonald K, et al. Lower neurocognitive function in U-2 pilots: Relationship to white matter hyperintensities. Neurology.

[7] Sherman PM, McGuire S. Subcortical white matter hyperintensity burden in astronauts

[8] Fayed N, Modrego PJ, Morales H. Evidence of brain damage after high-altitude climbing by means of magnetic resonance imaging. American Journal of Medicine. 2006;**119**:168.

[9] Anooshiravani M, Dumont L, Mardirosoff C, Soto-Debeuf G, Delavelle J. Brain magnetic resonance imaging (MRI) and neurological changes after a single high altitude climb.

[Abstract]. Aerospace Medicine and Human Performance. 2015;**86**(3):309

Medicine and Science in Sports and Exercise. 1999;**31**(7):969-972

ties on MRI in high-altitude U-2 pilots. Neurology. 2013;**81**(8):729-735

### **3. Conclusion**

Over the past 50–60 years, we have seen rapid developments in our aeronautics and space capabilities with planes such as the U-2S operating in the stratosphere along with the launch of the International Space Station in 1998. As we push the technical boundaries to attain various strategic and tactical advantages, we need to remain wary of the physiological effects that extreme and austere environments can impose on our military personnel and astronauts. While the effects of hypobaria and decompression sickness have been known for decades (brought to the forefront by Fulton's seminal work in 1951 [22]), the increase in NCDS experienced by our U-2 pilots from 2006 to 2010 has brought increased scrutiny. Furthermore, the findings of increased WMH coupled with subtle but significantly lower neurocognitive profiles (even among those that did not experience a clinical event of NCDS) heightens the concerns regarding the short and long-term effects that recurrent exposure to hypobaria carries. While the physiology has classically been thought to be secondary to VGE, other inflammatory factors may likely play a role which are being actively investigated. If elucidated, this allows the development for other therapeutic interventions in addition to the numerous prebreathing protocols to mitigate the risk of DCS. This has major significance for both military operations and further space exploration as we continue to press both the technological boundaries as well as our equipment and physiological limits of our personnel.

### **Acknowledgements**

Opinions, interpretations, conclusion and recommendations are those of the authors and are not necessarily endorsed by the United States Air Force. The authors thank Dr. Stephen McGuire for his critical evaluation of our chapter content, to Ms. Elaine Kawano for scientific editing of the chapter and to Ms. Debbie Middleton for assisting in procuring the numerous articles in preparation for this chapter.

### **Conflict of interest**

aerobic conditioning, presence of PFO, gender, hydration status and even timing of menstrual cycle that can influence the development of DCS in a hypobaric environment or vacuum such as space. The relative risk and importance of these physiologic risk factors in the genesis of DCS is unknown until a multivariate analysis such as logistic regression or survival analysis is undertaken. Lastly, these DCS risk-mitigation protocols will not likely be sufficient or applicable to future space exploration missions that utilize suitports, variable pressure suits, and require the ability to rapidly deorbit for medical therapy. Historically EVA has been a single event in a flight day. However, the standard operational concept for future exploration missions is the possibility of multiple EVA's in 1 day or performing a single EVA several days in a row. Development of the Exploration Atmosphere coupled with use of suitports is going to push the boundaries of EVA operations and the subsequent potential risk of DCS is

62 Into Space - A Journey of How Humans Adapt and Live in Microgravity

Over the past 50–60 years, we have seen rapid developments in our aeronautics and space capabilities with planes such as the U-2S operating in the stratosphere along with the launch of the International Space Station in 1998. As we push the technical boundaries to attain various strategic and tactical advantages, we need to remain wary of the physiological effects that extreme and austere environments can impose on our military personnel and astronauts. While the effects of hypobaria and decompression sickness have been known for decades (brought to the forefront by Fulton's seminal work in 1951 [22]), the increase in NCDS experienced by our U-2 pilots from 2006 to 2010 has brought increased scrutiny. Furthermore, the findings of increased WMH coupled with subtle but significantly lower neurocognitive profiles (even among those that did not experience a clinical event of NCDS) heightens the concerns regarding the short and long-term effects that recurrent exposure to hypobaria carries. While the physiology has classically been thought to be secondary to VGE, other inflammatory factors may likely play a role which are being actively investigated. If elucidated, this allows the development for other therapeutic interventions in addition to the numerous prebreathing protocols to mitigate the risk of DCS. This has major significance for both military operations and further space exploration as we continue to press both the technological boundaries as well as our equipment and physiological limits

Opinions, interpretations, conclusion and recommendations are those of the authors and are not necessarily endorsed by the United States Air Force. The authors thank Dr. Stephen McGuire for his critical evaluation of our chapter content, to Ms. Elaine Kawano for scientific editing of the chapter and to Ms. Debbie Middleton for assisting in procuring the numerous

unknown [26].

**3. Conclusion**

of our personnel.

**Acknowledgements**

articles in preparation for this chapter.

Neither Dr. Sherman nor Dr. Sladky report any conflicts of interest.

### **Author details**

Paul Sherman\* and John Sladky

\*Address all correspondence to: paul.m.sherman3.civ@mail.mil

711th Human Performance Wing, United States Air Force School of Aerospace Medicine, Dayton, Ohio, United States

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**Chapter 5**

Provisional chapter

**Spaceflight Induced Changes in the Central Nervous**

DOI: 10.5772/intechopen.74232

Although once a widely speculated about and largely theoretical topic, spaceflightinduced intracranial hypertension is more accepted as a distinct clinical phenomenon; yet, the underlying physiological mechanisms are still poorly understood. In the past, many terms were used to describe the symptoms of malaise, nausea, vomiting, and vertigo though longer duration spaceflights have increased the prevalence of overlapping symptoms of headache and visual disturbance. Spaceflight-induced visual pathology is thought to be a manifestation of increased intracranial pressure (ICP) because of its similar presentation to cases of known intracranial hypertension on Earth as well as the documentation of increased ICP by lumbar puncture in symptomatic astronauts upon return to gravity. The most likely mechanisms of spaceflight-induced increased ICP include a cephalad shift of body fluids, venous outflow obstruction, blood-brain barrier breakdown, and disruption to CSF flow. The relative contribution of increased ICP to the symptoms experienced during spaceflight is currently unknown though as other factors recently posited to contribute include local effects on ocular structures, individual differences in metabolism, and the vasodilator effects of carbon dioxide. Spaceflight-induced intracranial hypertension must be distinguished from other pathologies with similar symptomatology. The following chapter discusses the proposed physiologic causes and the pathological manifestations of increased ICP in the space-

flight environment and provides considerations for future long-term space travel.

Keywords: increased intracranial pressure, intracranial hypertension, spaceflight, space adaptation syndrome, VIIP, visual impairment, space flight-associated neuro-ocular

> © 2016 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and eproduction in any medium, provided the original work is properly cited.

© 2018 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use,

distribution, and reproduction in any medium, provided the original work is properly cited.

Spaceflight Induced Changes in the Central Nervous

**System**

System

Alex P. Michael

Abstract

syndrome, SANS

Alex P. Michael

Additional information is available at the end of the chapter

Additional information is available at the end of the chapter

http://dx.doi.org/10.5772/intechopen.74232


#### **Spaceflight Induced Changes in the Central Nervous System** Spaceflight Induced Changes in the Central Nervous System

DOI: 10.5772/intechopen.74232

Alex P. Michael Alex P. Michael

[90] Foster PP, Butler BD. Decompression to altitude: assumptions, experimental evidence, and future directions. Journal of Applied Physiology (1985). 2009;**106**(2):678-690

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HFM-124, Paper 16. Neuilly-sur-Seine (France): NATO RTO; 2005. pp. 16-1-16-6

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70 Into Space - A Journey of How Humans Adapt and Live in Microgravity

**377**(9760):153-164

872-875

1987;**58**(9 Pt 2):A97-A99

MMO-010; AFMAN 11-411(I))

Additional information is available at the end of the chapter Additional information is available at the end of the chapter

http://dx.doi.org/10.5772/intechopen.74232

#### Abstract

Although once a widely speculated about and largely theoretical topic, spaceflightinduced intracranial hypertension is more accepted as a distinct clinical phenomenon; yet, the underlying physiological mechanisms are still poorly understood. In the past, many terms were used to describe the symptoms of malaise, nausea, vomiting, and vertigo though longer duration spaceflights have increased the prevalence of overlapping symptoms of headache and visual disturbance. Spaceflight-induced visual pathology is thought to be a manifestation of increased intracranial pressure (ICP) because of its similar presentation to cases of known intracranial hypertension on Earth as well as the documentation of increased ICP by lumbar puncture in symptomatic astronauts upon return to gravity. The most likely mechanisms of spaceflight-induced increased ICP include a cephalad shift of body fluids, venous outflow obstruction, blood-brain barrier breakdown, and disruption to CSF flow. The relative contribution of increased ICP to the symptoms experienced during spaceflight is currently unknown though as other factors recently posited to contribute include local effects on ocular structures, individual differences in metabolism, and the vasodilator effects of carbon dioxide. Spaceflight-induced intracranial hypertension must be distinguished from other pathologies with similar symptomatology. The following chapter discusses the proposed physiologic causes and the pathological manifestations of increased ICP in the spaceflight environment and provides considerations for future long-term space travel.

Keywords: increased intracranial pressure, intracranial hypertension, spaceflight, space adaptation syndrome, VIIP, visual impairment, space flight-associated neuro-ocular syndrome, SANS

© 2016 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and eproduction in any medium, provided the original work is properly cited. © 2018 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

### 1. Introduction

Since the first manned spaceflight, many terms have been used to describe a collective group of seemingly related neurologic, ophthalmologic, and neurovestibular symptoms. Up to one half of astronauts are incapacitated by malaise, nausea, vomiting, and vertigo within the first few hours or days spent in space [1]. This constellation of symptoms, first described by Titov [2], was originally referred to as "space motion sickness" (SMS) [3] because of its similarity to motion sickness in the terrestrial environment. It is hypothesized that two physiologically distinct mechanisms converge to produce the symptoms of SMS [4, 5]: Cephalad fluid shifts are thought to alter the response properties of vestibular receptors while loss of tilt-related otolith signals in microgravity create a conflict between the actual and the anticipated signals collected from the external environment. The breadth of symptoms that astronauts report is likely due to a complex interaction between the neurovestibular system and autonomic nervous system [6]. A separate yet related term, "space adaptation syndrome," had similarly been used to include not only motion sickness, but also symptoms of head congestion and headaches brought on by a cephalad fluid shift into facial structures [7].

due to CSF flow disturbance from spaceflight-induced cephalad fluid shifts. A retrospective review of data has since identified eight additional cases of pathologic visual changes [10]

Spaceflight Induced Changes in the Central Nervous System

http://dx.doi.org/10.5772/intechopen.74232

73

In a follow-up study, Kramer, Sargsyan [11] evaluated 27 post-flight crewmembers using T2 weighted orbital and conventional brain sequences. They found various combinations of optic nerve sheath distention, posterior globe flattening, optic disk protrusion, increased optic nerve diameter, and greater concavity of the pituitary gland with posterior stalk displacement. Optic disk protrusion was only found with longer mission duration, indicating that clinical severity is associated with increasing spaceflight exposure. Repeat scans showed that some crewmembers continued to have posterior globe flattening 100 days after spaceflight suggesting that this condition may have a prolonged course or may not entirely return to normal. The authors determined that these findings were representative of intracranial hyper-

Clinically, visual pathology is considered a sensitive measure of increased ICP, as the perineural subarachnoid space of the optic nerve is contiguous with the intracranial subarachnoid space and therefore vulnerable to ICP fluctuations. This contiguity has been verified in a cadaver study which found that the subarachnoid pressures of the optic nerve sheath have a linear relationship to ICP [8, 12]. The National Aeronautics and Space Administration (NASA) has since referred to this spaceflight pathological phenomenon as vision impairment and intracranial pressure (VIIP) [10, 13] and recognized it as a serious threat to long duration

The Space Life Sciences at Johnson Space Center convened a summit in February of 2011 to address the topic of VIIP. At that meeting, a research and clinical advisory panel was created to provide guidance for the future clinical and fundamental research. After further investigation, the visual pathology seen in astronauts seemed to differ from those with intracranial hypertension in the terrestrial environment. Choroidal folds and hyperoptic shifts are sometimes seen in terrestrial intracranial hypertension but seemed to occur disproportionately in astronauts. Retinal cotton-wool spots are not typically seen in terrestrial intracranial hypertension but are prominent features in the visual pathology seen after space flight. Also, astronauts may experience unilateral pathology, which is again uncommon with global increases in intracranial pressure [14, 15]. Because of these discrepancies, visual pathology in astronauts has now been referred to as space flight-associated neuro-ocular syndrome (SANS) [14]. After considering all evidences, the panel concluded that the increase in ICP may not be the sole cause of visual disturbances following spaceflight and chose to examine other possible influences on

Space flight-induced compartmentalization of cerebrospinal fluid in the subarachnoid space with locally elevated cerebrospinal fluid sheath pressures has been proposed as an additional alternative hypothesis. Local orbital effects may explain ophthalmic structural and functional changes following spaceflight without an accompanying rise in ICP. This hypothesis purports

since the original publication.

tension due to elevated ICP.

spaceflight.

visual pathology [16].

2.1. Intraocular pressure

Most astronauts require only 2–3 days to acclimate to motion sickness in space and few continue to have residual symptoms during short term spaceflight [4]. As more time is spent in space, physiologically distinct yet overlapping symptoms seem to arise including headache and visual disturbance. These findings were noted to be similar to the cases of intracranial hypertension in the terrestrial environment which are caused by an elevation in intracranial pressure (ICP) [8]. Since the launch of the International Space Station (ISS) in 2000, the time that astronauts spend in space has dramatically increased. In addition, a 2015 partnership between the United States and Russia established the concept of 1-year mission onboard the ISS. Long-duration exposure to spaceflight has brought forth concern from the aerospace medicine community because its effects on the central nervous system are unknown.

### 2. Spaceflight increased intracranial pressure

Post-flight surveys of 300 astronauts from 1989 to 2011 found that approximately 29% reported deficits in distant and near visual acuity following short-duration missions (less than 2 weeks) while 60% reported deficits with long-duration space travel (typically 6 months) [9]. Starting in 2008, more detailed clinical data were collected for seven astronauts following 6 months of continuous orbital flight onboard the ISS. Complete visual and structural eye examinations before and after spaceflight revealed pathologic changes in the eye including optic disk edema, nerve fiber layer thickening, choroidal folds, posterior globe flattening, cotton wool spots, and decreased near vision accompanied by hyperopic shift. Of these seven crewmembers, lumbar punctures performed in the four cases with disk edema revealing opening pressures of 220, 210, 280, and 285 mm H2O at 60, 19, 12, and 57 days post-mission, respectively. It should be noted that no in-flight opening pressure have ever been attempted. With this clinical evidence, the authors hypothesized that the observed findings were due to cerebral venous congestion

due to CSF flow disturbance from spaceflight-induced cephalad fluid shifts. A retrospective review of data has since identified eight additional cases of pathologic visual changes [10] since the original publication.

In a follow-up study, Kramer, Sargsyan [11] evaluated 27 post-flight crewmembers using T2 weighted orbital and conventional brain sequences. They found various combinations of optic nerve sheath distention, posterior globe flattening, optic disk protrusion, increased optic nerve diameter, and greater concavity of the pituitary gland with posterior stalk displacement. Optic disk protrusion was only found with longer mission duration, indicating that clinical severity is associated with increasing spaceflight exposure. Repeat scans showed that some crewmembers continued to have posterior globe flattening 100 days after spaceflight suggesting that this condition may have a prolonged course or may not entirely return to normal. The authors determined that these findings were representative of intracranial hypertension due to elevated ICP.

Clinically, visual pathology is considered a sensitive measure of increased ICP, as the perineural subarachnoid space of the optic nerve is contiguous with the intracranial subarachnoid space and therefore vulnerable to ICP fluctuations. This contiguity has been verified in a cadaver study which found that the subarachnoid pressures of the optic nerve sheath have a linear relationship to ICP [8, 12]. The National Aeronautics and Space Administration (NASA) has since referred to this spaceflight pathological phenomenon as vision impairment and intracranial pressure (VIIP) [10, 13] and recognized it as a serious threat to long duration spaceflight.

The Space Life Sciences at Johnson Space Center convened a summit in February of 2011 to address the topic of VIIP. At that meeting, a research and clinical advisory panel was created to provide guidance for the future clinical and fundamental research. After further investigation, the visual pathology seen in astronauts seemed to differ from those with intracranial hypertension in the terrestrial environment. Choroidal folds and hyperoptic shifts are sometimes seen in terrestrial intracranial hypertension but seemed to occur disproportionately in astronauts. Retinal cotton-wool spots are not typically seen in terrestrial intracranial hypertension but are prominent features in the visual pathology seen after space flight. Also, astronauts may experience unilateral pathology, which is again uncommon with global increases in intracranial pressure [14, 15]. Because of these discrepancies, visual pathology in astronauts has now been referred to as space flight-associated neuro-ocular syndrome (SANS) [14]. After considering all evidences, the panel concluded that the increase in ICP may not be the sole cause of visual disturbances following spaceflight and chose to examine other possible influences on visual pathology [16].

#### 2.1. Intraocular pressure

1. Introduction

72 Into Space - A Journey of How Humans Adapt and Live in Microgravity

Since the first manned spaceflight, many terms have been used to describe a collective group of seemingly related neurologic, ophthalmologic, and neurovestibular symptoms. Up to one half of astronauts are incapacitated by malaise, nausea, vomiting, and vertigo within the first few hours or days spent in space [1]. This constellation of symptoms, first described by Titov [2], was originally referred to as "space motion sickness" (SMS) [3] because of its similarity to motion sickness in the terrestrial environment. It is hypothesized that two physiologically distinct mechanisms converge to produce the symptoms of SMS [4, 5]: Cephalad fluid shifts are thought to alter the response properties of vestibular receptors while loss of tilt-related otolith signals in microgravity create a conflict between the actual and the anticipated signals collected from the external environment. The breadth of symptoms that astronauts report is likely due to a complex interaction between the neurovestibular system and autonomic nervous system [6]. A separate yet related term, "space adaptation syndrome," had similarly been used to include not only motion sickness, but also symptoms of head congestion and head-

Most astronauts require only 2–3 days to acclimate to motion sickness in space and few continue to have residual symptoms during short term spaceflight [4]. As more time is spent in space, physiologically distinct yet overlapping symptoms seem to arise including headache and visual disturbance. These findings were noted to be similar to the cases of intracranial hypertension in the terrestrial environment which are caused by an elevation in intracranial pressure (ICP) [8]. Since the launch of the International Space Station (ISS) in 2000, the time that astronauts spend in space has dramatically increased. In addition, a 2015 partnership between the United States and Russia established the concept of 1-year mission onboard the ISS. Long-duration exposure to spaceflight has brought forth concern from the aerospace

medicine community because its effects on the central nervous system are unknown.

Post-flight surveys of 300 astronauts from 1989 to 2011 found that approximately 29% reported deficits in distant and near visual acuity following short-duration missions (less than 2 weeks) while 60% reported deficits with long-duration space travel (typically 6 months) [9]. Starting in 2008, more detailed clinical data were collected for seven astronauts following 6 months of continuous orbital flight onboard the ISS. Complete visual and structural eye examinations before and after spaceflight revealed pathologic changes in the eye including optic disk edema, nerve fiber layer thickening, choroidal folds, posterior globe flattening, cotton wool spots, and decreased near vision accompanied by hyperopic shift. Of these seven crewmembers, lumbar punctures performed in the four cases with disk edema revealing opening pressures of 220, 210, 280, and 285 mm H2O at 60, 19, 12, and 57 days post-mission, respectively. It should be noted that no in-flight opening pressure have ever been attempted. With this clinical evidence, the authors hypothesized that the observed findings were due to cerebral venous congestion

aches brought on by a cephalad fluid shift into facial structures [7].

2. Spaceflight increased intracranial pressure

Space flight-induced compartmentalization of cerebrospinal fluid in the subarachnoid space with locally elevated cerebrospinal fluid sheath pressures has been proposed as an additional alternative hypothesis. Local orbital effects may explain ophthalmic structural and functional changes following spaceflight without an accompanying rise in ICP. This hypothesis purports that a local disruption of CSF dynamics surrounding the optic nerve sheath results in an orbital compartment syndrome [17]. A microgravity-induced cephalad fluid shift may lead to choroidal engorgement and subsequent expansion of the choroid against the rigid scleral tissue leading to a sudden increase in intraocular pressure (IOP) [18, 19]. The initial spike in IOP is followed by a decrease over a period of days likely due to a compensatory decrease in aqueous volume [19]. Thus, in-flight, post-flight, and HDT studies suggest the possibility that a lowering of IOP may occur during extended microgravity exposure. Ocular hypotony, generally defined as an IOP of <6.5 mmHg, is well-documented to cause disk edema, posterior globe flattening, choroidal folds, and a hyperopic shift very similar to some of our observed changes [17].

to examine CBF in the middle cerebral artery of humans following 6 HDT. CBF velocity was found to increase immediately upon initiation of HDT, reach a peak at 3 h and then begin to decrease toward baseline after 9 h of HDT. Similarly, no significant differences in CBF velocity were found on transcranial Doppler measurements after up to 2 weeks of spaceflight when compared to pre-flight baseline values [7, 28, 29]. These findings suggested preserved or possibly improved cerebrovascular autoregulation during short-duration spaceflight. When time spent in microgravity is extended, though, there is evidence that autoregulation may

Spaceflight Induced Changes in the Central Nervous System

http://dx.doi.org/10.5772/intechopen.74232

75

Ex vivo examinations of mice following HDT technique in the terrestrial environment revealed increased intrinsic vasoconstrictor responsiveness of cerebral arteries [30–32], thickening of the medial smooth muscle cell layer in some cerebral arteries [33, 34], and decreased cerebral blood flow [31, 34]. These findings provide histological evidence for appropriate autoregulatory increases in sympathetic tone of cerebral vessels. However, similar examination of post-spaceflight mice, following 13 days on-board the STS-135 shuttle mission [27], differed from terrestrial HDT technique by exhibiting less vasoconstriction, more vascular distensibility, and lower effective elastic modulus and stiffness. These findings suggest a decrease in cerebral vascular resistance (CVR) and thus an increase in CBF [CBF = (Pa – ICP)/CVR, where CBF is proportional to arterial pressure (Pa) and ICP and inversely proportional to CVR]. This finding supports the fact that increased arterial perfusion pressure alone, as in the HDT, does not lead to increased CBF but that CBF may still be elevated in microgravity and may further

Although autoregulatory mechanisms in the cerebrovasculature have evolved to provide a steady CBF in the face of wide fluctuations of cerebral perfusion pressure, endothelial dysfunction may lower the threshold pressure required to increased deposition of fluid into the intracranial interstitial. Using an in silico model for intracranial pressure dynamics, Stevens et al. [35] originally determined that increased interstitial fluid volume in the brain lead to a decrease in ICP in microgravity. After modifying the model to account for reduction in the integrity of the blood-brain barrier, they found a much more significant increase in intracranial interstitial fluid as well as elevation of ICP high enough for symptoms to manifest [36].

