INTRODUCTION

When optic disk edema, globe flattening, choroidal folds, and hyperopic shifts were first reported in astronauts following long-duration spaceflight, some hypothesized that prolonged exposure to weightlessness caused a pathological elevation in intracranial pressure (ICP) leading to ocular findings similar to those in patients with idiopathic intracranial hypertension (IIH) (1, 2). Therefore, these ocular changes were originally named the visual impairment and intracranial pressure (VIIP) syndrome, despite the fact that the sentinel report highlighted multiple hypotheses not related to ICP as the cause of the ocular findings (1). As reports were published of additional structural changes to the eye (3–7) and brain (8–13) during spaceflight and brief periods of weightlessness in parabolic flight (14), the National Aeronautics and Space Administration (NASA) renamed the risk spaceflight associated neuro-ocular syndrome (SANS) to better allow for a broad range of etiological possibilities for the cause of the neuro-ocular findings in crewmembers.

On Earth, moving from seated to supine posture increases ICP by ∼10–15 mmHg (∼14–20 cmH₂O), and during 15° head-down tilt (HDT) ICP increases by an additional ∼5 mmHg (∼7 cmH₂O) (15–17). Direct measures of ICP obtained in the supine posture during ∼20 s of weightlessness induced by parabolic flight demonstrated that ICP was not elevated, but rather slightly less than the ICP measured in the supine posture during 1 g (13 mmHg while weightless vs. 15 mmHg in 1 g), although ICP was higher than that measured while seated in 1 g (4.1 mmHg) (14). Although ICP has never been directly measured in astronauts during spaceflight, postflight lumbar puncture opening pressure (LPOP) of cerebrospinal fluid pressure (CSFP) has been measured in a subset of long-duration astronauts presenting with Frisèn grade optic disk edema, with CSFPs ranging from 12 to 21 mmHg (16–29 cmH₂O) (1, 7, 18). Because some of these pressures are considered to be higher than normal (19), it was hypothesized that spaceflight may cause changes in CSF homeostasis that result in an augmented response of ICP to posture changes and therefore an increased ICP after flight when crewmembers are placed in the lateral decubitus posture for the lumbar puncture procedure (1). Thus, there remains a need to measure ICP during and following long-duration spaceflight in astronauts who present with and without optic disk edema to determine what role ICP may have in the observed ocular and brain changes of astronauts.

Techniques for assessing noninvasive indicators of ICP (nICP) include cerebral and cochlear fluid pressure (CCFP) (1, 5, 7, 14, 20, 21), otoacoustic emissions (OAE) (22, 23), and the use of ultrasonography to measure optic nerve sheath diameter (ONSD) (24, 25). Where CCFP values correlate with tympanic membrane displacement (TMD) (1, 5, 7, 14, 20), OAE measures correlate with the tension of the oval window and the middle ear (22, 23), and ONSD measures the engorgement of the optic nerve sheath due to accumulation of cerebrospinal fluid (CSF) near the optic nerve head (ONH) (24, 25). Noninvasive indicators of internal jugular vein pressure (IJVp) (18) also may reflect ICP, because pressure in the dural venous sinuses has a direct effect on ICP (26).

The aim of this study was to use multiple noninvasive methods to assess ICP before, during, and after long-duration spaceflight. A secondary aim was to determine if the use of lower body negative pressure (LBNP), a technique that sequesters blood volume in the lower body, could reduce ICP during spaceflight. We hypothesized that nICP indicator measurements during spaceflight would be significantly greater than the upright posture on Earth. In addition, we hypothesized that the use of LBNP would decrease nICP measures. To accomplish these aims, we assessed crewmembers before and after spaceflight in multiple postures on Earth, and during spaceflight, with and without use of LBNP. Using these data, we sought to determine how: 1) noninvasive indicators of ICP during spaceflight compare with noninvasive measures of ICP in various postures on Earth, 2) the effect of LBNP on nICP indicators during spaceflight, and 3) if the change in nICP indicators due to posture changes is augmented after spaceflight.

METHODS

RESULTS

DISCUSSION

The majority of nICP indicators used in the present study demonstrate that spaceflight values are not significantly different from the seated posture observed before spaceflight. These are noninvasive estimates of ICP change and each technique uses a different physiological mechanism as an indicator of ICP. Therefore, because each technique relies on a different physiological relationship to ICP, some differences among the measures are expected and definitive conclusions regarding the true ICP levels during long-duration spaceflight will require invasive gold standard measures of ICP. Unfortunately, due to the invasive nature of directly measuring CSF pressure via lumbar puncture, inflight measures of ICP on the ISS have not been performed. However, the nICP indicator data presented here provide important new information about the relative pattern of ICP change during long-duration spaceflight as compared with various posture conditions on Earth.

