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 r2 < 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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59

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

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61

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% O2 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% O2

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 belowa N/A Unlimited 13,000–19,999 feet Supplemental N/A Unlimited 20,000–24,999 feet 100% O2 30 min 110 min 25,000–29,999 feet 100% O2 30 min 60 min 30,000–34,999 feet 100% O2 45 min 30 min 35,000 feet or greater 100% O2 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

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e1-168.e6

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

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

\*Address all correspondence to<EMAIL_ADDRESS>
711th Human Performance Wing, United States Air Force School of Aerospace Medicine,

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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<EMAIL_ADDRESS>
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

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of Applied Physiology (1985). 2011;**110**(2):340-351

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]

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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

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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-

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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

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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

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### 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.