Endothelial cell gap junctions are held closed by the combined pressure of the interstitial fluid in the brain and the intracranial capillary pressure. Lakin et al. [36] proposed that in a 1-G environment, hydrostatic pressure is transmitted from the brain to the capillaries, thus increasing the pressure needed to close endothelial cell junctions. In spaceflight, the brain is unable to contribute its weight to maintaining the pressure balance, thereby allowing fluid to leak from

Aside from increased CBF, it has also been proposed that cephalad fluid shifts contribute to elevations in ICP by increasing the post-capillary venous pressure [1] through downstream

become altered.

contribute to an increase in ICP [27].

the intracranial capillaries into the interstitial fluid.

3.3. Venous outflow obstruction and CSF hydrodynamics

3.2. Endothelial breakdown

The lamina cribrosa is a mesh-like structure that acts as a pressure barrier between the intraocular space and cerebrospinal fluid space of the optic nerve sheath [20]. The difference in IOP and CSF pressure across the lamina cribrosa is known as the translaminar pressure difference. Small yet chronically elevated CSF pressure in combination with ocular hypotony would lead to a significant pressure gradient toward the intraocular space and could thereby be responsible for the ophthalmic structural and functional changes seen in astronauts secondary to spaceflight exposure.

### 3. Factors contributing neuro-ocular symptoms

#### 3.1. Microgravity-induced fluid shifts

Early studies found that exposure to both microgravity and simulated microgravity led to a cephalad shift of plasma fluid into the interstitial spaces of the head and neck [21, 22]. This led researchers to believe that microgravity-induced cephalad fluid shifts caused increased ICP and were a prominent contributor to both space adaptation syndrome [1] and space motion sickness [23]. The initial support for this mechanism was sought through the use of the headdown tilt (HDT) method which simulates the fluid shifts that occur in the spaceflight environment. In an early study by Murthy et al. [24], 10 min of 6 HDT was found to significantly increase the ICP of six healthy males as indicated by tympanic membrane displacement. Increasing the angle to 15, HDT generated a further increase in ICP. Although no long-term monitoring of the HDT method has been attempted in humans, ICP was evaluated for 7-days of 45 HDT using a subarachnoid catheter in rabbits [25]. An immediate increase in ICP was observed which peaked at 12 h of HDT and then decreased gradually toward the pre-HDT baseline value. These findings suggest that rabbits begin to adapt to HDT within the first few days.

Since cephalad fluid shift has been found to increase fluid in the interstitial soft tissue space of the head, it may seem intuitive that the increased filtration of plasma into the intracranial interstitium would lead to increased ICP. However, when autoregulatory mechanisms are intact, they prevent a sustained increase in cerebral blood flow (CBF) in the presence of an elevated cerebral perfusion pressure (CPP) [26, 27]. Kawai et al. [28] used transcranial Doppler to examine CBF in the middle cerebral artery of humans following 6 HDT. CBF velocity was found to increase immediately upon initiation of HDT, reach a peak at 3 h and then begin to decrease toward baseline after 9 h of HDT. Similarly, no significant differences in CBF velocity were found on transcranial Doppler measurements after up to 2 weeks of spaceflight when compared to pre-flight baseline values [7, 28, 29]. These findings suggested preserved or possibly improved cerebrovascular autoregulation during short-duration spaceflight. When time spent in microgravity is extended, though, there is evidence that autoregulation may become altered.

Ex vivo examinations of mice following HDT technique in the terrestrial environment revealed increased intrinsic vasoconstrictor responsiveness of cerebral arteries [30–32], thickening of the medial smooth muscle cell layer in some cerebral arteries [33, 34], and decreased cerebral blood flow [31, 34]. These findings provide histological evidence for appropriate autoregulatory increases in sympathetic tone of cerebral vessels. However, similar examination of post-spaceflight mice, following 13 days on-board the STS-135 shuttle mission [27], differed from terrestrial HDT technique by exhibiting less vasoconstriction, more vascular distensibility, and lower effective elastic modulus and stiffness. These findings suggest a decrease in cerebral vascular resistance (CVR) and thus an increase in CBF [CBF = (Pa – ICP)/CVR, where CBF is proportional to arterial pressure (Pa) and ICP and inversely proportional to CVR]. This finding supports the fact that increased arterial perfusion pressure alone, as in the HDT, does not lead to increased CBF but that CBF may still be elevated in microgravity and may further contribute to an increase in ICP [27].

#### 3.2. Endothelial breakdown

that a local disruption of CSF dynamics surrounding the optic nerve sheath results in an orbital compartment syndrome [17]. A microgravity-induced cephalad fluid shift may lead to choroidal engorgement and subsequent expansion of the choroid against the rigid scleral tissue leading to a sudden increase in intraocular pressure (IOP) [18, 19]. The initial spike in IOP is followed by a decrease over a period of days likely due to a compensatory decrease in aqueous volume [19]. Thus, in-flight, post-flight, and HDT studies suggest the possibility that a lowering of IOP may occur during extended microgravity exposure. Ocular hypotony, generally defined as an IOP of <6.5 mmHg, is well-documented to cause disk edema, posterior globe flattening, choroidal folds, and a hyperopic shift very similar to some of our observed changes

The lamina cribrosa is a mesh-like structure that acts as a pressure barrier between the intraocular space and cerebrospinal fluid space of the optic nerve sheath [20]. The difference in IOP and CSF pressure across the lamina cribrosa is known as the translaminar pressure difference. Small yet chronically elevated CSF pressure in combination with ocular hypotony would lead to a significant pressure gradient toward the intraocular space and could thereby be responsible for the ophthalmic structural and functional changes seen in astronauts second-

Early studies found that exposure to both microgravity and simulated microgravity led to a cephalad shift of plasma fluid into the interstitial spaces of the head and neck [21, 22]. This led researchers to believe that microgravity-induced cephalad fluid shifts caused increased ICP and were a prominent contributor to both space adaptation syndrome [1] and space motion sickness [23]. The initial support for this mechanism was sought through the use of the headdown tilt (HDT) method which simulates the fluid shifts that occur in the spaceflight environment. In an early study by Murthy et al. [24], 10 min of 6 HDT was found to significantly increase the ICP of six healthy males as indicated by tympanic membrane displacement. Increasing the angle to 15, HDT generated a further increase in ICP. Although no long-term monitoring of the HDT method has been attempted in humans, ICP was evaluated for 7-days of 45 HDT using a subarachnoid catheter in rabbits [25]. An immediate increase in ICP was observed which peaked at 12 h of HDT and then decreased gradually toward the pre-HDT baseline value. These findings suggest that rabbits begin to adapt to HDT within the first few

Since cephalad fluid shift has been found to increase fluid in the interstitial soft tissue space of the head, it may seem intuitive that the increased filtration of plasma into the intracranial interstitium would lead to increased ICP. However, when autoregulatory mechanisms are intact, they prevent a sustained increase in cerebral blood flow (CBF) in the presence of an elevated cerebral perfusion pressure (CPP) [26, 27]. Kawai et al. [28] used transcranial Doppler

[17].

days.

ary to spaceflight exposure.

3.1. Microgravity-induced fluid shifts

3. Factors contributing neuro-ocular symptoms

74 Into Space - A Journey of How Humans Adapt and Live in Microgravity

Although autoregulatory mechanisms in the cerebrovasculature have evolved to provide a steady CBF in the face of wide fluctuations of cerebral perfusion pressure, endothelial dysfunction may lower the threshold pressure required to increased deposition of fluid into the intracranial interstitial. Using an in silico model for intracranial pressure dynamics, Stevens et al. [35] originally determined that increased interstitial fluid volume in the brain lead to a decrease in ICP in microgravity. After modifying the model to account for reduction in the integrity of the blood-brain barrier, they found a much more significant increase in intracranial interstitial fluid as well as elevation of ICP high enough for symptoms to manifest [36].

Endothelial cell gap junctions are held closed by the combined pressure of the interstitial fluid in the brain and the intracranial capillary pressure. Lakin et al. [36] proposed that in a 1-G environment, hydrostatic pressure is transmitted from the brain to the capillaries, thus increasing the pressure needed to close endothelial cell junctions. In spaceflight, the brain is unable to contribute its weight to maintaining the pressure balance, thereby allowing fluid to leak from the intracranial capillaries into the interstitial fluid.

#### 3.3. Venous outflow obstruction and CSF hydrodynamics

Aside from increased CBF, it has also been proposed that cephalad fluid shifts contribute to elevations in ICP by increasing the post-capillary venous pressure [1] through downstream venous congestion [31, 37]. While supine, a majority of the cerebral outflow occurs through the internal jugular veins. However, internal jugular veins collapse in the standing position and blood is shunted through secondary venous channels (e.g., vertebral plexus and deep cervical veins). This has been confirmed using time of flight MRI techniques in the sitting versus supine positions [38, 39]. Termed "Space obstructive syndrome," Wiener [40] proposed that internal jugular vein compression along with loss of gravitational-induced cranial outflow of venous blood in the vertebral veins may lead to venous hypertension. Cerebral outflow may divert through the internal jugular veins when standing if there is a significant increase in CVP (e.g., with a Valsalva maneuver) [41]. This is relevant to spaceflight as the gravitational unloading of the thoracic space causes CVP to paradoxically decrease [42–44]. Decreased venous flow may lead to a rise in pressure high enough to disturb the gradient between the CSF and cerebral venous sinuses. CSF normally circulates through the subarachnoid space and is absorbed through arachnoid granulations into the cerebral venous sinuses. Similarly, cine phase-contrast MRI examining CSF flow in the upright posture found that a considerably smaller amount of CSF oscillated between the cranium and the spinal canal than in the supine position [38, 39, 41].

suggest that polymorphisms in enzymes of the one-carbon pathway may interact with micro-

Spaceflight Induced Changes in the Central Nervous System

http://dx.doi.org/10.5772/intechopen.74232

77

It has also been proposed that radiation exposure outside of Earth's atmosphere may disrupt the integrity of the blood-brain barrier [36]. The two cosmic sources of radiation that are considered to impact mission success are solar particle events and galactic cosmic rays. Sanzari et al. [51] found that exposure to doses of ionizing radiation similar to that experienced by astronauts during a solar particle event led to significant long-term elevation in ICP in a porcine model. Experiments involving cell phone radiation found that small amounts of radiation may activate endothelial cell proteins causing the endothelial cells to shrink and widen the gap junction [52–54]. Increased vessel permeability in turn leads to extravasation of albumin into brain parenchyma leading to cerebral edema [53]. There is little evidence, though, that the radiation generated by solar particle events or galactic cosmic rays produce effects

There have been several studies showing that resistive exercise during spaceflight may lead to a significant increase in IOP [55, 56]. The effect it has on increased ICP though remains controversial. Heavy loading and resistance exercise are important to prevent musculoskeletal losses, especially bone density [57]. For that reason, resistance exercises have been encouraged aboard the ISS. Inducing a Valsalva maneuver during weight lifting has been shown to increase intrathoracic pressure which may in turn elevate ICP [58]. Aerobic exercise though has not been found to increase ICP likely because it is accomplished without a Valsalva [59].

Prepackaged foods for the International Space Station were originally high in sodium at up to 5300 g per day [60]. High sodium levels create an osmotic shift of body fluid from the interstitial to the intravascular space contributing to increased venous volume, congestion and ultimate jugular venous outflow obstruction. In 1974, a prospective trial of sodium restriction reportedly lead to remission of papilledema in all 9 patients with idiopathic intracranial hypertension that were involved [61]. It is likely that improvement occurs due to concomitant weight loss and not entirely due to sodium and water distribution. However, it is suggested that astronauts consume a lower sodium diet in attempt to prevent long term visual damage. NASA has since reformulated to substantially reduce the intake of sodium in the daily diet of astronauts to less than 3 g per day [60].

Spaceflight imposes a short-term risk to mission operational success by contributing to headaches, malaise, and visual impairment and further may lead to long-term risks that have not

4. Cognitive and structural changes in the brain

gravity to cause ophthalmic changes.

similar to that of radiofrequency waves.

3.6. Radiation

3.7. Exercise

3.8. Sodium intake

#### 3.4. Carbon dioxide

Carbon dioxide (CO2), a natural byproduct of cellular respiration, is known to be a potent vasodilator in the cerebral vasculature. This normal physiologic event occurs to increased CBF to the brain in times of respiratory compromise [45]. Nominal CO2 levels on the ISS are between 2.3 and 5.3 mmHg [46] and the astronauts presenting with VIIP symptoms were exposed to levels less than 5 mmHg [46]. Although these levels are 20 higher than the normal 0.23 mmHg CO2 on Earth, this CO2 level is still relatively low and not thought to have detrimental physiological effects. However, as there is no natural convection in microgravity, astronauts may be exposed to localized areas of high CO2 when working in a small space, during exercise [46] and possibly during sleep [47]. In a computational fluid dynamics analysis, Son et al. (2012) determined that without natural convection of gases and ventilation, pCO2 could rise above 9 mmHg around a sleeping astronaut's mouth within just 10 min. These pockets of CO2 would not be detected by the major constituent analyzers onboard the ISS, and therefore would go unreported. Regular exposure to slightly increased ambient CO2 as well as potential exposure to pockets of high concentrations of CO2 may compromise the integrity of the blood-brain barrier impairing cerebrovascular resistance thus leading to increased CBF and ICP [45, 48]. The response CBF and CVR to CO2 was found to be reduced after long-duration missions on the ISS indicating impaired autoregulation and reduced cerebrovascular CO2 reactivity [27, 49].

#### 3.5. One-carbon metabolism

It has also been shown that variation in an important metabolic pathway, the one-carbon metabolism cycle, is associated with the occurrence of the VIIP syndrome in astronauts [50]. Zwart et al. (2012) found significantly higher serum levels of several one-carbon metabolites in astronauts affected by the VIIP syndrome compared to unaffected astronauts, including serum homocysteine, cystathionine, 2-methylcitric acid, and methylmalonic acid. These findings suggest that polymorphisms in enzymes of the one-carbon pathway may interact with microgravity to cause ophthalmic changes.

#### 3.6. Radiation

venous congestion [31, 37]. While supine, a majority of the cerebral outflow occurs through the internal jugular veins. However, internal jugular veins collapse in the standing position and blood is shunted through secondary venous channels (e.g., vertebral plexus and deep cervical veins). This has been confirmed using time of flight MRI techniques in the sitting versus supine positions [38, 39]. Termed "Space obstructive syndrome," Wiener [40] proposed that internal jugular vein compression along with loss of gravitational-induced cranial outflow of venous blood in the vertebral veins may lead to venous hypertension. Cerebral outflow may divert through the internal jugular veins when standing if there is a significant increase in CVP (e.g., with a Valsalva maneuver) [41]. This is relevant to spaceflight as the gravitational unloading of the thoracic space causes CVP to paradoxically decrease [42–44]. Decreased venous flow may lead to a rise in pressure high enough to disturb the gradient between the CSF and cerebral venous sinuses. CSF normally circulates through the subarachnoid space and is absorbed through arachnoid granulations into the cerebral venous sinuses. Similarly, cine phase-contrast MRI examining CSF flow in the upright posture found that a considerably smaller amount of CSF oscillated between the cranium and the spinal canal than in the supine position [38, 39, 41].

76 Into Space - A Journey of How Humans Adapt and Live in Microgravity

Carbon dioxide (CO2), a natural byproduct of cellular respiration, is known to be a potent vasodilator in the cerebral vasculature. This normal physiologic event occurs to increased CBF to the brain in times of respiratory compromise [45]. Nominal CO2 levels on the ISS are between 2.3 and 5.3 mmHg [46] and the astronauts presenting with VIIP symptoms were exposed to levels less than 5 mmHg [46]. Although these levels are 20 higher than the normal 0.23 mmHg CO2 on Earth, this CO2 level is still relatively low and not thought to have detrimental physiological effects. However, as there is no natural convection in microgravity, astronauts may be exposed to localized areas of high CO2 when working in a small space, during exercise [46] and possibly during sleep [47]. In a computational fluid dynamics analysis, Son et al. (2012) determined that without natural convection of gases and ventilation, pCO2 could rise above 9 mmHg around a sleeping astronaut's mouth within just 10 min. These pockets of CO2 would not be detected by the major constituent analyzers onboard the ISS, and therefore would go unreported. Regular exposure to slightly increased ambient CO2 as well as potential exposure to pockets of high concentrations of CO2 may compromise the integrity of the blood-brain barrier impairing cerebrovascular resistance thus leading to increased CBF and ICP [45, 48]. The response CBF and CVR to CO2 was found to be reduced after long-duration missions on the ISS indicating impaired autoregulation and reduced cere-

It has also been shown that variation in an important metabolic pathway, the one-carbon metabolism cycle, is associated with the occurrence of the VIIP syndrome in astronauts [50]. Zwart et al. (2012) found significantly higher serum levels of several one-carbon metabolites in astronauts affected by the VIIP syndrome compared to unaffected astronauts, including serum homocysteine, cystathionine, 2-methylcitric acid, and methylmalonic acid. These findings

3.4. Carbon dioxide

brovascular CO2 reactivity [27, 49].

3.5. One-carbon metabolism

It has also been proposed that radiation exposure outside of Earth's atmosphere may disrupt the integrity of the blood-brain barrier [36]. The two cosmic sources of radiation that are considered to impact mission success are solar particle events and galactic cosmic rays. Sanzari et al. [51] found that exposure to doses of ionizing radiation similar to that experienced by astronauts during a solar particle event led to significant long-term elevation in ICP in a porcine model. Experiments involving cell phone radiation found that small amounts of radiation may activate endothelial cell proteins causing the endothelial cells to shrink and widen the gap junction [52–54]. Increased vessel permeability in turn leads to extravasation of albumin into brain parenchyma leading to cerebral edema [53]. There is little evidence, though, that the radiation generated by solar particle events or galactic cosmic rays produce effects similar to that of radiofrequency waves.

#### 3.7. Exercise

There have been several studies showing that resistive exercise during spaceflight may lead to a significant increase in IOP [55, 56]. The effect it has on increased ICP though remains controversial. Heavy loading and resistance exercise are important to prevent musculoskeletal losses, especially bone density [57]. For that reason, resistance exercises have been encouraged aboard the ISS. Inducing a Valsalva maneuver during weight lifting has been shown to increase intrathoracic pressure which may in turn elevate ICP [58]. Aerobic exercise though has not been found to increase ICP likely because it is accomplished without a Valsalva [59].

#### 3.8. Sodium intake

Prepackaged foods for the International Space Station were originally high in sodium at up to 5300 g per day [60]. High sodium levels create an osmotic shift of body fluid from the interstitial to the intravascular space contributing to increased venous volume, congestion and ultimate jugular venous outflow obstruction. In 1974, a prospective trial of sodium restriction reportedly lead to remission of papilledema in all 9 patients with idiopathic intracranial hypertension that were involved [61]. It is likely that improvement occurs due to concomitant weight loss and not entirely due to sodium and water distribution. However, it is suggested that astronauts consume a lower sodium diet in attempt to prevent long term visual damage. NASA has since reformulated to substantially reduce the intake of sodium in the daily diet of astronauts to less than 3 g per day [60].