On Earth, direct measures of ICP document a posture-induced increase in ICP from the upright to the supine body position, highlighting the diurnal fluctuations in ICP that occur during a 24-h period, with about two-thirds of the day spent in the upright posture (14, 16, 17). The normal reference values of directly measured ICP in the upright and supine positions are ∼1 mmHg {−5.9 to 8.3 mmHg [1.3 cmH₂O (−8.7 to 11.2)]} and 8.6 mmHg {0.9 to 16.3 mmHg [11.7 cmH₂O (1.2 to 22.2 cmH₂O)]}, respectively (38). In addition, ICP measured in the 15° HDT posture is ∼26 ± 4 mmHg (39). In a majority of the four different noninvasive ICP approaches, we observed the expected posture-induced increase (18, 20, 22–26) before and after flight. Although three of these nICP indicators demonstrate a similar and expected pattern of posture-induced change, the ONSD measure in the present study was not sufficiently sensitive to detect this known change in ICP. Therefore, we focus our interpretation of the spaceflight-induced change in nICP indicators on TMD, OAE and IJVp outcome measures.

The TMD and OAE nICP indicators demonstrate that values during long-duration spaceflight are similar to those observed in the seated posture. Invasive ICP measures during acute weightlessness in parabolic flight demonstrated a significant decrease in ICP when transitioning from 1 g to 0 g in the supine posture by 3.8 ± 2.9 mmHg (mean 15 ± 2 mmHg in 1 g and 13 ± 2.6 mmHg during 0 g), supporting the idea that ICP during spaceflight may be less than when in the supine posture on Earth but remains greater than the value in the seated posture. This suggests that there may be ICP-lowering fluid volume adaptations during prolonged spaceflight that do not develop during 20 s of weightlessness. Indeed, IJV area during acute weightlessness in parabolic flight was twice as large as IJV area measured supine (14), whereas IJV area measured after ∼45 days of spaceflight was similar to preflight values in the supine posture (28). Our FD45 measures of IJVp were not significantly different from the supine posture, but some limitations in this measurement approach may address this finding. During spaceflight, the TMD and OAE nICP indicator values were significantly less than those in the supine posture and not different from the seated upright posture, whereas weightlessness IJVp measures were not significantly different from preflight supine values. However, these three ICP indicators during spaceflight were less than measures during the 15° HDT posture with invasive ICP documented to be ∼26 ± 4 mmHg (39). Therefore, we are cautious to draw a definitive conclusion in regard to how similar spaceflight IJVp values are relative to the seated or supine postures on Earth. Previous reports document that ICP in the supine posture is ∼9 mmHg (38), therefore the present data further suggest that ICP during spaceflight would be below this value.

All of the nICP indicators used in this study track ICP changes indirectly and do not produce an absolute ICP value. Furthermore, each ICP indicator technique relies on a different physiological mechanism to detect change and may explain why the spaceflight to supine IJVp trends were different than those detected with TMD or OAE methods. During seated posture, the IJVs often are collapsed as the majority of blood from the head drains through the vertebral veins. There may be a difference in the relationship between ICP within the skull, IJVp measured outside the skull, and the resulting changes in central venous pressure within the thorax. Indeed, during parabolic flight supine subjects’ entry into weightlessness led to a drop in central venous pressure, concomitant with a drop in ICP, yet IJV area increased by ∼100% (0.5–1.0 cm²). It is also possible that the absolute value of IJVp if measured invasively would be lower than that measured with the present IJVp technique. This difference may occur because the pressure value that we record is at full collapse of the vessel which may overestimate an invasively measured pressure. Further there may be some IJVp device gravity dependencies that have yet to be identified, however these were not evident in our use of the device. The IJVp spaceflight values are similar to those in the supine posture on Earth, but for the reasons outlined above some caution is warranted in concluding that these IJVp data suggest that ICP during spaceflight is greater than the seated body posture on Earth.

The ICP indicators measured during spaceflight in the present study were mostly similar to the seated posture on Earth. The finding that spaceflight IJVp values are similar to supine posture, and OAE and TMD are similar to seated may help explain why ONH edema tends to be mild or subclinical in most SANS cases. Further work is needed to understand if the lack of diurnal change in ICP contributes to the development of neuro-ocular changes observed in some astronauts during long-duration spaceflight. As our current conclusions are based on cohort mean values, it is also still possible that ICP is chronically and mildly elevated in a subset of astronauts, which could lead to SANS.