### 4. Cognitive and structural changes in the brain

Spaceflight imposes a short-term risk to mission operational success by contributing to headaches, malaise, and visual impairment and further may lead to long-term risks that have not yet fully been elicited. The long-term risks of spaceflight-induced intracranial hypertension may be best estimated through observations of chronically increased ICP on earth. Individuals with idiopathic intracranial hypertension (IIH) are plagued with well-documented symptoms of severe headache and vision loss but may also experience pulsatile tinnitus, ataxia, memory disturbances, and cognitive dysfunction [62–64]. Several small population studies have revealed significant cognitive deficits in patients with IIH especially within verbal and memory tests [65, 66]. In a study by Yri et al. [62], 31 patients with IIH performed significantly worse on tests of reaction time, processing speed, visuospatial memory, and attention compared to a demographically matched healthy control group. Individuals with IIH continued to exhibit cognitive dysfunction after 3 months of pharmacologic therapy despite improvement in ICP and headache. Further, quality of life measures have been found to be lower compared with population norms [67].

characterize fluid distribution and compartmentalization during long-term space travel to determine systemic and ocular factors of individual susceptibility to the development of ICP elevation and to evaluate noninvasive ICP monitoring devices for the clinical evaluation of ICP

Spaceflight Induced Changes in the Central Nervous System

http://dx.doi.org/10.5772/intechopen.74232

79

On land and in orbit, astronauts are subjected to a multitude of visual examinations including visual acuity tests, amsler grids, tonometry, fundoscopy, and optical coherence tomography. Following long duration space travel, researchers are applying MR imaging, visual field perimetry and cycloplegic refraction. Noninvasive techniques for in-flight ICP, intraocular pressure, and cerebral blood flow measurements are also being investigated including ophthalmodynamometry, tympanic membrane displacement and optic nerve ultrasound. A linear correlation has been found between central retinal vein pressure and ICP due to pressure gradients across the optic nerve sheath [76]. Ophthalmodynamometry is a useful method for determining the central retinal artery pressure and is therefore a useful indirect measure on ICP. Tympanic membrane displacement has been used to detect elevated ICP in hydrocephalus children in the terrestrial environment [77]. Because cerebrospinal fluid and perilymph communicate through the cochlear aqueduct, an increase in ICP is directly transmitted to the footplate of the stapes and resulting in inward displacement. The optic nerve ultrasound also seems to be a reliable non-invasive measure as optic nerve sheath diameter has been found to be highly sensitive and specific for the detection of elevated ICP using [78]. Noninvasive approaches though are correlation based and must be calibrated to each patient based on known ICP baseline measurements. This may lead to a high margin for error. Researchers are currently investigating how to correlate pre-flight to in-flight data across multiple modalities. As space tourism increases, there will be spaceflight participants that are not as physical fit and have not undergone the rigorous training as that of NASA astronauts. Intracranial hypertension may also pose a risk to future commercial spaceflight. The incidence of intracranial hypertension and visual pathology may rise with the increase in civilian space travelers who are not as physiological adept as their astronaut counterparts. Further, increased ICP in the spaceflight environment may become more concerning in someone who has a predilection, or underlying disease process that, combined with increased ICP, could cause in-flight or post-

The ultimate prevention of neuro-ocular dysfunction due to spaceflight would be reproduction of the normal 1G environment. This could theoretically be introduced by the Coriolis force through rotation of the entire space vehicle, part of the vehicle, or using an on-board centrifuge. Reintroduction of gravity is the only single measure than can protect all physiological systems in all individuals against the effects of weightlessness. Until that concept comes to

Pharmacological agents are capable of lowering ICP in the terrestrial environment and are being studied as a means of reducing the risk of visual impairment. Acetazolamide acts as a carbonic anhydrase inhibitor leading to decreased production of CSF at the choroid plexus. However, it also increases the risk for renal calculi and would lower intraocular pressure which could worsen choroidal swelling and potentially optic disk swelling. Other diuretics (e.g., furosemide and hydrochlorothiazide) are more potent diuretics and although may

fruition, other countermeasures are actively being researched.

preflight, in-flight, and post-flight [75].

flight problems [40].

At this time, there is no evidence for gross structural damage as a cause of cognitive dysfunction in IIH, as brain morphometric and volumetric analysis have also been insignificant compared to healthy controls [68]. Subtle disturbances to white or gray matter substance due to mechanical compression similar to that in normal pressure hydrocephalus has also been proposed [63].

The evidence to suggest impaired cognition in astronauts related to spaceflight is sparse, but terrestrial data could potentially predict long duration sequela and may influence how we monitor astronauts in the future. In 2017, scientists released the results of a study using MR imaging to compare the brain morphology of astronauts after long and short duration space flight. Astronauts who participated in long-duration flights had significantly more narrowing of the central sulcus, upward shift of the brain, and narrowing of CSF spaces [69]. Another study compared MRIs of the brain before and after spaceflight from 27 astronauts and found decreased volume of the frontotemporal gray matter and an increase in the volume of the medial primary sensorimotor cortexes. This finding was attributed to neuroplasticity during adaptation to microgravity [70]. Long duration spaceflight has also been associated with an increase in periventricular white matter hyperintensities seen on MRI. These hyperdensities are linked to an increase in ventricular CSF volume leading to transependymal CSF flow from the ventricles into the brain parenchyma. It appears it is at least partially reversible on return to normal gravity [71]. Similarly, a significantly increased number of white matter hyperintensities were found in high-altitude U-2 pilots compared to age-matched healthy controls [72]. The presence of these white matter changes were associated with cognitive impairments ranging from slowed though processes to confusion, unresponsiveness, and even permanent cognitive decline [73, 74].

### 5. Future considerations

Under NASA's Human Research Roadmap and its Path to Risk Reduction, VIIP/SANS continues to be identified as a top risk that may affect astronauts on long duration missions and remain under intensive investigation by space agencies. Projects are currently planned to characterize fluid distribution and compartmentalization during long-term space travel to determine systemic and ocular factors of individual susceptibility to the development of ICP elevation and to evaluate noninvasive ICP monitoring devices for the clinical evaluation of ICP preflight, in-flight, and post-flight [75].

yet fully been elicited. The long-term risks of spaceflight-induced intracranial hypertension may be best estimated through observations of chronically increased ICP on earth. Individuals with idiopathic intracranial hypertension (IIH) are plagued with well-documented symptoms of severe headache and vision loss but may also experience pulsatile tinnitus, ataxia, memory disturbances, and cognitive dysfunction [62–64]. Several small population studies have revealed significant cognitive deficits in patients with IIH especially within verbal and memory tests [65, 66]. In a study by Yri et al. [62], 31 patients with IIH performed significantly worse on tests of reaction time, processing speed, visuospatial memory, and attention compared to a demographically matched healthy control group. Individuals with IIH continued to exhibit cognitive dysfunction after 3 months of pharmacologic therapy despite improvement in ICP and headache. Further, quality of life measures have been found to be lower compared

At this time, there is no evidence for gross structural damage as a cause of cognitive dysfunction in IIH, as brain morphometric and volumetric analysis have also been insignificant compared to healthy controls [68]. Subtle disturbances to white or gray matter substance due to mechanical compression similar to that in normal pressure hydrocephalus has also been

The evidence to suggest impaired cognition in astronauts related to spaceflight is sparse, but terrestrial data could potentially predict long duration sequela and may influence how we monitor astronauts in the future. In 2017, scientists released the results of a study using MR imaging to compare the brain morphology of astronauts after long and short duration space flight. Astronauts who participated in long-duration flights had significantly more narrowing of the central sulcus, upward shift of the brain, and narrowing of CSF spaces [69]. Another study compared MRIs of the brain before and after spaceflight from 27 astronauts and found decreased volume of the frontotemporal gray matter and an increase in the volume of the medial primary sensorimotor cortexes. This finding was attributed to neuroplasticity during adaptation to microgravity [70]. Long duration spaceflight has also been associated with an increase in periventricular white matter hyperintensities seen on MRI. These hyperdensities are linked to an increase in ventricular CSF volume leading to transependymal CSF flow from the ventricles into the brain parenchyma. It appears it is at least partially reversible on return to normal gravity [71]. Similarly, a significantly increased number of white matter hyperintensities were found in high-altitude U-2 pilots compared to age-matched healthy controls [72]. The presence of these white matter changes were associated with cognitive impairments ranging from slowed though processes to confusion, unresponsiveness, and even

Under NASA's Human Research Roadmap and its Path to Risk Reduction, VIIP/SANS continues to be identified as a top risk that may affect astronauts on long duration missions and remain under intensive investigation by space agencies. Projects are currently planned to

with population norms [67].

78 Into Space - A Journey of How Humans Adapt and Live in Microgravity

permanent cognitive decline [73, 74].

5. Future considerations

proposed [63].

On land and in orbit, astronauts are subjected to a multitude of visual examinations including visual acuity tests, amsler grids, tonometry, fundoscopy, and optical coherence tomography. Following long duration space travel, researchers are applying MR imaging, visual field perimetry and cycloplegic refraction. Noninvasive techniques for in-flight ICP, intraocular pressure, and cerebral blood flow measurements are also being investigated including ophthalmodynamometry, tympanic membrane displacement and optic nerve ultrasound. A linear correlation has been found between central retinal vein pressure and ICP due to pressure gradients across the optic nerve sheath [76]. Ophthalmodynamometry is a useful method for determining the central retinal artery pressure and is therefore a useful indirect measure on ICP. Tympanic membrane displacement has been used to detect elevated ICP in hydrocephalus children in the terrestrial environment [77]. Because cerebrospinal fluid and perilymph communicate through the cochlear aqueduct, an increase in ICP is directly transmitted to the footplate of the stapes and resulting in inward displacement. The optic nerve ultrasound also seems to be a reliable non-invasive measure as optic nerve sheath diameter has been found to be highly sensitive and specific for the detection of elevated ICP using [78]. Noninvasive approaches though are correlation based and must be calibrated to each patient based on known ICP baseline measurements. This may lead to a high margin for error. Researchers are currently investigating how to correlate pre-flight to in-flight data across multiple modalities.

As space tourism increases, there will be spaceflight participants that are not as physical fit and have not undergone the rigorous training as that of NASA astronauts. Intracranial hypertension may also pose a risk to future commercial spaceflight. The incidence of intracranial hypertension and visual pathology may rise with the increase in civilian space travelers who are not as physiological adept as their astronaut counterparts. Further, increased ICP in the spaceflight environment may become more concerning in someone who has a predilection, or underlying disease process that, combined with increased ICP, could cause in-flight or postflight problems [40].

The ultimate prevention of neuro-ocular dysfunction due to spaceflight would be reproduction of the normal 1G environment. This could theoretically be introduced by the Coriolis force through rotation of the entire space vehicle, part of the vehicle, or using an on-board centrifuge. Reintroduction of gravity is the only single measure than can protect all physiological systems in all individuals against the effects of weightlessness. Until that concept comes to fruition, other countermeasures are actively being researched.

Pharmacological agents are capable of lowering ICP in the terrestrial environment and are being studied as a means of reducing the risk of visual impairment. Acetazolamide acts as a carbonic anhydrase inhibitor leading to decreased production of CSF at the choroid plexus. However, it also increases the risk for renal calculi and would lower intraocular pressure which could worsen choroidal swelling and potentially optic disk swelling. Other diuretics (e.g., furosemide and hydrochlorothiazide) are more potent diuretics and although may theoretically aid in decreasing CSF production would produce undesirable metabolic side effects. Topiramate has been used in the treatment of migraine headaches and has a weak carbonic anhydrase effect which may lower ICP. It too has undesirable side effects such as cognitive slowing [79].

Author details

Alex P. Michael

References

USA

Address all correspondence to: alexmichael87@gmail.com

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Division of Neurosurgery, Southern Illinois University School of Medicine, Springfield, IL,

Spaceflight Induced Changes in the Central Nervous System

http://dx.doi.org/10.5772/intechopen.74232

81

[1] Jennings T. Space adaptation syndrome is caused by elevated intracranial pressure. Med-

[3] Schneider RC, Crosby EC. Motion sickness: Part I—a theory. Aviation, Space, and Envi-

[4] Heer M, Paloski WH. Space motion sickness: Incidence, etiology, and countermeasures.

[5] Thornton WE, Bonato F. Space motion sickness and motion sickness: Symptoms and

[6] Williams D, Kuipers A, Mukai C, Thirsk R. Acclimation during space flight: Effects on human physiology. CMAJ: Canadian Medical Association Journal (Journal de l'Association

[7] Bagian JP, Hackett P. Cerebral blood flow: Comparison of ground-based and spaceflight data and correlation with space adaptation syndrome. Journal of Clinical Pharmacology.

[8] Friedman DI, Jacobson DM. Diagnostic criteria for idiopathic intracranial hypertension.

[9] Mader TH, Gibson CR, Pass AF, Kramer LA, Lee AG, Fogarty J, et al. Optic disc edema, globe flattening, choroidal folds, and hyperopic shifts observed in astronauts after long-

[10] Alexander DJ, Gibson CR, Hamilton DR, Lee SMC, Mader TH, Otto C, et al. Risk of spaceflight-induced intracranial hypertension and vision alterations. Lyndon B. Houston, Texas: National Aeronautics and Space Administration, Johnson Space Center; 2012

[11] Kramer LA, Sargsyan AE, Hasan KM, Polk JD, Hamilton DR. Orbital and intracranial effects of microgravity: Findings at 3-T MR imaging. Radiology. 2012;263(3):819-827

etiology. Aviation, Space, and Environmental Medicine. 2013;84(7):716-721

### 6. Conclusion

Many terms have been used to describe the symptoms of head congestion, nausea and vomiting, and visual disturbance in the space-flight environment. Over the years, attempts have been made to connect these seemingly related symptoms to a number of diverse pathophysiological origins. At this time, the contribution of increased ICP to the symptoms experienced during spaceflight is unknown. Although direct measurements of CSF pressure have not been performed in actual spaceflight conditions, the best evidence comes from the presentation of symptoms shared with cases of known intracranial hypertension on Earth as well as the documentation of increase ICP in symptomatic astronauts upon return to gravity. Documentation of CSF opening pressure via a lumbar puncture during spaceflight would provide definitive proof of elevated ICP during spaceflight but carries with it inherent procedural risks of post-lumbar puncture headache, hemorrhage, infection and spinal cord injury [80]. For that reason, noninvasive techniques are being studies though they too have inherent drawbacks.

Spaceflight-induced visual disturbance, first termed by NASA as VIIP, has been identified as a serious risk to astronauts during future long-duration space travel, having already affected over 40% of ISS inhabitants [81]. Although VIIP was originally attributed to spaceflight-induced elevated ICP, further factors now seem to contribute. For that reason, it has more recently been referred to as space flight-associated neuro-ocular syndrome [14].

Although prior research has provided better insight into the mechanisms of increased ICP in space, the exact pathophysiology is still unclear. It is likely that no entity discussed previously is the sole contributor to the neurological phenomena experienced in long-term spaceflight but a combination of many. Cephalad fluid shift plays a large role along with major contributions from venous outflow obstruction, blood-brain barrier breakdown, alterations in cerebrovascular tone, and disruption of CSF flow. Since not all individuals manifest with symptoms, it is likely that a combination of genetic, anatomical, and lifestyle related factors make some astronauts more susceptive to spaceflight-induced visual pathology as well as intracranial hypertension [10].

Little is known as to how the spaceflight environment setting will alter the anatomical and physiological integrity of our nervous systems and related structures, but aerospace physicians and astronauts should be educated in the current understanding of how human physiology reacts to this extreme environment. The goal of extending the duration of missions and sending individuals further into space than ever before will challenge the current capabilities of aerospace medicine. It will be critical to develop countermeasures to these known obstacles so that astronauts can participate at their peak in these missions and return safely to earth.

### Author details

theoretically aid in decreasing CSF production would produce undesirable metabolic side effects. Topiramate has been used in the treatment of migraine headaches and has a weak carbonic anhydrase effect which may lower ICP. It too has undesirable side effects such as

Many terms have been used to describe the symptoms of head congestion, nausea and vomiting, and visual disturbance in the space-flight environment. Over the years, attempts have been made to connect these seemingly related symptoms to a number of diverse pathophysiological origins. At this time, the contribution of increased ICP to the symptoms experienced during spaceflight is unknown. Although direct measurements of CSF pressure have not been performed in actual spaceflight conditions, the best evidence comes from the presentation of symptoms shared with cases of known intracranial hypertension on Earth as well as the documentation of increase ICP in symptomatic astronauts upon return to gravity. Documentation of CSF opening pressure via a lumbar puncture during spaceflight would provide definitive proof of elevated ICP during spaceflight but carries with it inherent procedural risks of post-lumbar puncture headache, hemorrhage, infection and spinal cord injury [80]. For that reason, noninvasive techniques are being studies though they too have inherent drawbacks.

Spaceflight-induced visual disturbance, first termed by NASA as VIIP, has been identified as a serious risk to astronauts during future long-duration space travel, having already affected over 40% of ISS inhabitants [81]. Although VIIP was originally attributed to spaceflight-induced elevated ICP, further factors now seem to contribute. For that reason, it has more recently been

Although prior research has provided better insight into the mechanisms of increased ICP in space, the exact pathophysiology is still unclear. It is likely that no entity discussed previously is the sole contributor to the neurological phenomena experienced in long-term spaceflight but a combination of many. Cephalad fluid shift plays a large role along with major contributions from venous outflow obstruction, blood-brain barrier breakdown, alterations in cerebrovascular tone, and disruption of CSF flow. Since not all individuals manifest with symptoms, it is likely that a combination of genetic, anatomical, and lifestyle related factors make some astronauts more susceptive to spaceflight-induced visual pathology as well as intracranial

Little is known as to how the spaceflight environment setting will alter the anatomical and physiological integrity of our nervous systems and related structures, but aerospace physicians and astronauts should be educated in the current understanding of how human physiology reacts to this extreme environment. The goal of extending the duration of missions and sending individuals further into space than ever before will challenge the current capabilities of aerospace medicine. It will be critical to develop countermeasures to these known obstacles so that astronauts can participate at their peak in these missions and return safely to earth.

referred to as space flight-associated neuro-ocular syndrome [14].

cognitive slowing [79].

80 Into Space - A Journey of How Humans Adapt and Live in Microgravity

6. Conclusion

hypertension [10].

Alex P. Michael

Address all correspondence to: alexmichael87@gmail.com

Division of Neurosurgery, Southern Illinois University School of Medicine, Springfield, IL, USA

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**Chapter 6**

**Provisional chapter**

**The Effect of Gravity on the Nervous System**

**The Effect of Gravity on the Nervous System**

DOI: 10.5772/intechopen.74715

Gravity affects the nervous system of living organisms. This book chapter reviews historical and recent findings on how changes in gravity affect cellular and subcellular parameters of human and animal cells as well as the timing and shaping of complex sensorimotor responses. With an emphasize on weightlessness, partial, and hypergravity conditions, the gravity dependencies of living organisms have been manifested on different levels of organization, ranging from changes in biophysical properties of single cells to the intact nervous system. An effort has been made to integrate the various findings into a consistent model for a better understanding of how the components of the nervous system interact as a response to acute and long-term gravitational variation. Especially with planned long-term manned missions to Mars and beyond, knowledge about the impact of increased and decreased gravity on the nervous system is essential for the physical and cognitive preparation to assure the success of space missions and human

**Keywords:** gravity, microgravity, hypergravity, adaptation, reflex, sensorimotor

The gravitational force on Earth has remained constant in direction and magnitude since the formation of the planet [1]. Therefore, living species including plants, animals, and humans have evolved to cope with and rely upon gravity equal to 1 g. Throughout the history of the Earth, all living organisms adapted their cellular and behavioral function to this particular physical environment characteristic for our home planet. Gravity—as a permanent and constant vector-calibrated stimulus—led to various gravity-perceiving systems in organisms

function, biophysical properties, electrophysiology

© 2016 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

© 2018 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use,

distribution, and reproduction in any medium, provided the original work is properly cited.

Florian P.M. Kohn, Claudia Koch and

Florian P.M. Kohn, Claudia Koch and

http://dx.doi.org/10.5772/intechopen.74715

Additional information is available at the end of the chapter

Additional information is available at the end of the chapter

Ramona Ritzmann

Ramona Ritzmann

**Abstract**

survival in space.

**1. Introduction**


#### **The Effect of Gravity on the Nervous System The Effect of Gravity on the Nervous System**

DOI: 10.5772/intechopen.74715

Florian P.M. Kohn, Claudia Koch and Ramona Ritzmann Florian P.M. Kohn, Claudia Koch and Ramona Ritzmann

Additional information is available at the end of the chapter Additional information is available at the end of the chapter

http://dx.doi.org/10.5772/intechopen.74715

#### **Abstract**

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detail.aspx?experiment\_type\_code=21&research\_type=current

raised intracranial pressure. Neurocritical Care. 2011;15(3):506-515

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spaceflight. NPJ Microgravity. 2016;2:2

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Marriot City Center, CO; 2012

2014

Journal of Neurosurgery. 1998;88(6):983-995

Neurology. 2014;71(6):693-701

86 Into Space - A Journey of How Humans Adapt and Live in Microgravity

Gravity affects the nervous system of living organisms. This book chapter reviews historical and recent findings on how changes in gravity affect cellular and subcellular parameters of human and animal cells as well as the timing and shaping of complex sensorimotor responses. With an emphasize on weightlessness, partial, and hypergravity conditions, the gravity dependencies of living organisms have been manifested on different levels of organization, ranging from changes in biophysical properties of single cells to the intact nervous system. An effort has been made to integrate the various findings into a consistent model for a better understanding of how the components of the nervous system interact as a response to acute and long-term gravitational variation. Especially with planned long-term manned missions to Mars and beyond, knowledge about the impact of increased and decreased gravity on the nervous system is essential for the physical and cognitive preparation to assure the success of space missions and human survival in space.