We also designed this study to investigate if LBNP application during spaceflight could be used to lower ICP. LBNP is a technique used to sequester fluid in the lower limbs and has historically been used as a technique to evaluate cardiovascular physiology and function through a reduction in venous blood volume returning to the heart (40, 41). Here, we implemented the use of a moderate level of LBNP (25 mmHg) to minimize untoward cardiovascular stress and thus reduce the possibility of crewmembers developing symptoms of presyncope. When healthy subjects on Earth were exposed to 20–30 mmHg of LBNP while in the supine posture, which based on IJV area elicits a similar venous headward fluid shift as occurs during spaceflight (28), LBNP did not impair cardiac output or cerebral perfusion pressure (34, 39). During spaceflight, we did not observe a significant reduction in nICP indicators during the use of 25-mmHg LBNP. One likely explanation for this finding is that the baseline ICP surrogate values were not significantly elevated. Direct invasive ICP measures in healthy subjects during moderate levels of LBNP (20 to 30 mmHg) in the supine posture reduced ICP by only ∼3 to 4 mmHg (39). Thus, if a similar magnitude decrease in ICP occurred in crewmembers during spaceflight studied in the present study, our noninvasive approaches may not have had the sensitivity to detect a change induced by LBNP (42, 43). When subjects were exposed to 15° HDT on Earth, ICP was elevated to ∼26 ± 4 mmHg and the use of the same moderate level of LBNP (20–30 mmHg) reduced ICP by 6–8 mmHg (39). These data highlight that use of LBNP may have a greater magnitude effect at higher baseline ICP levels and less of an effect at lower ICP values, which is consistent with the nonlinear intracranial pressure-volume curve (42). Therefore, based on intracranial compliance, the effectiveness of LBNP at lowering ICP is dependent on ICP magnitude. Larger reductions in ICP would likely be possible when LBNP reduces the headward fluid shift in individuals operating at the higher end of their intracranial compliance curve. The fact that LBNP did not reduce ICP in these experiments is therefore further evidence that ICP is not substantially elevated during spaceflight.

The potential role for LBNP as a SANS countermeasure may not rely solely on ICP outcomes. Previously, we reported in the same subjects studied here that 25-mmHg LBNP causes a reduction of IJV area and pressure and improvements in IJV flow in some crewmembers during spaceflight (34). This suggests that the spaceflight-induced headward fluid shift in the cerebral venous compartment can be altered by LBNP, despite the lack of a direct effect on nICP indicators as reported here. However, invasive measures of ICP would have greater sensitivity and higher fidelity to definitively document the effects of mechanical countermeasures on ICP. It is important to note that LBNP reduces intraocular pressure during spaceflight, which suggests an effect on ocular venous hemodynamics (29). This highlights the reality that ICP should not be the only outcome measure used to determine the effectiveness of possible SANS fluid-shift countermeasures (44), especially given that ICP has not been proven to be the sole cause of SANS.

Although these nICP indicators did not demonstrate significant effects of 25-mmHg LBNP on ICP during spaceflight, it is possible that the effect of LBNP on the cerebral vasculature could reduce capillary pressure at the optic nerve head, and thereby reduce the development of optic disk edema, independent of changes to ICP. Mean arterial pressure at the level of the eye is elevated during weightlessness relative to the upright posture on Earth because of the lack of a hydrostatic column (20, 45). Engorgement of the IJV is evident during weightlessness (14, 28) and reduced with LBNP (28). Thus, if venule and arterial pressure are elevated, this would result in increased capillary pressures. Similar to the cerebral microcirculation, the retinal microvasculature contains blood-brain barrier proteins and tight junctions that should effectively prevent changes in arterial and venous pressure from causing increased capillary filtration and accumulation of extravascular fluid. Indeed, despite arterial and venous pressures affecting the entire retinal vasculature equally, we do not observe edema throughout the entire retina (3, 46). Instead, we have previously hypothesized (3) that the lack of blood-brain barrier markers in the prelaminar region of the optic nerve head (46) may make this region specifically susceptible to increases in capillary filtration secondary to elevated arterial and venous pressures in this region. Therefore, if reducing venous pressure at the level of the eye, independent of effects on ICP, causes a reduction in capillary filtration that contributes to optic disk edema, then LBNP represents a potential approach to mitigate SANS. This notion is independent of any potential changes to translaminar pressure difference (TLPD), which are possible with LBNP use. LBNP during spaceflight reduces IOP by ∼1.4 mmHg in the same subjects studied here (29) and if ICP during spaceflight is similar to the seated posture on Earth and unchanged by LBNP, then TLPD could in theory be reduced by 1–2 mmHg. Given that daily posture changes on Earth change TLPD by ∼10 mmHg, it seems unlikely that reducing TLPD by ∼1–2 mmHg during LBNP use would negatively affect the optic nerve head, however, this potentially deleterious effect of LBNP should be considered during interpretation and application of data collected during LBNP experiments.