**Keywords:** gravity, microgravity, hypergravity, adaptation, reflex, sensorimotor function, biophysical properties, electrophysiology

### **1. Introduction**

The gravitational force on Earth has remained constant in direction and magnitude since the formation of the planet [1]. Therefore, living species including plants, animals, and humans have evolved to cope with and rely upon gravity equal to 1 g. Throughout the history of the Earth, all living organisms adapted their cellular and behavioral function to this particular physical environment characteristic for our home planet. Gravity—as a permanent and constant vector-calibrated stimulus—led to various gravity-perceiving systems in organisms

© 2016 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. © 2018 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

that control growth or influence movement and behavior. But what happens if this constant stimulus is changed?

the molecular and cellular level, up to the whole NS and its interconnection with movement control and mobility. The functional properties of these levels were thoroughly investigated,

The Effect of Gravity on the Nervous System http://dx.doi.org/10.5772/intechopen.74715 89

This chapter systematically reviews results on how changes in gravity affect neurons of human and animal as well as temporal and spatial characteristics of complex sensorimotor responses. For that purpose, the subject of this chapter is divided in three subthemes: the gravity dependence of subcellular and cellular parameters associated with neuronal activation is followed by an outline of the sensitivity of the human NS to gravitational variation in the context of movement. To interconnect these transdisciplinary findings, a working model is introduced on how the effects observed on the molecular and biophysical level may impact the sensorimotor control of the NS. The chapter ends with a conclusive statement that refers to movement in terms of long-term interplanetary manned space

A variety of life science experiments executed in gravity conditions different from Earth gravitation, 1 g, have been executed in cellular model systems. With an emphasize on subcellular and cellular parameters and the associated biophysical attributes, most of the *in vitro* experiments have been conducted on short-term gravity-research platforms as drop towers and parabolic flights. Findings from the late twentieth century and recent findings manifest a significant gravity dependency of the basic cell function associated with changes in membrane and channel properties as well as the underlying biophysical characteristics. Results are

From experiments with unicellular organisms [15] and various cell types as immune cells [16] and neuronal cells [17], it is well established that single cells react to changes in gravity even though they do not have dedicated gravity-sensing structures. One of the major components that all these cell types and organisms have in common is the cell membrane. These complex

To communicate, cells of the nervous system are able to modify their membrane potential. This ability is based on the activity of integrated membrane proteins as ion channels and ion pumps. But it is well known that the physicochemical state of the lipid membrane can directly modify the function of membrane proteins [19, 20]. In non-space-related experiments, it was shown that the closed-state probability of nicotinic acetylcholine receptors (nAChRs) increased with a decreased membrane fluidity [21]. These nAChRs are a major player in the sensorimotor system as they are located in the motor end plates that form the interface

however, with barely any interconnection.

**2. Gravity and the nervous system**

outlined in the following subchapter.

*2.1.1. Membrane parameters*

**2.1. The gravity dependence of subcellular and cellular parameters**

structures are mainly composed of proteins and lipids [18].

between the neuronal system and the muscles.

missions.

Future challenges in terms of long-term interplanetary manned space missions moved the adaptability of living organisms and their vital systems to heterogravitational habitats into scientific focus [2]. With emphasis on our astronomical neighbors Mars and Moon with a reduced gravitational force of approximately a third and a fifth of the Earth's gravitation, it became apparent that orbital or interplanetary space explorations require knowledge about gravity-perceiving systems, which determine movement, cognition, and survival [3]. In the past decades, space research manifested a significant gravity dependency for various biological processes and vital systems. A special focus lies on the animal and human nervous system (NS) as it is crucial for integration of sensory input, for example, from the vestibular system, movement control, and terrestrial locomotion on Earth. The NS governs muscle contraction enabling the body to counteract the gravitational force and controlling locomotor patterns and reflexes during the evolutionary shift from aqueous to terrestrial life. For interplanetary and orbital missions in future human space flight, knowledge about the gravity sensitivity of the NS is crucial to anticipate major challenges, train the astronauts, and prepare adequate countermeasures to conserve elementary sensorimotor skills during long-term partial-gravity exposure.

The NS is a network of neurons and fibers which transmits nerve impulses between parts of the body. It is composed of interconnected nerve and supporting glial cells. The mechanism of neuronal communication is based on electrochemical coupling, the modulation of intra- and extracellular ions to modify the electrical properties of a cell (intracellular signaling), and the controlled release of transmitters (intercellular communication). Resulting action potentials (APs) are the basic communication unit, and their conduction frequency serves as the coding for the stimulus' intensity.

One of the fundamental circuits within the central nervous system (CNS) to control muscle contraction is the monosynaptic reflex arch [4]. These reflexes are neuromuscular reactions in response to an external stimulus, which lead to fast muscle contractions. The magnitude of muscle contraction depends on the magnitude of sensory input. Allowing mobility of terrestrial life, sensory input from the vestibular and visual systems and proprioception is processed by the NS, and by means of muscle innervation, appropriate forces are generated to control simple posture or movement [5–10]. These sensorimotor competencies are crucial for life. Since the first manned spaceflight of Yuri Gagarin in 1961, the effect of microgravity on the human body has been intensively investigated. In the decades since his first spaceflight, many experiments have been performed which made gravity-induced changes on astronauts and cosmonauts apparent. With an emphasis on weightlessness and our astronomical neighbors Mars and Moon [2, 5], the authors found directly related health effects, among others a persistent modulation in the sensory [7, 11] and motor system [12] and the resulting structural loss of muscle [13] and bone mass [14]. In addition, there are modulations in the neuromuscular system underlying those health-related changes that open up many questions on how the variation of gravity influences the NS. These questions led to numerous experiments to investigate the effect of varying gravity conditions on the different levels of organization, from the molecular and cellular level, up to the whole NS and its interconnection with movement control and mobility. The functional properties of these levels were thoroughly investigated, however, with barely any interconnection.

This chapter systematically reviews results on how changes in gravity affect neurons of human and animal as well as temporal and spatial characteristics of complex sensorimotor responses. For that purpose, the subject of this chapter is divided in three subthemes: the gravity dependence of subcellular and cellular parameters associated with neuronal activation is followed by an outline of the sensitivity of the human NS to gravitational variation in the context of movement. To interconnect these transdisciplinary findings, a working model is introduced on how the effects observed on the molecular and biophysical level may impact the sensorimotor control of the NS. The chapter ends with a conclusive statement that refers to movement in terms of long-term interplanetary manned space missions.

### **2. Gravity and the nervous system**

#### **2.1. The gravity dependence of subcellular and cellular parameters**

A variety of life science experiments executed in gravity conditions different from Earth gravitation, 1 g, have been executed in cellular model systems. With an emphasize on subcellular and cellular parameters and the associated biophysical attributes, most of the *in vitro* experiments have been conducted on short-term gravity-research platforms as drop towers and parabolic flights. Findings from the late twentieth century and recent findings manifest a significant gravity dependency of the basic cell function associated with changes in membrane and channel properties as well as the underlying biophysical characteristics. Results are outlined in the following subchapter.

#### *2.1.1. Membrane parameters*

that control growth or influence movement and behavior. But what happens if this constant

Future challenges in terms of long-term interplanetary manned space missions moved the adaptability of living organisms and their vital systems to heterogravitational habitats into scientific focus [2]. With emphasis on our astronomical neighbors Mars and Moon with a reduced gravitational force of approximately a third and a fifth of the Earth's gravitation, it became apparent that orbital or interplanetary space explorations require knowledge about gravity-perceiving systems, which determine movement, cognition, and survival [3]. In the past decades, space research manifested a significant gravity dependency for various biological processes and vital systems. A special focus lies on the animal and human nervous system (NS) as it is crucial for integration of sensory input, for example, from the vestibular system, movement control, and terrestrial locomotion on Earth. The NS governs muscle contraction enabling the body to counteract the gravitational force and controlling locomotor patterns and reflexes during the evolutionary shift from aqueous to terrestrial life. For interplanetary and orbital missions in future human space flight, knowledge about the gravity sensitivity of the NS is crucial to anticipate major challenges, train the astronauts, and prepare adequate countermeasures to conserve elementary sensorimotor skills during long-term partial-gravity

The NS is a network of neurons and fibers which transmits nerve impulses between parts of the body. It is composed of interconnected nerve and supporting glial cells. The mechanism of neuronal communication is based on electrochemical coupling, the modulation of intra- and extracellular ions to modify the electrical properties of a cell (intracellular signaling), and the controlled release of transmitters (intercellular communication). Resulting action potentials (APs) are the basic communication unit, and their conduction frequency serves as the coding

One of the fundamental circuits within the central nervous system (CNS) to control muscle contraction is the monosynaptic reflex arch [4]. These reflexes are neuromuscular reactions in response to an external stimulus, which lead to fast muscle contractions. The magnitude of muscle contraction depends on the magnitude of sensory input. Allowing mobility of terrestrial life, sensory input from the vestibular and visual systems and proprioception is processed by the NS, and by means of muscle innervation, appropriate forces are generated to control simple posture or movement [5–10]. These sensorimotor competencies are crucial for life. Since the first manned spaceflight of Yuri Gagarin in 1961, the effect of microgravity on the human body has been intensively investigated. In the decades since his first spaceflight, many experiments have been performed which made gravity-induced changes on astronauts and cosmonauts apparent. With an emphasis on weightlessness and our astronomical neighbors Mars and Moon [2, 5], the authors found directly related health effects, among others a persistent modulation in the sensory [7, 11] and motor system [12] and the resulting structural loss of muscle [13] and bone mass [14]. In addition, there are modulations in the neuromuscular system underlying those health-related changes that open up many questions on how the variation of gravity influences the NS. These questions led to numerous experiments to investigate the effect of varying gravity conditions on the different levels of organization, from

stimulus is changed?

88 Into Space - A Journey of How Humans Adapt and Live in Microgravity

exposure.

for the stimulus' intensity.

From experiments with unicellular organisms [15] and various cell types as immune cells [16] and neuronal cells [17], it is well established that single cells react to changes in gravity even though they do not have dedicated gravity-sensing structures. One of the major components that all these cell types and organisms have in common is the cell membrane. These complex structures are mainly composed of proteins and lipids [18].

To communicate, cells of the nervous system are able to modify their membrane potential. This ability is based on the activity of integrated membrane proteins as ion channels and ion pumps. But it is well known that the physicochemical state of the lipid membrane can directly modify the function of membrane proteins [19, 20]. In non-space-related experiments, it was shown that the closed-state probability of nicotinic acetylcholine receptors (nAChRs) increased with a decreased membrane fluidity [21]. These nAChRs are a major player in the sensorimotor system as they are located in the motor end plates that form the interface between the neuronal system and the muscles.

Due to these findings, experiments have been performed to monitor the changes of membrane viscosity in micro- and hypergravity with several models (artificial asolectin vesicles and human neuronal SH-SY5Y cells). In all models, the membrane fluidity significantly increases in microgravity and decreases in hypergravity, but in a different distinctness [22]. The difference in distinctness might be explained with the absence of a cytoskeleton in artificial membranes or a different lipid composition.

frequency differs dependent on the stimulus strength. In microgravity obtained by drop tower, the rate of action potentials triggered by spontaneous active leech neurons is significantly increased [29]. This means on the level of single cells, more action potentials are

The Effect of Gravity on the Nervous System http://dx.doi.org/10.5772/intechopen.74715 91

Simultaneously, the conduction velocity of APs on the axonal level is decreased in microgravity and increased in hypergravity. This was demonstrated in parabolic flight missions *in vitro* in isolated earthworm axons and isolated rat axons and *in vivo* in intact earthworms. [29].

In addition to the abovementioned molecular and cellular experiments, a variety of studies have been conducted to investigate the effect of gravity on the nervous system in humans [4, 10, 30–34]. In the context of movement control, it becomes apparent that the biophysical attributes underlying cell communication and the nervous capacity to inhibit and facilitate neural pathways are of fundamental importance to activate and control the skeletal muscle, allowing the living organisms to displace themselves. On the complex sensorimotor level, the gravitational force determines human movement control, and its impact is considered to be of major relevance for the astronaut's safety management in scenarios that require spontaneous or chronic adaptation to an astronomical environment different from the Earth. Not only are short-term platforms as parabolic flights and centrifuges used for this research, the experiments are also conducted during long-term space missions or exploration class missions (up

A frequently used technique is the peripheral nerve stimulation (PNS) as it is a noninvasive and reliable approach, providing information about nerve communication including temporal and spatial characteristics of direct motor (M-wave) and reflector responses (Hoffmann(H)-reflex) of the skeletal muscle [35, 36]. By external electrical stimulation, neurons, axons, or cell bodies are depolarized, and the bipolar potential difference of the muscle is measured and interpreted [4]. The nerve *tibialis posterior* and the muscle *soleus* have been established as a model for describing the adaptation processes of the neuromuscular system with emphasize on the temporal and spatial characteristics of the electromyo-

The shaping of the potential difference includes peak-to-peak amplitudes normalized to the input stimulus and is associated with the magnitude of the muscle output [37]. Furthermore, the stimulation threshold corresponds to the threshold for axonal excitation with a minimal

The needed electrical stimulation to depolarize an axon to generate a constant muscle response can be interpreted as the responsiveness of a nerve to external stimuli. In reduced gravity conditions, similar to Moon (0.16 g) and Mars (0.36 g), generated in parabolic flights, higher

generated in weightlessness.

to 1.5 years).

graphic signal.

*2.2.1. Spatial attributes*

current evoking a muscle contraction [4].

*2.2.2. Stimulation threshold of the H-reflex*

Again, the changes are fast and fully reversible.

**2.2. The gravity dependence of the human nervous system**

Nevertheless, this finding, that the membrane fluidity is gravity-dependent, will have a huge impact on biological and medical gravity research, as this is a basic physical mechanism that affects every cell in an organism [23].

#### *2.1.2. Ion channel parameters*

Ion channels are crucial for neuronal communication. They form controllable pores through the cell membrane. Charged ions can diffuse through these pores, following electrical and chemical gradients, changing the electrical properties of the cell. Ion channel parameters as open- and closed-state probability have been investigated by using pore-forming peptides which can be used as ion channel analogs. Until now, no native ion channel proteins have been used for gravity research.

The open-state probability of porin channels from *Escherichia coli* is significantly decreased in microgravity, whereas in hypergravity, it is increased. No effect on conductance was found [24].

Similar findings have been made with alamethicin, a pore-forming peptide from *Trichoderma viride*. In microgravity, the activity of alamethicin is decreased, whereas in hypergravity, it is increased [25, 26].

The effect on ion channels is—similar to changes in membrane fluidity—fully reversible and fast. With the onset of a different gravity condition, the open-state probability is changed, returning to normal as soon as the experiment returns to normal 1 g gravity.

#### *2.1.3. Electrophysiological properties of single cells*

By having a stable-resting potential, a cell is able to communicate. By changing the activity of relevant ion channels, the membrane potential can be modulated. During parabolic flight, the resting potential of human neuronal cells is significantly depolarized in microgravity and it is hyperpolarized in hypergravity. During microgravity, the depolarization is about 3 mV [27]. This gravity dependence of resting potential is not limited to excitable cells as neuronal cells; it was also found during a drop-tower mission in SF21 cells, an ovary cell line from the insect *Spodoptera frugiperda* [17].

Again in parabolic flight, in microgravity, the transmembrane currents in oocytes from *Xenopus laevis* show a significant decrease at a holding potential of −100 mV, whereas in hypergravity, there is a tendency of increased currents [28].

#### *2.1.4. Propagation of action potentials*

Action potentials (APs) are the basic communication unit in the nervous system. The intensity of a stimulus is frequency-coded: while the amplitude of APs remains constant, their frequency differs dependent on the stimulus strength. In microgravity obtained by drop tower, the rate of action potentials triggered by spontaneous active leech neurons is significantly increased [29]. This means on the level of single cells, more action potentials are generated in weightlessness.

Simultaneously, the conduction velocity of APs on the axonal level is decreased in microgravity and increased in hypergravity. This was demonstrated in parabolic flight missions *in vitro* in isolated earthworm axons and isolated rat axons and *in vivo* in intact earthworms. [29]. Again, the changes are fast and fully reversible.

### **2.2. The gravity dependence of the human nervous system**

In addition to the abovementioned molecular and cellular experiments, a variety of studies have been conducted to investigate the effect of gravity on the nervous system in humans [4, 10, 30–34]. In the context of movement control, it becomes apparent that the biophysical attributes underlying cell communication and the nervous capacity to inhibit and facilitate neural pathways are of fundamental importance to activate and control the skeletal muscle, allowing the living organisms to displace themselves. On the complex sensorimotor level, the gravitational force determines human movement control, and its impact is considered to be of major relevance for the astronaut's safety management in scenarios that require spontaneous or chronic adaptation to an astronomical environment different from the Earth. Not only are short-term platforms as parabolic flights and centrifuges used for this research, the experiments are also conducted during long-term space missions or exploration class missions (up to 1.5 years).

A frequently used technique is the peripheral nerve stimulation (PNS) as it is a noninvasive and reliable approach, providing information about nerve communication including temporal and spatial characteristics of direct motor (M-wave) and reflector responses (Hoffmann(H)-reflex) of the skeletal muscle [35, 36]. By external electrical stimulation, neurons, axons, or cell bodies are depolarized, and the bipolar potential difference of the muscle is measured and interpreted [4]. The nerve *tibialis posterior* and the muscle *soleus* have been established as a model for describing the adaptation processes of the neuromuscular system with emphasize on the temporal and spatial characteristics of the electromyographic signal.

#### *2.2.1. Spatial attributes*

Due to these findings, experiments have been performed to monitor the changes of membrane viscosity in micro- and hypergravity with several models (artificial asolectin vesicles and human neuronal SH-SY5Y cells). In all models, the membrane fluidity significantly increases in microgravity and decreases in hypergravity, but in a different distinctness [22]. The difference in distinctness might be explained with the absence of a cytoskeleton in artificial mem-

Nevertheless, this finding, that the membrane fluidity is gravity-dependent, will have a huge impact on biological and medical gravity research, as this is a basic physical mechanism that

Ion channels are crucial for neuronal communication. They form controllable pores through the cell membrane. Charged ions can diffuse through these pores, following electrical and chemical gradients, changing the electrical properties of the cell. Ion channel parameters as open- and closed-state probability have been investigated by using pore-forming peptides which can be used as ion channel analogs. Until now, no native ion channel proteins have

The open-state probability of porin channels from *Escherichia coli* is significantly decreased in microgravity, whereas in hypergravity, it is increased. No effect on conductance was found [24]. Similar findings have been made with alamethicin, a pore-forming peptide from *Trichoderma viride*. In microgravity, the activity of alamethicin is decreased, whereas in hypergravity, it is

The effect on ion channels is—similar to changes in membrane fluidity—fully reversible and fast. With the onset of a different gravity condition, the open-state probability is changed,

By having a stable-resting potential, a cell is able to communicate. By changing the activity of relevant ion channels, the membrane potential can be modulated. During parabolic flight, the resting potential of human neuronal cells is significantly depolarized in microgravity and it is hyperpolarized in hypergravity. During microgravity, the depolarization is about 3 mV [27]. This gravity dependence of resting potential is not limited to excitable cells as neuronal cells; it was also found during a drop-tower mission in SF21 cells, an ovary cell line from the insect

Again in parabolic flight, in microgravity, the transmembrane currents in oocytes from *Xenopus laevis* show a significant decrease at a holding potential of −100 mV, whereas in

Action potentials (APs) are the basic communication unit in the nervous system. The intensity of a stimulus is frequency-coded: while the amplitude of APs remains constant, their

returning to normal as soon as the experiment returns to normal 1 g gravity.

branes or a different lipid composition.

90 Into Space - A Journey of How Humans Adapt and Live in Microgravity

affects every cell in an organism [23].

*2.1.2. Ion channel parameters*

been used for gravity research.

*2.1.3. Electrophysiological properties of single cells*

hypergravity, there is a tendency of increased currents [28].

increased [25, 26].

*Spodoptera frugiperda* [17].

*2.1.4. Propagation of action potentials*

The shaping of the potential difference includes peak-to-peak amplitudes normalized to the input stimulus and is associated with the magnitude of the muscle output [37]. Furthermore, the stimulation threshold corresponds to the threshold for axonal excitation with a minimal current evoking a muscle contraction [4].

#### *2.2.2. Stimulation threshold of the H-reflex*

The needed electrical stimulation to depolarize an axon to generate a constant muscle response can be interpreted as the responsiveness of a nerve to external stimuli. In reduced gravity conditions, similar to Moon (0.16 g) and Mars (0.36 g), generated in parabolic flights, higher stimulation currents for PNS were needed to depolarize the neurons. In hypergravity (1.8 g), the needed currents were smaller [4]. Although the respective partial-gravity level lasts only 24–33 s [10] and effects are reversible within seconds, it can be concluded that the stimulation threshold is acutely increased in reduced gravity and decreased in hypergravity.

to Mars to Lunar gravity) with a simultaneous tendency of an increase of M-wave latencies [4]. However, Ohira et al. showed that hyper- and microgravity had no immediate effect on the H-reflex and M-wave latencies; unfortunately, they did not give information about the

The Effect of Gravity on the Nervous System http://dx.doi.org/10.5772/intechopen.74715 93

By interpreting the IPI between the negative and the positive maxima of the biphasic amplitude, information about the conduction velocity from the motor end plate to the muscle fibers can be gained. The motor end plates (or neuromuscular junction) are the interface between the nervous system and the muscles. It could be showed that the IPIs of the peak *M. soleus* M-wave and H-reflex significantly increase with decreasing gravity from hyper- to 1 g to Mars to Moon gravity conditions [4]. This finding can be interpreted that the conduction velocity at the neuromuscular junction is decreasing in reduced gravity and is increasing in hypergrav-

The duration of the H-reflex is established as the interval from the first rise of the electromyographic signal until return to baseline. Ritzmann et al. demonstrated a gradual decrease in H-reflex duration with increasing gravitation from lunar to Martian to earth gravitation to hypergravity [4]. Accordingly, the duration of the M-waves showed a strong tendency to decline with increasing gravitation. As the duration of the motor and reflectory responses cover information about the conduction velocity of signal transmission from the motor end plate to the muscle fibers, results indicate a major impact of gravity on the temporal charac-

**3. A model for the immediate adaptation of the nervous system to** 

The following model integrates the results from the various experiments that have been carried out in the past decades from cellular level up to the neuromuscular interface. To avoid long-term adaptation processes, only immediate effects have been taken into account. The model was designed in a bottom-up approach, starting at the very base level of gravity dependence. Therefore, it can be used as a framework for future—more complex data—as longterm adaptation processes and the gravity dependence of for example, the human brain.