Direct measures of ICP in six astronauts have been collected in those presenting with Frisèn grade 1 edema or greater after return from long-duration spaceflight missions (Table 2) (1, 7, 37). Interestingly, the range of the postflight ICP values reported in astronauts with optic disk edema were similar to the ICP values reported in healthy individuals before parabolic flight (14). Despite this, some have considered these values in astronauts postflight to be at the higher end of normal, and two exceeded the 25 cmH₂O (18.4 mmHg) threshold of IIH (1, 7, 37), although there are data that support raising the ICP threshold for IIH diagnosis to 30 cmH₂O (47). We and others have hypothesized that spaceflight may have changed the shape of the intracranial compliance curve. Even if the mean ICP is unchanged, there may be a higher ICP pulse amplitude. However, these data have not been reported in astronauts and these nICP indicator data only provide estimates of the mean change in ICP and do not provide insight into the ICP pulse amplitude. Invasive ICP measures of pulse amplitude would be highly beneficial in directly addressing changes in craniospinal compliance.

As each of the nICP indicator methods have limitations, we chose to use multiple approaches to demonstrate consistent findings across techniques and therefore increase confidence in the interpretation of the findings of the overall cohort. The crewmember with Frisèn-grade optic disk edema did not demonstrate consistently different nICP indicator findings relative to other participants in this cohort. Although this subject appeared to demonstrate a larger shift in OAE phase during spaceflight, this finding was not replicated by the other nICP indicator approaches. Recent reports of optic disk edema in crewmembers assessed using optical coherence tomography suggest that early signs of optic disk edema are present in most crewmembers (3, 5). This indicates that there is some common cause that we have not detected in these experiments, and due to the inconsistency in the nICP indicators in this single SANS case in our cohort, we cannot conclude that ICP was a primary contributor to SANS in this subject. The nICP indicators of the present study provide insight into ICP at a single point in time and represent a time-averaged value over the course of the measurement. We acknowledge that these nICP indicator techniques do not provide an absolute ICP value in units of pressure, and as an indirect measure may not follow the same nonlinear intracranial —pressure-volume curve. Finally, we acknowledge that the inflight measures of nICP indicators with and without LBNP were not collected on the same study day. Due to crewmember scheduling constraints, coordination of moving equipment between the US and Russian modules on the ISS, and the total time needed to conduct all experiments, the measures needed to be obtained on separate study days.

In conclusion, these data demonstrate that the nICP indicators during spaceflight are overall similar to measures obtained in the seated posture on Earth, with three of the four measures demonstrating values not different than those obtained in the seated posture. LBNP did not lower nICP indicators during spaceflight, possibly because ICP was not substantially elevated. Future investigations of invasive gold standard measures of ICP would provide absolute ICP values and more specific pressure change values, but the results presented here further our understanding of ICP during and after long-duration spaceflight.

GRANTS

This work was supported by funding provided by NASA Human Research Program Grants NNJ11ZSA002NA, NNX13AJ12G, and NNX13AK30G.

DISCLOSURES

No conflicts of interest, financial or otherwise, are declared by the authors.

AUTHOR CONTRIBUTIONS

S.S.L., S.M.C.L., D.S.M., D.J.E., I.V.A., A.S., S.A.D., M.B.S., and B.R.M. conceived and designed research; S.S.L., A.H., M.B.S., and B.R.M. performed experiments; J.V.J., S.S.L., D.K., D.J.E., R.P-S., R.W.D., and B.R.M. analyzed data; J.V.J., S.S.L., D.T.K., D.J.E., R.P-S., K.M-G., R.W.D., A.H., and B.R.M. interpreted results of experiments; J.V.J., S.S.L., and D.J.E. prepared figures; J.V.J., S.S.L., S.M.C.L., D.T.K., D.J.E., R.P-S., K.M-G., A.H., and B.R.M. drafted manuscript; J.V.J., S.S.L., S.M.C.L., D.T.K., D.J.E., R.P-S., K.M-G., A.H., M.B.S., and B.R.M. edited and revised manuscript; J.V.J., S.S.L., D.J.E., I.V.A., and B.R.M. approved final version of manuscript.