Micro- and hypergravity change the biophysical properties of biological membranes in every cell in the body. This is not due to some biological effect or process, it is a change in thermodynamic properties of biological membranes [20]; therefore, this can be seen as the basic

principle of how gravity affects cells as neuronal cells, for example.

ity. This effect occurs immediately and is fully reversible.

sample size [32].

*2.2.7. Duration*

teristics of sensorimotor responses.

**changes in gravity**

**3.1. Molecular level**

*2.2.6. Inter-peak interval*

#### *2.2.3. Amplitude of the H-reflex*

The H-reflex amplitude describes the neuronal output signal of the reflectory reaction of muscles and is proportional to the muscle contraction after peripheral electrical stimulation of sensory fibers in their innervating nerves. Gravity dependency has been reported in crosssectional study designs with neuroplastic changes for amplitudes of H-reflexes and stretch reflexes [10, 30–34]. The peak-to-peak amplitudes increased during hypergravity, independently from the method of stimulation [10, 33].

In micro- and reduced gravity, the results are more inhomogeneous. Experiments in Mars and Moon gravity showed a gravity dependence in the decrease of peak-to-peak amplitudes of Hmax. Less gravity resulted in a higher decrease in Hmax amplitude [4]. Nevertheless, in microgravity, the H-reflex was either not changed [10, 34] or it was increased [30–33]. A longterm experiment on the International Space Station (ISS) revealed a decrease of H-reflexes in space [38]. This decrease was found for 5 months in space, but it was recovered shortly after the return to Earth.

The inhomogeneous findings might be explained by (1) active adaptation processes during long-term missions and (2) mainly due to differences in methodology [4].

The amplitudes of the different sections of the H-reflex depend on the stimulation threshold. As the threshold is gravity-dependent, this has to be taken into account when a constant stimulus intensity is used during the experiments [30–33]. H/M-wave recruitment curves are independent of stimulation threshold [10, 34]. As a consequence, gravity-induced changes in H-reflex amplitudes elicited with a constant and submaximal stimulus are rather attributed to threshold shifts than changes in gravity [30–33].

#### *2.2.4. Temporal attributes*

Temporal characteristics of motor and reflectory responses are characterized by latencies relying on the nerve's conduction velocity [39], duration, and inter-peak intervals (IPI) associated with the conduction speed along the muscle fibers at the neuromuscular junction where the nerve interconnects with the muscle [40].

#### *2.2.5. Neuromuscular latency*

Neuromuscular latency describes the time between a given stimulus and the measured muscle response. The latency of H-reflex and M-wave in the *Soleus* muscle was investigated in many experiments, short term [4, 32] and long term [40], but the results are again ambiguous, similar to the findings for the amplitudes of H-reflex. In eight subjects, Ritzmann et al. showed an increase in H-reflex latencies with gradually decreasing gravity (from hyper to 1 g to Mars to Lunar gravity) with a simultaneous tendency of an increase of M-wave latencies [4]. However, Ohira et al. showed that hyper- and microgravity had no immediate effect on the H-reflex and M-wave latencies; unfortunately, they did not give information about the sample size [32].

### *2.2.6. Inter-peak interval*

stimulation currents for PNS were needed to depolarize the neurons. In hypergravity (1.8 g), the needed currents were smaller [4]. Although the respective partial-gravity level lasts only 24–33 s [10] and effects are reversible within seconds, it can be concluded that the stimulation

The H-reflex amplitude describes the neuronal output signal of the reflectory reaction of muscles and is proportional to the muscle contraction after peripheral electrical stimulation of sensory fibers in their innervating nerves. Gravity dependency has been reported in crosssectional study designs with neuroplastic changes for amplitudes of H-reflexes and stretch reflexes [10, 30–34]. The peak-to-peak amplitudes increased during hypergravity, indepen-

In micro- and reduced gravity, the results are more inhomogeneous. Experiments in Mars and Moon gravity showed a gravity dependence in the decrease of peak-to-peak amplitudes of Hmax. Less gravity resulted in a higher decrease in Hmax amplitude [4]. Nevertheless, in microgravity, the H-reflex was either not changed [10, 34] or it was increased [30–33]. A longterm experiment on the International Space Station (ISS) revealed a decrease of H-reflexes in space [38]. This decrease was found for 5 months in space, but it was recovered shortly after

The inhomogeneous findings might be explained by (1) active adaptation processes during

The amplitudes of the different sections of the H-reflex depend on the stimulation threshold. As the threshold is gravity-dependent, this has to be taken into account when a constant stimulus intensity is used during the experiments [30–33]. H/M-wave recruitment curves are independent of stimulation threshold [10, 34]. As a consequence, gravity-induced changes in H-reflex amplitudes elicited with a constant and submaximal stimulus are rather attributed to

Temporal characteristics of motor and reflectory responses are characterized by latencies relying on the nerve's conduction velocity [39], duration, and inter-peak intervals (IPI) associated with the conduction speed along the muscle fibers at the neuromuscular junction where the

Neuromuscular latency describes the time between a given stimulus and the measured muscle response. The latency of H-reflex and M-wave in the *Soleus* muscle was investigated in many experiments, short term [4, 32] and long term [40], but the results are again ambiguous, similar to the findings for the amplitudes of H-reflex. In eight subjects, Ritzmann et al. showed an increase in H-reflex latencies with gradually decreasing gravity (from hyper to 1 g

long-term missions and (2) mainly due to differences in methodology [4].

threshold is acutely increased in reduced gravity and decreased in hypergravity.

*2.2.3. Amplitude of the H-reflex*

the return to Earth.

*2.2.4. Temporal attributes*

*2.2.5. Neuromuscular latency*

dently from the method of stimulation [10, 33].

92 Into Space - A Journey of How Humans Adapt and Live in Microgravity

threshold shifts than changes in gravity [30–33].

nerve interconnects with the muscle [40].

By interpreting the IPI between the negative and the positive maxima of the biphasic amplitude, information about the conduction velocity from the motor end plate to the muscle fibers can be gained. The motor end plates (or neuromuscular junction) are the interface between the nervous system and the muscles. It could be showed that the IPIs of the peak *M. soleus* M-wave and H-reflex significantly increase with decreasing gravity from hyper- to 1 g to Mars to Moon gravity conditions [4]. This finding can be interpreted that the conduction velocity at the neuromuscular junction is decreasing in reduced gravity and is increasing in hypergravity. This effect occurs immediately and is fully reversible.

#### *2.2.7. Duration*

The duration of the H-reflex is established as the interval from the first rise of the electromyographic signal until return to baseline. Ritzmann et al. demonstrated a gradual decrease in H-reflex duration with increasing gravitation from lunar to Martian to earth gravitation to hypergravity [4]. Accordingly, the duration of the M-waves showed a strong tendency to decline with increasing gravitation. As the duration of the motor and reflectory responses cover information about the conduction velocity of signal transmission from the motor end plate to the muscle fibers, results indicate a major impact of gravity on the temporal characteristics of sensorimotor responses.

### **3. A model for the immediate adaptation of the nervous system to changes in gravity**

The following model integrates the results from the various experiments that have been carried out in the past decades from cellular level up to the neuromuscular interface. To avoid long-term adaptation processes, only immediate effects have been taken into account. The model was designed in a bottom-up approach, starting at the very base level of gravity dependence. Therefore, it can be used as a framework for future—more complex data—as longterm adaptation processes and the gravity dependence of for example, the human brain.

#### **3.1. Molecular level**

Micro- and hypergravity change the biophysical properties of biological membranes in every cell in the body. This is not due to some biological effect or process, it is a change in thermodynamic properties of biological membranes [20]; therefore, this can be seen as the basic principle of how gravity affects cells as neuronal cells, for example.

On Earth, it is well known that the properties of membrane-integrated proteins as ion channels depend on the physical state of the membrane. Lateral pressure or membrane fluidity is an important component, for example, the open state of alamethicin pores clearly depends on the lateral pressure of the membrane [41], and the pore activity increases with an increased lateral pressure. An increased lateral pressure can be interpreted as decreased membrane fluidity. This was also shown for other ion channels, for example, the closed-state probability of nicotinic acetylcholine receptor channels increases (the open-state probability decreases) toward decreased membrane fluidity [21].

The pore activity of alamethicin and the open-state probability of ion channels is also gravitydependent [24, 25]. In microgravity, the open-state probability decreases, whereas in hypergravity, it increases.

As membrane fluidity is affected by gravity and due to the fact that ion channels are affected by membrane fluidity, the first part of the model can be described as follows:

In microgravity, the membrane fluidity is increased. This changed membrane fluidity decreases the open-state probability of ion channels. This effect is inversed in hypergravity: membrane fluidity decreases and the open-state probability of ion channels increases (**Figure 1**).

**3.3. Neuronal system: Sensorimotor system**

tion speed—the APs are slower in microgravity.

(**Figure 3**).

The influence of different gravity conditions on neuronal tissue is clearly visible. In isolated single axons as well as in living animals and in human test subjects, the propagation velocity

The Effect of Gravity on the Nervous System http://dx.doi.org/10.5772/intechopen.74715 95

Neuromuscular reflex arcs in humans are influenced by gravity. In microgravity, increased latencies can be measured. An increased latency can be explained with a decreased conduc-

In Mars and Moon gravity, a higher stimulus has to be given to get the same Hmax as in 1 g, and the peak-to peak amplitude of the H-reflex is decreased (with heterogeneous data at real microgravity). Unfortunately, as the methods of single-cell electrophysiology and peripheral nerve stimulation are different, their results cannot be compared directly. Nevertheless, a decreased propagation velocity of APs in the axons can also explain the decrease in Hmax in microgravity. Less APs per time arrive at the muscle, which leads to a reduced contraction. Two findings support this explanation: first, the decrease can be compensated with a higher stimulus. Due to the frequency coding of sensory input, a higher stimulus generates more APs per time. With more APs per time arriving at the muscle, the contraction force is increased. Second, the decrease in inter-peak intervals of the H-reflex indicates a decreased signal speed at the neuromuscular junction. In increased gravity, these effects are reversed

In microgravity, the rate of action potentials is increased, while at the same time, the propagation speed of APs is decreased. This might look like an inconsistency, but it is not. It can be explained with a mathematical equation. Matsumoto and Tasaki developed a mathematical model to calculate the conduction speed of APs in unmyelinated axons [43]. This equation can

also be used to estimate the conduction velocity of APs in myelinated axons

of APs is decreased in microgravity and it is increased in hypergravity.

**Figure 2.** The gravity dependence of a single neuronal cell. Modified from [42].

#### **3.2. Single cells**

It was shown that cells slightly depolarize in microgravity—the membrane potential gets more positive—and they hyperpolarize in hypergravity. With a light depolarization of the resting potential, the threshold to trigger action potentials is reached more easily. This effect was demonstrated in spontaneous active leech neurons. The rate of APs increased in microgravity.

With these findings, the model of gravity dependence on the molecular level can be extended to explain the cellular gravity dependence of single (neuronal) cells (**Figure 2**).

**Figure 1.** The biophysical gravity dependence of cell membranes and incorporated ion channel proteins. Modified from [42].

**Figure 2.** The gravity dependence of a single neuronal cell. Modified from [42].

#### **3.3. Neuronal system: Sensorimotor system**

On Earth, it is well known that the properties of membrane-integrated proteins as ion channels depend on the physical state of the membrane. Lateral pressure or membrane fluidity is an important component, for example, the open state of alamethicin pores clearly depends on the lateral pressure of the membrane [41], and the pore activity increases with an increased lateral pressure. An increased lateral pressure can be interpreted as decreased membrane fluidity. This was also shown for other ion channels, for example, the closed-state probability of nicotinic acetylcholine receptor channels increases (the open-state probability decreases)

The pore activity of alamethicin and the open-state probability of ion channels is also gravitydependent [24, 25]. In microgravity, the open-state probability decreases, whereas in hyper-

As membrane fluidity is affected by gravity and due to the fact that ion channels are affected

In microgravity, the membrane fluidity is increased. This changed membrane fluidity decreases the open-state probability of ion channels. This effect is inversed in hypergravity: membrane

It was shown that cells slightly depolarize in microgravity—the membrane potential gets more positive—and they hyperpolarize in hypergravity. With a light depolarization of the resting potential, the threshold to trigger action potentials is reached more easily. This effect was demonstrated in spontaneous active leech neurons. The rate of APs increased in microgravity. With these findings, the model of gravity dependence on the molecular level can be extended

**Figure 1.** The biophysical gravity dependence of cell membranes and incorporated ion channel proteins. Modified from [42].

by membrane fluidity, the first part of the model can be described as follows:

to explain the cellular gravity dependence of single (neuronal) cells (**Figure 2**).

fluidity decreases and the open-state probability of ion channels increases (**Figure 1**).

toward decreased membrane fluidity [21].

94 Into Space - A Journey of How Humans Adapt and Live in Microgravity

gravity, it increases.

**3.2. Single cells**

The influence of different gravity conditions on neuronal tissue is clearly visible. In isolated single axons as well as in living animals and in human test subjects, the propagation velocity of APs is decreased in microgravity and it is increased in hypergravity.

Neuromuscular reflex arcs in humans are influenced by gravity. In microgravity, increased latencies can be measured. An increased latency can be explained with a decreased conduction speed—the APs are slower in microgravity.

In Mars and Moon gravity, a higher stimulus has to be given to get the same Hmax as in 1 g, and the peak-to peak amplitude of the H-reflex is decreased (with heterogeneous data at real microgravity). Unfortunately, as the methods of single-cell electrophysiology and peripheral nerve stimulation are different, their results cannot be compared directly. Nevertheless, a decreased propagation velocity of APs in the axons can also explain the decrease in Hmax in microgravity. Less APs per time arrive at the muscle, which leads to a reduced contraction. Two findings support this explanation: first, the decrease can be compensated with a higher stimulus. Due to the frequency coding of sensory input, a higher stimulus generates more APs per time. With more APs per time arriving at the muscle, the contraction force is increased. Second, the decrease in inter-peak intervals of the H-reflex indicates a decreased signal speed at the neuromuscular junction. In increased gravity, these effects are reversed (**Figure 3**).

In microgravity, the rate of action potentials is increased, while at the same time, the propagation speed of APs is decreased. This might look like an inconsistency, but it is not. It can be explained with a mathematical equation. Matsumoto and Tasaki developed a mathematical model to calculate the conduction speed of APs in unmyelinated axons [43]. This equation can also be used to estimate the conduction velocity of APs in myelinated axons

**Figure 3.** The gravity dependence of a multicellular network, connected via synapses as the sensorimotor system. Modified from [42].

$$
\upsilon\_{ann} \approx \sqrt{\frac{d}{8 \cdot \mathbb{Q} \cdot \mathbb{C}^2 \cdot \mathbb{R}^\*}} \tag{1}
$$

Adaptation processes occur on all levels of organization, from the subcellular level up to the neuromuscular system (and even up to the brain). Unfortunately, till date, the discrete results of these experiments were never brought together to see (1) whether they can be integrated to a working model of neuronal adaptation in varying gravity or (2) to reveal inconsistencies or (3) areas, which have not been investigated yet. This model aims at bringing insight to the short-term adaptation of the neuronal system to varying gravity conditions. Simultaneously as some points still are based on reasoned assumptions [42]—it has to be seen as a framework, which should be fleshed out more in future experiments to include long-term adaptation processes and the adaptation of the human brain. A more interconnected and interdisciplinary analysis of all the data can serve as a "roadmap," aiming for giving more structure to ongoing

The Effect of Gravity on the Nervous System http://dx.doi.org/10.5772/intechopen.74715 97

Findings are of major functional relevance in the application field of manned space flight as well as countermeasure development. As more and more space agencies and private space companies are planning long-term missions into space, for example, to Mars, the effect of gravity—and its absence—on the human organisms has to be understood overreaching all vital body systems to minimize the risks for space-faring humans [2]. Today, scientific outcomes of life science experiments executed in samples of astronauts and cosmonauts encompass a variety of long-term adaptation in regard to their sensory perception, motor execution, and planning as well as complex body motion. They are interrelated to neural adaptation to varying gravity and have been verified as follows (for review, see [44]): a recalibration of sensory perception, vestibular and proprioceptive dysfunction [7, 11], changes in muscle synergies and coordination, a decline of muscle force as well as deficits in posture control [6], locomotion, and functional mobility [8]. Reduced and delayed reflex responses and a decline in intramuscular and intermuscular function occur concomitantly with an increased muscle weakness, fatigue concomitant with a higher fall, and injury prevalence [40, 44]. With a persistency beyond the acute period of space flight, these adaptations are of clinical relevance as manifested by significant adverse effects which entail fragility and bone fractures [14, 44]. To reduce health and life risk throughout long-term exposure to low gravity during manned space explorations, scientists and space agencies developed intelligent exercise technologies and efficient interventions validated in cohorts of space crew members to prevent the human body from deconditioning [2]. Empirical outcomes subject to the NS and its adaptability to changes in gravity are included in the concepts of ancient and future countermeasures as manifested, for instance, for strength or jump exercises, vibration treatment, sensorimotor

Although great efforts have been made to optimize countermeasures, limitation on the cellular level such as changes in membrane fluidity as well as complex adaptations on the spinal level encompassing mechanisms of facilitating and inhibiting is of major relevance and can-

As astronauts traveling to Mars will live in the absence of gravity for approximately 2 years with transition between weightlessness and planetary gravitational forces at the beginning, middle, and end of the mission, further research and countermeasure development considering the gravity dependency of the NS will be obligate to assure a safe space travel and Earth

and future research.

training, and artificial gravity [44].

return in the future [44].

not be diminished by countermeasures, only [4, 10, 23].

where vaxon = conduction velocity, C = membrane capacity, d = diameter of the nerve, R\* = resistance of the membrane, and ρ = axoplasmic resistance.

By integrating the data from gravity research and Matsumoto and Tasaki's model, at first view, the inconsistent findings from single-cell electrophysiology and the data from PNS can be brought together quite nicely to a working model on how the sensorimotor system adapts to changes in gravity.

The increased membrane viscosity in microgravity decreases the open-state probability of ion channels, leading to a slightly depolarized membrane potential. With a reduced open-state probability, the resistance of the membrane (R\*) is increased. If axoplasmic resistance (ρ), membrane capacity (C), and the diameter of the axon (d) are treated as constant in changed gravity, the increased resistance of the membrane leads to a decreased conduction velocity of APs (vaxon) while simultaneously APs can be triggered more easily.

To sum up, the described effects are a gravity-dependent decrease in neuronal conduction velocity–or, more general, an increase in electrical and chemical time constants—under reduced gravity and vice versa in hypergravity.

#### **4. Conclusion**

In the decades since the first manned space mission, many *in vitro* and *in vivo* experiments have been conducted to investigate the effect of micro- and hypergravity on neuronal processes. Adaptation processes occur on all levels of organization, from the subcellular level up to the neuromuscular system (and even up to the brain). Unfortunately, till date, the discrete results of these experiments were never brought together to see (1) whether they can be integrated to a working model of neuronal adaptation in varying gravity or (2) to reveal inconsistencies or (3) areas, which have not been investigated yet. This model aims at bringing insight to the short-term adaptation of the neuronal system to varying gravity conditions. Simultaneously as some points still are based on reasoned assumptions [42]—it has to be seen as a framework, which should be fleshed out more in future experiments to include long-term adaptation processes and the adaptation of the human brain. A more interconnected and interdisciplinary analysis of all the data can serve as a "roadmap," aiming for giving more structure to ongoing and future research.

Findings are of major functional relevance in the application field of manned space flight as well as countermeasure development. As more and more space agencies and private space companies are planning long-term missions into space, for example, to Mars, the effect of gravity—and its absence—on the human organisms has to be understood overreaching all vital body systems to minimize the risks for space-faring humans [2]. Today, scientific outcomes of life science experiments executed in samples of astronauts and cosmonauts encompass a variety of long-term adaptation in regard to their sensory perception, motor execution, and planning as well as complex body motion. They are interrelated to neural adaptation to varying gravity and have been verified as follows (for review, see [44]): a recalibration of sensory perception, vestibular and proprioceptive dysfunction [7, 11], changes in muscle synergies and coordination, a decline of muscle force as well as deficits in posture control [6], locomotion, and functional mobility [8]. Reduced and delayed reflex responses and a decline in intramuscular and intermuscular function occur concomitantly with an increased muscle weakness, fatigue concomitant with a higher fall, and injury prevalence [40, 44]. With a persistency beyond the acute period of space flight, these adaptations are of clinical relevance as manifested by significant adverse effects which entail fragility and bone fractures [14, 44].

*<sup>v</sup>axon* <sup>≈</sup> <sup>√</sup>

96 Into Space - A Journey of How Humans Adapt and Live in Microgravity

to changes in gravity.

Modified from [42].

**4. Conclusion**

tance of the membrane, and ρ = axoplasmic resistance.

APs (vaxon) while simultaneously APs can be triggered more easily.

reduced gravity and vice versa in hypergravity.

\_\_\_\_\_\_\_\_\_ \_\_\_\_\_\_\_\_\_ *d*

where vaxon = conduction velocity, C = membrane capacity, d = diameter of the nerve, R\* = resis-

**Figure 3.** The gravity dependence of a multicellular network, connected via synapses as the sensorimotor system.

By integrating the data from gravity research and Matsumoto and Tasaki's model, at first view, the inconsistent findings from single-cell electrophysiology and the data from PNS can be brought together quite nicely to a working model on how the sensorimotor system adapts

The increased membrane viscosity in microgravity decreases the open-state probability of ion channels, leading to a slightly depolarized membrane potential. With a reduced open-state probability, the resistance of the membrane (R\*) is increased. If axoplasmic resistance (ρ), membrane capacity (C), and the diameter of the axon (d) are treated as constant in changed gravity, the increased resistance of the membrane leads to a decreased conduction velocity of

To sum up, the described effects are a gravity-dependent decrease in neuronal conduction velocity–or, more general, an increase in electrical and chemical time constants—under

In the decades since the first manned space mission, many *in vitro* and *in vivo* experiments have been conducted to investigate the effect of micro- and hypergravity on neuronal processes.

<sup>8</sup> <sup>∙</sup> <sup>ρ</sup> *<sup>C</sup>*<sup>2</sup> <sup>∙</sup> *<sup>R</sup>*<sup>∗</sup> (1)

To reduce health and life risk throughout long-term exposure to low gravity during manned space explorations, scientists and space agencies developed intelligent exercise technologies and efficient interventions validated in cohorts of space crew members to prevent the human body from deconditioning [2]. Empirical outcomes subject to the NS and its adaptability to changes in gravity are included in the concepts of ancient and future countermeasures as manifested, for instance, for strength or jump exercises, vibration treatment, sensorimotor training, and artificial gravity [44].

Although great efforts have been made to optimize countermeasures, limitation on the cellular level such as changes in membrane fluidity as well as complex adaptations on the spinal level encompassing mechanisms of facilitating and inhibiting is of major relevance and cannot be diminished by countermeasures, only [4, 10, 23].

As astronauts traveling to Mars will live in the absence of gravity for approximately 2 years with transition between weightlessness and planetary gravitational forces at the beginning, middle, and end of the mission, further research and countermeasure development considering the gravity dependency of the NS will be obligate to assure a safe space travel and Earth return in the future [44].

### **Acknowledgements**

The research was supported by the German Aerospace Center (DLR), the European Space Agency (ESA), and Novespace.

[10] Ritzmann R, Freyler K, Weltin E, Krause A, Gollhofer A. Load dependency of postural control—kinematic and neuromuscular changes in response to over and under load con-

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[13] Di Prampero P, Narici M. Muscles in microgravity: From fibres to human motion.

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### **Author details**

Florian P.M. Kohn<sup>1</sup> \*, Claudia Koch<sup>1</sup> and Ramona Ritzmann<sup>2</sup>

\*Address all correspondence to: florian.p.m.kohn@uni-hohenheim.de

1 Department of Membrane Physiology (230b), University of Hohenheim, Stuttgart, Germany

2 Departments for Sports and Sport Science, University of Freiburg, Freiburg, Germany

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**Chapter 7**

**Provisional chapter**

**Spaceflight: Immune Effects and Nutritional**

**Spaceflight: Immune Effects and Nutritional** 

DOI: 10.5772/intechopen.74709

Microgravity is predicted to be a significant challenge to immune system during space travel. Consequences of weakened immune responses range from increased disease susceptibility to neoplastic growth. Degree of immune dysfunction is considered proportional to duration of stay in spaceflights. As a result of these risks, there is major concern over potential health risk for space travels that ultimately result in serious and considerable loss of mission objectives. Therefore, here is a need to explore the immune effects of spaceflight and its countermeasures. Several attempts have been made to develop effective measure to alleviate or prevent immune dysfunction due to microgravity. Among them, immunonutritional model has been shown to effectively modulate and upregulate immune system. This is further supported by our experiments demonstrating that supplementation of nutritional substrates like nucleotide and mushroom extracts active hexose-correlated compound (AHCC) effective in maintaining or restoring immunity in microgravity analog models.

Microgravity and stress of space travel affect many organ systems and their functions in the body. Exposure to microgravity may produce changes in the performance of the immune system at the cellular level and in the major physiological systems of the body. Consequently, abnormal immune responses observed in microgravity may pose serious consequences, especially in future long-term space missions. Existing evidence suggests that spaceflight

**Keywords:** space travel, immune system, countermeasures, nutrition

© 2016 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

© 2018 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use,

distribution, and reproduction in any medium, provided the original work is properly cited.

Anil D Kulkarni, Marie-Francoise Doursout, Asmita Kulkarni, Alamelu Sundaresan,

Anil D Kulkarni, Marie-Francoise Doursout, Asmita Kulkarni, Alamelu Sundaresan,

Takehito Miura, Koji Wakame and Hajime Fujii

Takehito Miura, Koji Wakame and Hajime Fujii

Additional information is available at the end of the chapter

Additional information is available at the end of the chapter

http://dx.doi.org/10.5772/intechopen.74709

**Countermeasure**

**Abstract**

**1. Introduction**

**Countermeasure**

#### **Chapter 7 Provisional chapter**

#### **Spaceflight: Immune Effects and Nutritional Countermeasure Spaceflight: Immune Effects and Nutritional Countermeasure**

DOI: 10.5772/intechopen.74709

Anil D Kulkarni, Marie-Francoise Doursout, Asmita Kulkarni, Alamelu Sundaresan, Takehito Miura, Koji Wakame and Hajime Fujii Anil D Kulkarni, Marie-Francoise Doursout, Asmita Kulkarni, Alamelu Sundaresan, Takehito Miura, Koji Wakame and Hajime Fujii

Additional information is available at the end of the chapter Additional information is available at the end of the chapter

http://dx.doi.org/10.5772/intechopen.74709

#### **Abstract**

Microgravity is predicted to be a significant challenge to immune system during space travel. Consequences of weakened immune responses range from increased disease susceptibility to neoplastic growth. Degree of immune dysfunction is considered proportional to duration of stay in spaceflights. As a result of these risks, there is major concern over potential health risk for space travels that ultimately result in serious and considerable loss of mission objectives. Therefore, here is a need to explore the immune effects of spaceflight and its countermeasures. Several attempts have been made to develop effective measure to alleviate or prevent immune dysfunction due to microgravity. Among them, immunonutritional model has been shown to effectively modulate and upregulate immune system. This is further supported by our experiments demonstrating that supplementation of nutritional substrates like nucleotide and mushroom extracts active hexose-correlated compound (AHCC) effective in maintaining or restoring immunity in microgravity analog models.

**Keywords:** space travel, immune system, countermeasures, nutrition

#### **1. Introduction**

Microgravity and stress of space travel affect many organ systems and their functions in the body. Exposure to microgravity may produce changes in the performance of the immune system at the cellular level and in the major physiological systems of the body. Consequently, abnormal immune responses observed in microgravity may pose serious consequences, especially in future long-term space missions. Existing evidence suggests that spaceflight

© 2016 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. © 2018 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

environment impairs immune system function in space travelers. Spaceflight environment has a cumulative effect on the body due to inherent stressors such as microgravity, cosmic radiation, and increase in corticosteroids [1]. A weakened immune system increases susceptibility to diseases and infectious pathogenesis. Immunosuppression puts hosts at risk for adverse effects such as infection from previously innocuous microorganisms that they are harboring or from microorganisms in their surroundings. Level of immune dysfunction is considered proportional to duration of stay in spaceflights. Longer the durations, such as missions to Moon and Mars and other deep space exploration flights, the effects are likely to be irreversible [2]. Maintenance of a healthy immune system is vital for resistance to infection and is essential in the homeostasis required for resistance to neoplastic disease, for prevention of autoimmune disease, tissue repair, and wound healing.

in suspended mice has been correlated to increased susceptibility to viral infection similar to that observed in rats flown on the US Space Shuttle. Therefore, there is an increased risk of infections among crewmembers during spaceflight resulting from working and living in a crowded, closed environment with limited capabilities for air revitalization and disinfection. Consequently, alterations in the immune response during spaceflight, as well as stress, aerosols, and altered fluid distribution within the body could increase the incidence of infectious diseases during long-duration space missions. Importantly, bacterial infection can be a major cause of morbidity after any traumatic injury, but trauma during spaceflight may substantially increase the infectious risk. An increase in neutrophil counts has been reported in tail-suspended rats [29, 30]. It is well established that activation of large numbers of neutrophils is likely to result in excessive generation of free radicals and associated tissue damage. Neutrophils also produce nitric oxide (NO), another free radical that reacts with superoxide

Spaceflight: Immune Effects and Nutritional Countermeasure

http://dx.doi.org/10.5772/intechopen.74709

105

Enclosed cabin of spacecraft and free-floating environment increase the potential for infections among the crewmembers. Like all the objects, microbes are also in free-floating state increasing the potential for inoculation by inhalation increasing the regional susceptibility of respiratory tract. Altered metabolism and virulence reported in *in vivo* models of simulatory microgravity [31–35]. Increased morbidity and slower rate of wound healing in *S. aureus* sepsis reported in experimental animals exposed to test environment. The evidence is significant as the possibility of sepsis increases in space cabin environment as well as after return to earth from space mission. Spaceflights has profound effect on ecologic control of the gastrointestinal tract as cosmonauts, upon returning to earth, were found to have their normal gut flora

Oxidative stress is known to occur in disuse and in many pathological conditions, and is now widely considered a major trigger of the imbalance between protein synthesis and degradation leading to muscle atrophy [36]. Reactive oxygen species (ROS) and elevated proinflammatory cytokines, in particular, TNF-α, mediate muscle atrophy via the redox-sensitive transcription factor nuclear factor-κB (NF-κB). It has been suggested that the exposure of brain to simulated microgravity can induce expression of certain transcription factors, which are oxidative stress dependent [37]. We have reported that the regulation and production of free radicals, and the relationship between oxidative stress and production of inflammatory cytokines and their subsequent effects on the healing of traumatic skeletal injuries in animals

US Apollo missions were the first to identify the immune dysfunction [38]. The study of spaceflight immunology is limited due to relative inaccessibility, difficulty of performing experiments in space and inadequate provisions in this area in the United States and Russian space programs [39]. Most of the immune studies performed in the early days of spaceflight era had astronauts and cosmonauts participated in such studies. These studies assessed the immune effects by in vitro analysis of blood samples that were obtained before and after spaceflights.

to form peroxynitrite, decomposing to the highly toxic hydroxyl radical.

replaced by potential pathogenic microorganisms.

as well as cells subjected to analog microgravity.

**3. Space travel and immune response studies**

Based on the evidence, NASA in its roadmap has documented the immunological risks and consequences in space travel and exploration [3]. Among the highlighted risks are carcinogenesis caused by immune system changes, immunodeficiency, infections, altered wound healing, allergies and hypersensitivities, altered host-microbial interactions. As a result of these risks, NASA is concerned of major impact on health and mission objectives and irreversible potential loss of life which ultimately will result in serious and considerable loss of mission objectives. Therefore, it is essential to consider and highlight the immune effects of spaceflight and its preventive measures.

### **2. Spaceflight: stress and immune response**

Space travelers are subjected to myriad of stressors of psychosocial, physical and environmental origin like microgravity, increased radiation, sleep deprivation, persistent circadian misalignment, and nutritional factors [4]. A common clinical observation is often the adverse relationship between stress and human disease. Stress such as injury or physical and physiological stress can result in metabolic stress and can cause severe impact on host health. Metabolic response to stress almost always results in adverse effects on the host defense mechanisms. Stress-related events cause breakdown in physical barrier, disrupt phagocytic cell function, and decreased antigen presentation altering cellular immune reactions. Stress is also suspected to play a role in morbidity and mortality in other immune-based diseases such as cancer, inflammatory bowel diseases, and even aging [5–13]. Although such dysfunctions have been thought of primarily as immunosuppressive, recent data have suggested immunoregulatory dysfunctions may play a more central role in stress-induced immune alterations [14]. Sleep alterations are suggested to modulate the stress-health relationship [15, 16]. Poor sleep, in turn, is associated with subsequent decrements in mental health including symptom reporting, incident cases of mood and anxiety disorders, and immune function [17–20]. Recent research suggests that stress is also associated with increased latent viral reactivation, upper respiratory tract infections, and increased wound healing time [21–26].

For instance, the decrease in immune cell function has been observed after flights of varying duration in the Soyuz, Skylab, Salyut, and Space Shuttle programs [27, 28]; these studies have also reported a reduction in lymphocyte proliferation. Reduced interferon-γ (IFN-γ) production in suspended mice has been correlated to increased susceptibility to viral infection similar to that observed in rats flown on the US Space Shuttle. Therefore, there is an increased risk of infections among crewmembers during spaceflight resulting from working and living in a crowded, closed environment with limited capabilities for air revitalization and disinfection. Consequently, alterations in the immune response during spaceflight, as well as stress, aerosols, and altered fluid distribution within the body could increase the incidence of infectious diseases during long-duration space missions. Importantly, bacterial infection can be a major cause of morbidity after any traumatic injury, but trauma during spaceflight may substantially increase the infectious risk. An increase in neutrophil counts has been reported in tail-suspended rats [29, 30]. It is well established that activation of large numbers of neutrophils is likely to result in excessive generation of free radicals and associated tissue damage. Neutrophils also produce nitric oxide (NO), another free radical that reacts with superoxide to form peroxynitrite, decomposing to the highly toxic hydroxyl radical.

environment impairs immune system function in space travelers. Spaceflight environment has a cumulative effect on the body due to inherent stressors such as microgravity, cosmic radiation, and increase in corticosteroids [1]. A weakened immune system increases susceptibility to diseases and infectious pathogenesis. Immunosuppression puts hosts at risk for adverse effects such as infection from previously innocuous microorganisms that they are harboring or from microorganisms in their surroundings. Level of immune dysfunction is considered proportional to duration of stay in spaceflights. Longer the durations, such as missions to Moon and Mars and other deep space exploration flights, the effects are likely to be irreversible [2]. Maintenance of a healthy immune system is vital for resistance to infection and is essential in the homeostasis required for resistance to neoplastic disease, for preven-

Based on the evidence, NASA in its roadmap has documented the immunological risks and consequences in space travel and exploration [3]. Among the highlighted risks are carcinogenesis caused by immune system changes, immunodeficiency, infections, altered wound healing, allergies and hypersensitivities, altered host-microbial interactions. As a result of these risks, NASA is concerned of major impact on health and mission objectives and irreversible potential loss of life which ultimately will result in serious and considerable loss of mission objectives. Therefore, it is essential to consider and highlight the immune effects of

Space travelers are subjected to myriad of stressors of psychosocial, physical and environmental origin like microgravity, increased radiation, sleep deprivation, persistent circadian misalignment, and nutritional factors [4]. A common clinical observation is often the adverse relationship between stress and human disease. Stress such as injury or physical and physiological stress can result in metabolic stress and can cause severe impact on host health. Metabolic response to stress almost always results in adverse effects on the host defense mechanisms. Stress-related events cause breakdown in physical barrier, disrupt phagocytic cell function, and decreased antigen presentation altering cellular immune reactions. Stress is also suspected to play a role in morbidity and mortality in other immune-based diseases such as cancer, inflammatory bowel diseases, and even aging [5–13]. Although such dysfunctions have been thought of primarily as immunosuppressive, recent data have suggested immunoregulatory dysfunctions may play a more central role in stress-induced immune alterations [14]. Sleep alterations are suggested to modulate the stress-health relationship [15, 16]. Poor sleep, in turn, is associated with subsequent decrements in mental health including symptom reporting, incident cases of mood and anxiety disorders, and immune function [17–20]. Recent research suggests that stress is also associated with increased latent viral reactivation,

upper respiratory tract infections, and increased wound healing time [21–26].

For instance, the decrease in immune cell function has been observed after flights of varying duration in the Soyuz, Skylab, Salyut, and Space Shuttle programs [27, 28]; these studies have also reported a reduction in lymphocyte proliferation. Reduced interferon-γ (IFN-γ) production

tion of autoimmune disease, tissue repair, and wound healing.

104 Into Space - A Journey of How Humans Adapt and Live in Microgravity

spaceflight and its preventive measures.

**2. Spaceflight: stress and immune response**

Enclosed cabin of spacecraft and free-floating environment increase the potential for infections among the crewmembers. Like all the objects, microbes are also in free-floating state increasing the potential for inoculation by inhalation increasing the regional susceptibility of respiratory tract. Altered metabolism and virulence reported in *in vivo* models of simulatory microgravity [31–35]. Increased morbidity and slower rate of wound healing in *S. aureus* sepsis reported in experimental animals exposed to test environment. The evidence is significant as the possibility of sepsis increases in space cabin environment as well as after return to earth from space mission. Spaceflights has profound effect on ecologic control of the gastrointestinal tract as cosmonauts, upon returning to earth, were found to have their normal gut flora replaced by potential pathogenic microorganisms.

Oxidative stress is known to occur in disuse and in many pathological conditions, and is now widely considered a major trigger of the imbalance between protein synthesis and degradation leading to muscle atrophy [36]. Reactive oxygen species (ROS) and elevated proinflammatory cytokines, in particular, TNF-α, mediate muscle atrophy via the redox-sensitive transcription factor nuclear factor-κB (NF-κB). It has been suggested that the exposure of brain to simulated microgravity can induce expression of certain transcription factors, which are oxidative stress dependent [37]. We have reported that the regulation and production of free radicals, and the relationship between oxidative stress and production of inflammatory cytokines and their subsequent effects on the healing of traumatic skeletal injuries in animals as well as cells subjected to analog microgravity.

### **3. Space travel and immune response studies**

US Apollo missions were the first to identify the immune dysfunction [38]. The study of spaceflight immunology is limited due to relative inaccessibility, difficulty of performing experiments in space and inadequate provisions in this area in the United States and Russian space programs [39]. Most of the immune studies performed in the early days of spaceflight era had astronauts and cosmonauts participated in such studies. These studies assessed the immune effects by in vitro analysis of blood samples that were obtained before and after spaceflights. Most of the experimental studies are of a pre- and postflight nature involving both humans and experimental animals and are divided into categories of short duration (< 2 weeks) and long duration (> 2 weeks) missions. In short duration flights, the majority of the outcomes are from postflight period analysis showing decreased cellular response to mitogens, decreased T cell counts and somewhat variable leukocyte counts [39]. Long-duration studies (1–12 months) that are performed by Russians, on board the Mir space station, have documented a 50% reduction in lymphocytic response to phytohemagglutinin (PHA) on the day after the mission, as compared with the preflight response. Levels returned to normal by day seven postlanding. Other studies showed decreased graft-versus-host response to xenoantigens and mitogen-induced IL-2 production [40]. The limited in-flight studies of delayed-type hypersensitivity (DTH) using commercial kits for the assessment of cell-mediated immunity showed significant suppression in half the subjects of 3–5 months in space and upon landing [41]. There have been several studies reported from space shuttle missions indicating alterations in lymphocyte response and decreased production of cytokines including interferons-α, β and γ and interleukin-2 [42].

it relates to prolonged bed rest or inactive geriatric patients. Exclusive use of human subjects for space research has severe limitations due to the ethical issues involved. Animal models provide more opportunities for research as it allows wider range of possible experiments. With variety of techniques available, rodents are preferred choice for space research studies. Several

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Hind limb suspension of rodents was initially developed to study musculoskeletal system. In this system, the hind limbs of rodents are elevated to produce a 30° head-down tilt, which results in a cephalad-fluid shift and avoids weight-bearing by the hindquarters. When spaceflight effects were compared with ground-based weight unloading models, such as, bed rest studies and hind limb suspension model, there are many common features and effects [47– 49]. These are shown in **Table 1**. Similar to many physiologic effects, the immune function and its dysfunction in both ground-based models is also very similar to spaceflight effects on the body. Many of the areas correlate with the spaceflight and its stress that have many

Antiorthostatic hind limb suspension of rodents, a ground-based model for simulation of microgravity, has summarized the physiologic and immunologic changes induced by antiorthostatic suspension and indicates a correlation with physiologic changes induced by spaceflight [50]. This position simulates the cephalad fluid and organ shift, a negative balance of water, nitrogen, and potassium; and increased metabolic turnover observed in astronauts during spaceflight. Studies using this model have shown interesting contradictory observations relative to organ-specific immunologic changes. Overall results of such antiorthostatic

**Spaceflight Bed rest Tail Suspension**

models were designed with specific effects to be studied in each individual model.

**4.1.** *In vivo* **studies with rodent hind limb unloading model**

consequential responses produced in body.

suspension models have shown a decrease in immunity.

Cephalic fluid shift + + + Redistribution of bones + + + Bone resorption ↓→ ↓→ ↓→ Calcium balance ↓ ↓ ↓ Fecal calcium ↑ ↑ ↑ Urine calcium ↑ ↑ ↑ Serum calcium ↑ ↑→ ↑→ PTH ↓ → → 1, 25 (OH)2 D ↓ ↓ ↓ Serum osteocalcin ↓ → ↓ Bone strength ↓ ND ↓ Immune function ↓ ↓→ ↓

**Table 1.** Comparison of spaceflight to ground-based models of skeletal unloading.

Several studies have indicated that spaceflight can adversely affect tissue repair in muscle and bone. Mechanical unloading and physical deconditioning, which are thought to be central components in the effects of microgravity on the human body, have also broader clinical applications on Earth, for example, as it relates to prolonged bed rest or inactive geriatric patients. As a result, ground-based animal models have been used to mimic the mechanical unloading and physical deconditioning associated with microgravity and bed rest in humans. Because the phenotype of skeletal muscle is importantly dependent on mechanical loading, muscle plasticity is highlighted by the severe loss of mass (atrophy) after a few days of reduced weight-bearing activity such as bed rest or spaceflight. Hind limb unloaded (HU) of rats is an established model for atrophy which produces many of the muscular and systemic changes seen in humans as a consequence of muscle disuse [43, 44]. Consequently, results indicated that microgravity adversely affects the capacity of wounds to heal and that this may be related to a diminished cellular response to growth factors known to be present at sites of wounding [45, 46]. However, one such area of biomedical research where little is known concerns the effects of mechanical unloading and physical deconditioning on bone fracture repair and wound healing.

These research studies suggest that stress-induced changes in psychological, behavioral, and/ or physiological functioning can be harmful and may result in negative health consequences. The clinical significance of these stressors and immune system changes must be defined, evaluated, and identified in space travelers.

### **4. Ground-based simulated microgravity studies**

Due to high cost of spaceflight experiments and infrequency of flights, ground-based models that mimic the effect of microgravity have been extensively used. Among the models developed were human analogs model such as bed rest, physical stress, academic stress, and confinement, which allow some aspects of the spaceflight stressors [39]. Mechanical unloading and physical deconditioning, which are thought to be central components in the effects of microgravity on the human body, have also broader clinical applications on Earth, for example, as it relates to prolonged bed rest or inactive geriatric patients. Exclusive use of human subjects for space research has severe limitations due to the ethical issues involved. Animal models provide more opportunities for research as it allows wider range of possible experiments. With variety of techniques available, rodents are preferred choice for space research studies. Several models were designed with specific effects to be studied in each individual model.

#### **4.1.** *In vivo* **studies with rodent hind limb unloading model**

Most of the experimental studies are of a pre- and postflight nature involving both humans and experimental animals and are divided into categories of short duration (< 2 weeks) and long duration (> 2 weeks) missions. In short duration flights, the majority of the outcomes are from postflight period analysis showing decreased cellular response to mitogens, decreased T cell counts and somewhat variable leukocyte counts [39]. Long-duration studies (1–12 months) that are performed by Russians, on board the Mir space station, have documented a 50% reduction in lymphocytic response to phytohemagglutinin (PHA) on the day after the mission, as compared with the preflight response. Levels returned to normal by day seven postlanding. Other studies showed decreased graft-versus-host response to xenoantigens and mitogen-induced IL-2 production [40]. The limited in-flight studies of delayed-type hypersensitivity (DTH) using commercial kits for the assessment of cell-mediated immunity showed significant suppression in half the subjects of 3–5 months in space and upon landing [41]. There have been several studies reported from space shuttle missions indicating alterations in lymphocyte response and decreased production of cytokines including interferons-α, β and γ and interleukin-2 [42].

106 Into Space - A Journey of How Humans Adapt and Live in Microgravity

Several studies have indicated that spaceflight can adversely affect tissue repair in muscle and bone. Mechanical unloading and physical deconditioning, which are thought to be central components in the effects of microgravity on the human body, have also broader clinical applications on Earth, for example, as it relates to prolonged bed rest or inactive geriatric patients. As a result, ground-based animal models have been used to mimic the mechanical unloading and physical deconditioning associated with microgravity and bed rest in humans. Because the phenotype of skeletal muscle is importantly dependent on mechanical loading, muscle plasticity is highlighted by the severe loss of mass (atrophy) after a few days of reduced weight-bearing activity such as bed rest or spaceflight. Hind limb unloaded (HU) of rats is an established model for atrophy which produces many of the muscular and systemic changes seen in humans as a consequence of muscle disuse [43, 44]. Consequently, results indicated that microgravity adversely affects the capacity of wounds to heal and that this may be related to a diminished cellular response to growth factors known to be present at sites of wounding [45, 46]. However, one such area of biomedical research where little is known concerns the effects of mechanical

unloading and physical deconditioning on bone fracture repair and wound healing.

uated, and identified in space travelers.

**4. Ground-based simulated microgravity studies**

These research studies suggest that stress-induced changes in psychological, behavioral, and/ or physiological functioning can be harmful and may result in negative health consequences. The clinical significance of these stressors and immune system changes must be defined, eval-

Due to high cost of spaceflight experiments and infrequency of flights, ground-based models that mimic the effect of microgravity have been extensively used. Among the models developed were human analogs model such as bed rest, physical stress, academic stress, and confinement, which allow some aspects of the spaceflight stressors [39]. Mechanical unloading and physical deconditioning, which are thought to be central components in the effects of microgravity on the human body, have also broader clinical applications on Earth, for example, as Hind limb suspension of rodents was initially developed to study musculoskeletal system. In this system, the hind limbs of rodents are elevated to produce a 30° head-down tilt, which results in a cephalad-fluid shift and avoids weight-bearing by the hindquarters. When spaceflight effects were compared with ground-based weight unloading models, such as, bed rest studies and hind limb suspension model, there are many common features and effects [47– 49]. These are shown in **Table 1**. Similar to many physiologic effects, the immune function and its dysfunction in both ground-based models is also very similar to spaceflight effects on the body. Many of the areas correlate with the spaceflight and its stress that have many consequential responses produced in body.

Antiorthostatic hind limb suspension of rodents, a ground-based model for simulation of microgravity, has summarized the physiologic and immunologic changes induced by antiorthostatic suspension and indicates a correlation with physiologic changes induced by spaceflight [50]. This position simulates the cephalad fluid and organ shift, a negative balance of water, nitrogen, and potassium; and increased metabolic turnover observed in astronauts during spaceflight. Studies using this model have shown interesting contradictory observations relative to organ-specific immunologic changes. Overall results of such antiorthostatic suspension models have shown a decrease in immunity.


**Table 1.** Comparison of spaceflight to ground-based models of skeletal unloading.

### **4.2.** *In vitro* **studies in simulated microgravity using clinostat bioreactors**

Numerous attempts to identify and separate the effects of microgravity and stress have met with difficult challenges, further raising the issue whether single cells are also affected by microgravity. Among the microgravity simulator models, an apparatus called a rotating wall vessel (RWV) developed by NASA is an ideal ground-based model system for examining the effects of microgravity on cells of the immune system without the presence of psychoneuroendocrine factors [51]. The RWV, based on clinostat technology, is a microgravity simulator Couette flow bioreactor. It consists of a zero-head space, aqueous filled culture vessel that suspends cells by rotating at low speed (10–60 rpm) around a horizontal axis. These conditions subject the cells to a randomized gravity field and low shear forces [52, 53]. Cells in the RWV are estimated to experience acceleration forces that simulate microgravity as low as 2 × 10–4 g. Using a Clinostat tissue culture apparatus, Cogoli [54] has shown that microgravity alters cell membrane permeability and thickness as well as cytoplasmic streaming. Several studies have reported the effect of microgravity on T lymphocyte activation. Clinostat culture studies showed that T cell responses to concanavalin-A (Con-A) were decreased by 50% [54]. Cooper and Pellis [55] have documented, using a clinostatic RWV bioreactor, that during polyclonal activation the signaling pathways leading to protein kinase C (PKC) activation are sensitive to simulated microgravity. Although several investigators used cell cultures subjected to analog microgravity to study potential impacts that space travel imposes on humans, the *ex vivo* has a serious lack of *in vivo* measurements of immune-physiological responses.

immune system. The use of immunomodifying preparations such as LPS, MDP, and proteoglycans had no beneficial effects. In clinical practice, these compounds exhibited toxicity. Use of growth factors and interleukins was beneficial to small extent but had no influence on the increased corticosteroid (due to microgravity environment) levels [57, 58]. Most of the microgravity studies have documented and analyzed the immunosuppressive effects of true or simulated microgravity; however, there are scanty reports of efforts to modulate the immune system, host defense system, and its function. Especially, scarce are the studies that approach

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Nutrition has played a critical role throughout the history of exploration, and space exploration is no exception. Environmental impacts like radiation, and spacecraft and spacesuit atmospheres can alter nutritional status and nutritional requirements of spaceflight. The physiological changes that occur during spaceflight influence spaceflight nutritional requirements. Therefore, understanding the nutritional requirements of space travelers and the role of nutrition in human adaptation to microgravity are as critical to crew safety and mission success. Many potential targets for nutritional countermeasures proposed to counteract or mitigate some of the negative effects of spaceflight on the human body. Recently, immunenutritional model has been shown to effectively modulate and upregulate immune system where a nutritional substrate has benefits beyond basic nutrition. Based on our extensive experience in R&D of nutritional immunomodulation, we evaluated two nutrients, which we have been studying for several years.

Dietary nucleotides are reported to restore innate and adaptive T-cell mediated immunity both at the peripheral mature immune compartment and stem cell level (**Figure 1**) [59, 60]. Nutritional upregulation of the global host defense mechanisms would have the great advantage of being technically feasible and applicable in people and it would be economical without the untoward effects. Laboratory findings and progress in multidisciplinary emerging field of nutritional immunology justify emphatically the proposed novel approach of nutritional modulation of host defense system in space travel. With the experimental evidence and information of nucleotide nutrition on immunity, it is plausible to provide both the prophylactic and therapeutic approach to the modulation of host defense mechanisms during spaceflights (**Figure 2**) [61].

We have documented that nucleotide supplementation significantly reversed the immunosuppression observed *in vivo* HLU model and *in vitro* BIO model [62]. The results were dramatic in the HLU group where the control chow group had significantly lower popliteal lymph node (PLN) response as compared to other housing groups. This effect of immunosuppression was reversed by dietary supplementation of nucleotides with Uracil effect reported the highest and significant as compared to the chow group in HU. Thus, the antiorthostatic HLU model of modeled microgravity can be used successfully to document nutritional immunomodulatory countermeasure. We also assessed the stress effect by measuring the serum levels

the issue of the maintenance and restoration of immunosurveillance.

**6.1. Nucleotide supplementation in microgravity experiments**

*6.1.1. Hind limb unloading (HLU) in vivo model*

**6. Dietary nucleotides**

In the bioreactor microgravity cultured cells, there was a reproducibility of significantly suppressed PHA response when compared to static cultured cells as described by Cooper and Pellis [55]. In preliminary experiments, supplementation of the culture medium with nucleoside-nucleotide mixture or uridine (preferred nucleotides for solubility and bioavailability) significantly enhanced the PHA response in bioreactor microgravity. To our knowledge, this is the first observation documenting the reversal of decreased PHA response in simulated microgravity using the NASA bioreactor. Continuation of these studies using the biotechnology of *in vitro* modeled microgravity will provide additional data to support the hypothesis and prove the countermeasure effects of nucleotides.

During the countermeasure experiments, we studied the effects of housing environments on the production and expression of biologically and immunologically important molecules, namely cytokines, nitric oxide (NO), and inducible nitric oxide synthase (iNOS).

### **5. Countermeasure for prevention of immunosuppressive effects**

Several attempts have been made to develop effective measure to alleviate or prevent immune dysfunction. There is definitely a need for countermeasures that will maintain normal immune system during spaceflight, especially when missions are prolonged. Almost all were found to be inadequate and presented adverse responses. For example, the use of immunomodulator agents and neurohormonal regulation was suggested to ameliorate the immune dysfunction in space [56]. However, the suggested methods of neurohormonal regulation by using agents that act upon the nervous system may have deleterious effects on systems besides the immune system. The use of immunomodifying preparations such as LPS, MDP, and proteoglycans had no beneficial effects. In clinical practice, these compounds exhibited toxicity. Use of growth factors and interleukins was beneficial to small extent but had no influence on the increased corticosteroid (due to microgravity environment) levels [57, 58]. Most of the microgravity studies have documented and analyzed the immunosuppressive effects of true or simulated microgravity; however, there are scanty reports of efforts to modulate the immune system, host defense system, and its function. Especially, scarce are the studies that approach the issue of the maintenance and restoration of immunosurveillance.

Nutrition has played a critical role throughout the history of exploration, and space exploration is no exception. Environmental impacts like radiation, and spacecraft and spacesuit atmospheres can alter nutritional status and nutritional requirements of spaceflight. The physiological changes that occur during spaceflight influence spaceflight nutritional requirements. Therefore, understanding the nutritional requirements of space travelers and the role of nutrition in human adaptation to microgravity are as critical to crew safety and mission success. Many potential targets for nutritional countermeasures proposed to counteract or mitigate some of the negative effects of spaceflight on the human body. Recently, immunenutritional model has been shown to effectively modulate and upregulate immune system where a nutritional substrate has benefits beyond basic nutrition. Based on our extensive experience in R&D of nutritional immunomodulation, we evaluated two nutrients, which we have been studying for several years.

### **6. Dietary nucleotides**

**4.2.** *In vitro* **studies in simulated microgravity using clinostat bioreactors**

108 Into Space - A Journey of How Humans Adapt and Live in Microgravity

*vivo* measurements of immune-physiological responses.

and prove the countermeasure effects of nucleotides.

Numerous attempts to identify and separate the effects of microgravity and stress have met with difficult challenges, further raising the issue whether single cells are also affected by microgravity. Among the microgravity simulator models, an apparatus called a rotating wall vessel (RWV) developed by NASA is an ideal ground-based model system for examining the effects of microgravity on cells of the immune system without the presence of psychoneuroendocrine factors [51]. The RWV, based on clinostat technology, is a microgravity simulator Couette flow bioreactor. It consists of a zero-head space, aqueous filled culture vessel that suspends cells by rotating at low speed (10–60 rpm) around a horizontal axis. These conditions subject the cells to a randomized gravity field and low shear forces [52, 53]. Cells in the RWV are estimated to experience acceleration forces that simulate microgravity as low as 2 × 10–4 g. Using a Clinostat tissue culture apparatus, Cogoli [54] has shown that microgravity alters cell membrane permeability and thickness as well as cytoplasmic streaming. Several studies have reported the effect of microgravity on T lymphocyte activation. Clinostat culture studies showed that T cell responses to concanavalin-A (Con-A) were decreased by 50% [54]. Cooper and Pellis [55] have documented, using a clinostatic RWV bioreactor, that during polyclonal activation the signaling pathways leading to protein kinase C (PKC) activation are sensitive to simulated microgravity. Although several investigators used cell cultures subjected to analog microgravity to study potential impacts that space travel imposes on humans, the *ex vivo* has a serious lack of *in* 

In the bioreactor microgravity cultured cells, there was a reproducibility of significantly suppressed PHA response when compared to static cultured cells as described by Cooper and Pellis [55]. In preliminary experiments, supplementation of the culture medium with nucleoside-nucleotide mixture or uridine (preferred nucleotides for solubility and bioavailability) significantly enhanced the PHA response in bioreactor microgravity. To our knowledge, this is the first observation documenting the reversal of decreased PHA response in simulated microgravity using the NASA bioreactor. Continuation of these studies using the biotechnology of *in vitro* modeled microgravity will provide additional data to support the hypothesis

During the countermeasure experiments, we studied the effects of housing environments on the production and expression of biologically and immunologically important molecules,

Several attempts have been made to develop effective measure to alleviate or prevent immune dysfunction. There is definitely a need for countermeasures that will maintain normal immune system during spaceflight, especially when missions are prolonged. Almost all were found to be inadequate and presented adverse responses. For example, the use of immunomodulator agents and neurohormonal regulation was suggested to ameliorate the immune dysfunction in space [56]. However, the suggested methods of neurohormonal regulation by using agents that act upon the nervous system may have deleterious effects on systems besides the

namely cytokines, nitric oxide (NO), and inducible nitric oxide synthase (iNOS).

**5. Countermeasure for prevention of immunosuppressive effects**

Dietary nucleotides are reported to restore innate and adaptive T-cell mediated immunity both at the peripheral mature immune compartment and stem cell level (**Figure 1**) [59, 60]. Nutritional upregulation of the global host defense mechanisms would have the great advantage of being technically feasible and applicable in people and it would be economical without the untoward effects. Laboratory findings and progress in multidisciplinary emerging field of nutritional immunology justify emphatically the proposed novel approach of nutritional modulation of host defense system in space travel. With the experimental evidence and information of nucleotide nutrition on immunity, it is plausible to provide both the prophylactic and therapeutic approach to the modulation of host defense mechanisms during spaceflights (**Figure 2**) [61].

#### **6.1. Nucleotide supplementation in microgravity experiments**

#### *6.1.1. Hind limb unloading (HLU) in vivo model*

We have documented that nucleotide supplementation significantly reversed the immunosuppression observed *in vivo* HLU model and *in vitro* BIO model [62]. The results were dramatic in the HLU group where the control chow group had significantly lower popliteal lymph node (PLN) response as compared to other housing groups. This effect of immunosuppression was reversed by dietary supplementation of nucleotides with Uracil effect reported the highest and significant as compared to the chow group in HU. Thus, the antiorthostatic HLU model of modeled microgravity can be used successfully to document nutritional immunomodulatory countermeasure. We also assessed the stress effect by measuring the serum levels

**Figure 1.** Pleiogenic immunologic responses by supplemental nucleotides.

of corticosterone (CORT) in experimental groups. The experimental evidence showed that in non-HLU animals, there was minimal effect of supplemented nucleotides (at the given dose) and did not encounter the immune depressive effects seen in HLU animals. Thus, nucleotide supplementation was beneficial for immune restoration in modeled microgravity environmental conditions. These results confirm our observations that RNA and Uracil are effective in maintaining or restoring immunity when the animals are under stressful situations (such as protein starvation, total starvation or dietary nucleotide deficiency, and HLU) or other trauma (such as sepsis, or inflammatory hypersensitivity stimulations). Our data also show the HU group had increased oxygen radicals (ROS) to 130% in the brain as compared to control mouse brain. This ROS increase was inversely proportional to glutathione levels (75%) in the brains. Therefore, our data confirm that oxidative stress is induced in animals subjected to hind limb unloaded.

We have studied the effects of dietary nucleotides on bone loss after a disuse model of tail suspension in rats and have found that, in addition to exerting positive effects on the immune system, a nucleotide-enriched diet reduced the amount of bone loss seen in these animals. In a different model of bone demineralization, we have recently found that providing a diet of normal rat chow enriched with enhanced nucleotides reduces bone density loss in the femur

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In microgravity, immune suppression is a documented phenomenon in astronauts. It is also documented in *in vitro* and *in vivo* studies in modeled microgravity and the antiorthostatic rodent models of microgravity. In our earlier study, we reported that in the BIO microgravity cultured cells, there was a reproducibility of significantly suppressed phytohemaglutinin, a T cell mitogen response when compared to static cultured cells [1, 55]. We also reported that supplementation of the culture medium with nucleoside-nucleotide mixture or uridine (preferred nucleotides for solubility and bioavailability) significantly enhanced the PHA response

Lymphocyte locomotion along the interstitium is integral to the immune response. Microgravity is a stressor that inhibits this phenomenon. The microgravity cell culture analog system also has the same effect on locomotion inhibition of lymphocytes [64]. Since locomotion is critical for an optimal immune response, countermeasure strategies for its restoration in lymphocytes

when initiated immediately following spinal contusion injury [63].

**Figure 2.** Potential mechanism of action of dietary nucleotides on immunity.

*locomotion*

in bioreactor microgravity.

*6.1.3. Bioreactor in vitro modeled microgravity for T cell suppression and lymphocyte* 

#### *6.1.2. Bone density after hind limb suspension or spinal cord injury in a rat model of osteoporosis*

Space travelers are subjected to significant bone loss due to increased resorption and altered remodeling of bone tissue. In spite of calcium supplementation, increased excretion of calcium, reduced absorption of calcium from intestine, and diminished vitamin D synthesis due to space suit ultimately result in bone loss. Bone loss is proportional to the length of time in space. The changes in bone during spaceflight are similar to those seen in osteoporosis. Dietary nucleotides have long been known to positively affect the immune system and more recently have been shown to have beneficial effects in rapidly proliferating tissues.

**Figure 2.** Potential mechanism of action of dietary nucleotides on immunity.

of corticosterone (CORT) in experimental groups. The experimental evidence showed that in non-HLU animals, there was minimal effect of supplemented nucleotides (at the given dose) and did not encounter the immune depressive effects seen in HLU animals. Thus, nucleotide supplementation was beneficial for immune restoration in modeled microgravity environmental conditions. These results confirm our observations that RNA and Uracil are effective in maintaining or restoring immunity when the animals are under stressful situations (such as protein starvation, total starvation or dietary nucleotide deficiency, and HLU) or other trauma (such as sepsis, or inflammatory hypersensitivity stimulations). Our data also show the HU group had increased oxygen radicals (ROS) to 130% in the brain as compared to control mouse brain. This ROS increase was inversely proportional to glutathione levels (75%) in the brains. Therefore, our data confirm that oxidative stress is induced in animals subjected

**Figure 1.** Pleiogenic immunologic responses by supplemental nucleotides.

110 Into Space - A Journey of How Humans Adapt and Live in Microgravity

*6.1.2. Bone density after hind limb suspension or spinal cord injury in a rat model of* 

recently have been shown to have beneficial effects in rapidly proliferating tissues.

Space travelers are subjected to significant bone loss due to increased resorption and altered remodeling of bone tissue. In spite of calcium supplementation, increased excretion of calcium, reduced absorption of calcium from intestine, and diminished vitamin D synthesis due to space suit ultimately result in bone loss. Bone loss is proportional to the length of time in space. The changes in bone during spaceflight are similar to those seen in osteoporosis. Dietary nucleotides have long been known to positively affect the immune system and more

to hind limb unloaded.

*osteoporosis*

We have studied the effects of dietary nucleotides on bone loss after a disuse model of tail suspension in rats and have found that, in addition to exerting positive effects on the immune system, a nucleotide-enriched diet reduced the amount of bone loss seen in these animals. In a different model of bone demineralization, we have recently found that providing a diet of normal rat chow enriched with enhanced nucleotides reduces bone density loss in the femur when initiated immediately following spinal contusion injury [63].

### *6.1.3. Bioreactor in vitro modeled microgravity for T cell suppression and lymphocyte locomotion*

In microgravity, immune suppression is a documented phenomenon in astronauts. It is also documented in *in vitro* and *in vivo* studies in modeled microgravity and the antiorthostatic rodent models of microgravity. In our earlier study, we reported that in the BIO microgravity cultured cells, there was a reproducibility of significantly suppressed phytohemaglutinin, a T cell mitogen response when compared to static cultured cells [1, 55]. We also reported that supplementation of the culture medium with nucleoside-nucleotide mixture or uridine (preferred nucleotides for solubility and bioavailability) significantly enhanced the PHA response in bioreactor microgravity.

Lymphocyte locomotion along the interstitium is integral to the immune response. Microgravity is a stressor that inhibits this phenomenon. The microgravity cell culture analog system also has the same effect on locomotion inhibition of lymphocytes [64]. Since locomotion is critical for an optimal immune response, countermeasure strategies for its restoration in lymphocytes were sought. When lymphocytes were treated with 0.5 ng/ml phorbol myristate acetate (PMA) after exposure to microgravity culture, recovery of locomotion through type I collagen was 87%. However, in the human setting, PMA is a tumor promoter and cannot be administered. Studies with hind limb suspended mouse splenocytes displayed immune suppression, which was mitigated by the use of nucleotides and nucleosides (NS/NT). In lymphocytes cultured in modeled microgravity using the NASA BIO model of microgravity, it is shown that the NS/ NT mixture used was able to orchestrate locomotion recovery by more than 87% documented with PMA in lymphocytes from three normal human donors.

We examined the effect of AHCC on microgravity-induced immune changes by using a hind limb unloading (HLU) of mice as a microgravity analog [68]. A beneficial effect of AHCC on T cells has been reported in various models [69–71]. We induced immune changes by using a hind limb unloading (HLU) of mice as a microgravity analog and accessed the effect of AHCC supplementation on various immune functions. To access the immune function, Popliteal lymph node (PLN) response was analyzed as it involves all phases of immune response, e.g., antigen processing and presentation, followed by proliferative phase of immune response. PLN response was significantly decreased in mice in the HLU group compared to that in mice in the control group, and AHCC supplementation significantly reversed this response (**Figure 3**). AHCC reversed HLU-induced T cell dysfunction in PLNs. Since T cells play an important role in acquired immunity, a countermeasure for T cell dys-

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113

Spaceflight environment is one of the serious immune-compromised conditions due to closed space, and recycling of air and water may increase the risk of microbial load and reactivation of opportunistic pathogens, latent bacteria, and viruses. Neutrophils-, macrophages-, or monocytes-mediated innate immunity is the first step to exclude pathogens. To assess over-

**Figure 4.** Production of cytokines and chemokines vs. AHCC dose in control and HLU mice.

function is imperative.

### **7. Active hexose-correlated compound (AHCC)**

AHCC is a nutritional substrate known for immune enhancing properties in humans and in laboratory studies. It is being widely used around the globe as a nutritional supplement for health and well-being in normal and patients with various afflictions to improve quality of life. AHCC is a compound obtained from enzyme-fermented extract of the mycelia of basidiomycetes mushrooms. AHCC consists of oligosaccharides, amino acids, lipids, and minerals [65]. The main components of AHCC are oligosaccharides (~74% of AHCC), and approximately 20% of AHCC are partially acetylated α-1, 4-glucans with a mean molecular weight of 5 kDa. These oligosaccharides including α-1, 4-glucans are believed to be the active components of AHCC [66, 67].

**Figure 3.** Stimulation index for *in vivo* PLN proliferative response vs. AHCC dose in control and HLU mice. means ± SEM; \*p <0.05, \*\*p =0.001, † P <0.05.

We examined the effect of AHCC on microgravity-induced immune changes by using a hind limb unloading (HLU) of mice as a microgravity analog [68]. A beneficial effect of AHCC on T cells has been reported in various models [69–71]. We induced immune changes by using a hind limb unloading (HLU) of mice as a microgravity analog and accessed the effect of AHCC supplementation on various immune functions. To access the immune function, Popliteal lymph node (PLN) response was analyzed as it involves all phases of immune response, e.g., antigen processing and presentation, followed by proliferative phase of immune response. PLN response was significantly decreased in mice in the HLU group compared to that in mice in the control group, and AHCC supplementation significantly reversed this response (**Figure 3**). AHCC reversed HLU-induced T cell dysfunction in PLNs. Since T cells play an important role in acquired immunity, a countermeasure for T cell dysfunction is imperative.

were sought. When lymphocytes were treated with 0.5 ng/ml phorbol myristate acetate (PMA) after exposure to microgravity culture, recovery of locomotion through type I collagen was 87%. However, in the human setting, PMA is a tumor promoter and cannot be administered. Studies with hind limb suspended mouse splenocytes displayed immune suppression, which was mitigated by the use of nucleotides and nucleosides (NS/NT). In lymphocytes cultured in modeled microgravity using the NASA BIO model of microgravity, it is shown that the NS/ NT mixture used was able to orchestrate locomotion recovery by more than 87% documented

AHCC is a nutritional substrate known for immune enhancing properties in humans and in laboratory studies. It is being widely used around the globe as a nutritional supplement for health and well-being in normal and patients with various afflictions to improve quality of life. AHCC is a compound obtained from enzyme-fermented extract of the mycelia of basidiomycetes mushrooms. AHCC consists of oligosaccharides, amino acids, lipids, and minerals [65]. The main components of AHCC are oligosaccharides (~74% of AHCC), and approximately 20% of AHCC are partially acetylated α-1, 4-glucans with a mean molecular weight of 5 kDa. These oligosaccharides including α-1, 4-glucans are believed to be the active compo-

**Figure 3.** Stimulation index for *in vivo* PLN proliferative response vs. AHCC dose in control and HLU mice. means ±

with PMA in lymphocytes from three normal human donors.

112 Into Space - A Journey of How Humans Adapt and Live in Microgravity

**7. Active hexose-correlated compound (AHCC)**

nents of AHCC [66, 67].

SEM; \*p <0.05, \*\*p =0.001, †

P <0.05.

Spaceflight environment is one of the serious immune-compromised conditions due to closed space, and recycling of air and water may increase the risk of microbial load and reactivation of opportunistic pathogens, latent bacteria, and viruses. Neutrophils-, macrophages-, or monocytes-mediated innate immunity is the first step to exclude pathogens. To assess over-

**Figure 4.** Production of cytokines and chemokines vs. AHCC dose in control and HLU mice.

all functions of these types of cells, we measured the levels of LPS-stimulated cytokine and chemokine production from splenocytes. Both inflammatory cytokines and chemokines were increased in mice in the HLU group and AHCC supplementation in HLU mice tended to further enhance the inflammatory cytokine and chemokine production (**Figure 4**). Increased interleukin like IL-6 is implicated in increased stimulated immune responses, e.g., during infection and after trauma, especially burns or other tissue damage leading to inflammation [72], while increased IL-12 (T cell stimulating factor) is known to be a stimulator of the TNF-α pathway and increases adaptive immunity. Enhancement of inflammatory cytokine and chemokine production by AHCC supplementation suggested to be effective for preventing infection [69, 73].

**Author details**

Takehito Miura<sup>3</sup>

Houston, Texas, USA

Houston, Texas, USA

**References**

Anil D Kulkarni\*, Marie-Francoise Doursout<sup>1</sup>

, Koji Wakame<sup>4</sup>

3 Texas Southern University, Houston, Texas, USA

4 Amino Up Chemical Co, Sapporo, Hokkaido, Japan

5 Hokkaido Pharmaceutical University, Hokkaido, Japan

Report—Human Research Roadmap—NASA. 2005

Theoretical Medicine. 1994;**15**:337-347

[1] Kulkarni AD, Kogiso M, Wakame K. AHCC Newsletter. 2006;**3-4**:3-4

\*Address all correspondence to: anil.d.kulkami@ uth.tmc.edu

and Hajime Fujii<sup>3</sup>

1 Department of Surgery, The University of Texas Health McGovern Medical School,

2 Department of Anesthesiology, The University of Texas Health McGovern Medical School,

[2] Lang T, Van Loon JJWA, Bloomfield S, Vico L, Chopard A, Rittweger J, Kyparos A, Blottner D, Vuori I, Gerzer R, Cavanagh PR. Towards human exploration of space: The THESEUS

[3] Crucian B, Kunz H, Sams CF. Risk of Crew Adverse Health Event Due to Altered Immune Response. Human Research Program Human Health Countermeasures Element. Evidence

[4] Frippiat JP, Crucian BE, de Quervain DJ, Grimm D, Montano N, Praun S, Roozendaal B, Schelling G, Thiel M, Ullrich O, Choukèr A. Towards human exploration of space: The THESEUS review series on immunology research priorities. NPJ Microgravity. 2016;**2**:16040

[5] Bergsma J. Illness, the mind and the body: Cancer and immunology: An introduction.

[6] Chorot P, Sandín B. Life events and stress reactivity as predictors of cancer, coronary heart disease and anxiety disorders. International Journal of Psychosomatics. 1994;**41**(1-4):34-40

[7] Kusnecov AW, Rabin BS. Stressor-induced alterations of immune function: Mechanisms and issues. International Archives of Allergy and Immunology. 1994;**105**(2):107-121

[8] Levenstein S, Prantera C, Varvo V, Scribano ML, Berto E, Andreoli A, Luzi C.Psychological stress and disease activity in ulcerative colitis: A multidimensional cross-sectional study.

The American Journal of Gastroenterology. 1994;**89**(8):1219-1225

review series on muscle and bone research priorities. NPJ Microgravity. 2017;**3**:8

, Asmita Kulkarni, Alamelu Sundaresan<sup>2</sup>

Spaceflight: Immune Effects and Nutritional Countermeasure

http://dx.doi.org/10.5772/intechopen.74709

,

115

### **8. Summary and significance**

Spaceflight observations thus far clearly document the adverse effects on the immune system, concomitant persistence of space environment stressors, and potential increase in virulence of infectious agents. It is imperative to design and develop effective countermeasures to secure health aspects of humans in space. The literature from experimental models and clinical human applications clearly documents that supplemental dietary nucleotides have beneficial effects on the immune system under stress conditions and environments. It is also known that supplemental dietary nucleotides had beneficial enhanced resistance to *Staphylococcus aureus* (SA), methicillin-resistant SA (MRSA), and *Candida albicans* infections in mice [74–77]. Similarly, use of a nucleotide containing formula in humans showed that there is a significant decrease in infectious complications in various patients. Immune enhancing nutritional supplements like AHCC have also found to be effective in restoring and maintaining immune system function in spaceflight analog animal model. These results emphasize the role of nucleotide nutrition and nutritional substrates like AHCC as a promising and plausible preventive measure to the immunologic consequences pre-/during /postspaceflight. A multipronged research will be an effective and safe countermeasure for spaceflight effects and to obviate stress and observed immune dysfunction. These studies should be of significant interest to NASA and other space agencies around the world by identifying profiles (immune, endocrine, and psychological) of individuals at risk for these immune dysfunctions with subsequent clinical manifestations and how nutritional countermeasures may impact such profiles. Such approaches should provide pragmatic clinical interventions for alleviation of stress and preservation of crew health particularly during long-term flights such as ISS, long-term interplanetary excursions, and deep space explorations.

### **Acknowledgements**

NASA; Department of Surgery, UTMMS; Amino Up Chemical Company, Sapporo, Japan.

### **Author details**

all functions of these types of cells, we measured the levels of LPS-stimulated cytokine and chemokine production from splenocytes. Both inflammatory cytokines and chemokines were increased in mice in the HLU group and AHCC supplementation in HLU mice tended to further enhance the inflammatory cytokine and chemokine production (**Figure 4**). Increased interleukin like IL-6 is implicated in increased stimulated immune responses, e.g., during infection and after trauma, especially burns or other tissue damage leading to inflammation [72], while increased IL-12 (T cell stimulating factor) is known to be a stimulator of the TNF-α pathway and increases adaptive immunity. Enhancement of inflammatory cytokine and chemokine production by AHCC supplementation suggested to be effective for prevent-

Spaceflight observations thus far clearly document the adverse effects on the immune system, concomitant persistence of space environment stressors, and potential increase in virulence of infectious agents. It is imperative to design and develop effective countermeasures to secure health aspects of humans in space. The literature from experimental models and clinical human applications clearly documents that supplemental dietary nucleotides have beneficial effects on the immune system under stress conditions and environments. It is also known that supplemental dietary nucleotides had beneficial enhanced resistance to *Staphylococcus aureus* (SA), methicillin-resistant SA (MRSA), and *Candida albicans* infections in mice [74–77]. Similarly, use of a nucleotide containing formula in humans showed that there is a significant decrease in infectious complications in various patients. Immune enhancing nutritional supplements like AHCC have also found to be effective in restoring and maintaining immune system function in spaceflight analog animal model. These results emphasize the role of nucleotide nutrition and nutritional substrates like AHCC as a promising and plausible preventive measure to the immunologic consequences pre-/during /postspaceflight. A multipronged research will be an effective and safe countermeasure for spaceflight effects and to obviate stress and observed immune dysfunction. These studies should be of significant interest to NASA and other space agencies around the world by identifying profiles (immune, endocrine, and psychological) of individuals at risk for these immune dysfunctions with subsequent clinical manifestations and how nutritional countermeasures may impact such profiles. Such approaches should provide pragmatic clinical interventions for alleviation of stress and preservation of crew health particularly during long-term flights such as ISS, long-term interplanetary excursions, and deep space

NASA; Department of Surgery, UTMMS; Amino Up Chemical Company, Sapporo, Japan.

ing infection [69, 73].

explorations.

**Acknowledgements**

**8. Summary and significance**

114 Into Space - A Journey of How Humans Adapt and Live in Microgravity

Anil D Kulkarni\*, Marie-Francoise Doursout<sup>1</sup> , Asmita Kulkarni, Alamelu Sundaresan<sup>2</sup> , Takehito Miura<sup>3</sup> , Koji Wakame<sup>4</sup> and Hajime Fujii<sup>3</sup>

\*Address all correspondence to: anil.d.kulkami@ uth.tmc.edu

1 Department of Surgery, The University of Texas Health McGovern Medical School, Houston, Texas, USA

2 Department of Anesthesiology, The University of Texas Health McGovern Medical School, Houston, Texas, USA

3 Texas Southern University, Houston, Texas, USA

4 Amino Up Chemical Co, Sapporo, Hokkaido, Japan

5 Hokkaido Pharmaceutical University, Hokkaido, Japan

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**Chapter 8**

**Provisional chapter**

**Countermeasure Development for Lumbopelvic**

**Countermeasure Development for Lumbopelvic** 

DOI: 10.5772/intechopen.72881

Physical inactivity and lumbopelvic deconditioning have been linked to increased incidence of non-specific low back pain (LBP) and spinal injury in those who are exposed to microgravity (e.g. astronauts and individuals on long-duration bed rest) and in the general population. Astronauts have an increased risk of experiencing moderate to severe LBP during microgravity exposure and herniated intervertebral discs within 1 year following spaceflight. Atrophy and reduced motor control of the lumbar multifidus (LM) and transversus abdominis (TrA) muscles resulting from periods of deconditioning are linked to non-specific LBP and spinal injury risk in both post-flight astronauts and general populations. However, voluntary recruitment of these two key muscles is difficult and presents a rehabilitation challenge. This chapter reviews the concept of spinal stability as it relates to microgravity, discusses how existing exercise countermeasures used in space do not successfully maintain lumbopelvic muscle size, and introduces the functional readaptive exercise device (FRED) that shows potential to activate the LM and TrA muscles automatically and in a tonic fashion, which has relevance to rehabilitation

> © 2016 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution,

© 2018 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use,

distribution, and reproduction in any medium, provided the original work is properly cited.

and reproduction in any medium, provided the original work is properly cited.

There is a 53–68% risk of experiencing moderate to severe low back pain (LBP) during microgravity exposure [1] and fourfold increased risk of herniated intervertebral discs within 1 year following the spaceflight [2], which demonstrate a need to understand the underlying mechanisms of LBP and spinal changes that result from exposure to microgravity. Developing an effective rehabilitation programme to address and rehabilitate spaceflight-related spinal changes is also required. Atrophy and reduced motor control of the lumbar multifidus (LM)

**Deconditioning in Space**

**Deconditioning in Space**

http://dx.doi.org/10.5772/intechopen.72881

Nick Caplan

**Abstract**

**1. Introduction**

Andrew Winnard, Dorothee Debuse and

Andrew Winnard, Dorothee Debuse and Nick Caplan

Additional information is available at the end of the chapter

of both astronaut and terrestrial populations.

**Keywords:** spinal, lumbopelvic, deconditioning, rehabilitation, astronaut

Additional information is available at the end of the chapter


**Provisional chapter**

### **Countermeasure Development for Lumbopelvic Deconditioning in Space Countermeasure Development for Lumbopelvic Deconditioning in Space**

DOI: 10.5772/intechopen.72881

Andrew Winnard, Dorothee Debuse and Nick Caplan Andrew Winnard, Dorothee Debuse and Nick Caplan Additional information is available at the end of the chapter

Additional information is available at the end of the chapter

http://dx.doi.org/10.5772/intechopen.72881

#### **Abstract**

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Physical inactivity and lumbopelvic deconditioning have been linked to increased incidence of non-specific low back pain (LBP) and spinal injury in those who are exposed to microgravity (e.g. astronauts and individuals on long-duration bed rest) and in the general population. Astronauts have an increased risk of experiencing moderate to severe LBP during microgravity exposure and herniated intervertebral discs within 1 year following spaceflight. Atrophy and reduced motor control of the lumbar multifidus (LM) and transversus abdominis (TrA) muscles resulting from periods of deconditioning are linked to non-specific LBP and spinal injury risk in both post-flight astronauts and general populations. However, voluntary recruitment of these two key muscles is difficult and presents a rehabilitation challenge. This chapter reviews the concept of spinal stability as it relates to microgravity, discusses how existing exercise countermeasures used in space do not successfully maintain lumbopelvic muscle size, and introduces the functional readaptive exercise device (FRED) that shows potential to activate the LM and TrA muscles automatically and in a tonic fashion, which has relevance to rehabilitation of both astronaut and terrestrial populations.

**Keywords:** spinal, lumbopelvic, deconditioning, rehabilitation, astronaut

### **1. Introduction**

There is a 53–68% risk of experiencing moderate to severe low back pain (LBP) during microgravity exposure [1] and fourfold increased risk of herniated intervertebral discs within 1 year following the spaceflight [2], which demonstrate a need to understand the underlying mechanisms of LBP and spinal changes that result from exposure to microgravity. Developing an effective rehabilitation programme to address and rehabilitate spaceflight-related spinal changes is also required. Atrophy and reduced motor control of the lumbar multifidus (LM)

© 2016 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. © 2018 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

and transversus abdominis (TrA) muscles, resulting from periods of deconditioning, are linked to non-specific LBP and spinal injury risk in both post-flight astronauts and general populations [3–6]. However, voluntary recruitment of these two key muscles is difficult and presents a rehabilitation challenge [7].

stability as the ability of the spine, under physiological loads, to limit structural displacement so as to prevent damage to spinal structures including the discs, ligaments and neural structures. The spine gains passive stability from bones, ligaments, tendons and fascia, while it was suggested that active stability is provided by deep muscles [21]. Studies using in vitro cadaveric specimens of human spinal segments found that the specimens became mechanically unstable at loads much less than those experienced by in vivo spines [25]. This finding highlighted the importance of the stabilising force provided by the LM and TrA muscles in

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To achieve spinal stability, the deep muscles must be controlled by precise coordination of activation and timing. The complete spinal stabilising system was, therefore, conceptualised by Panjabi [29] as having a neural control element, a passive spinal column (and ligaments) and an active system of deep muscles. The control system assesses and directs the deep muscles to provide varying levels of extrinsic stability while the passive elements of the spinal column provide intrinsic stability. To successfully provide control, actions are based on feedback from both the active and passive components. Mechanoreceptors in the passive structures indicate levels of force and stress, while feedback on muscle activation patterns and stretch are provided by the active system. In addition to the muscle feedback system, there is now strong evidence that LM and TrA are ideally activated in a feedforward mechanism, that is, they act in anticipation of changing loads. Importantly, the dysfunction of this feedforward

During dynamic loads into spinal flexion and extension, there is displacement of each vertebra, which allows flexibility. At low loads, the spine was observed to be highly flexible and then stiffening as loads increased. A neutral zone was defined as the range of segmental displacement within which there is a minimal resistance to the displacement [29]. This is represented graphically in **Figure 1** with the neutral zone being represented by a ball in a bowl. The motion of the ball represents the displacement motion of the vertebral segment, while the steepness of the sides represents varying stability with steeper sides demonstrating increased resistance to displacement. As segmental spinal stability increases, the neutral zone becomes smaller, demonstrated by placing the ball in a wine glass. As segmental spinal stability decreases, the neutral zone gets larger, demonstrated by placing the ball in a flat bowl

It was hypothesised that decreased stability may be caused either by damage to the passive stability system and/or abnormal activity or control of the active system that leads to a larger neutral zone [29]. An increase in the neutral zone is likely to be associated with increased stress on spinal structures so, it results in pain. Therefore, interventions were suggested for unstable painful spines which aimed at reducing the neutral zone through retraining control

of the active stability system or through the use of spinal fusion [29].

allowing the spine to function under everyday loading.

**2.2. Spinal stabilising system and motor control**

control system has been linked with LBP [28].

**2.3. Segmental stability and the neutral zone**

(**Figure 1**).

This chapter discusses the key factors contributing to lumbopelvic deconditioning in spaceflight and shows how exercise countermeasures against deconditioning can be developed to aid both astronauts and people on Earth with LBP.
