Long duration habitation on the International Space Station (ISS) is associated with chronic elevations in arterial blood pressure in the brain compared with normal upright posture on Earth and elevated inspired CO2. Although results from short-duration spaceflights suggested possibly improved cerebrovascular autoregulation, animal models provided evidence of structural and functional changes in cerebral vessels that might negatively impact autoregulation with longer periods in microgravity. Seven astronauts (1 woman) spent 147 ± 49 days on ISS. Preflight testing (30–60 days before launch) was compared with postflight testing on landing day (n = 4) or the morning 1 (n = 2) or 2 days (n = 1) after return to Earth. Arterial blood pressure at the level of the middle cerebral artery (BPMCA) and expired CO2 were monitored along with transcranial Doppler ultrasound assessment of middle cerebral artery (MCA) blood flow velocity (CBFV). Cerebrovascular resistance index was calculated as (CVRi = BPMCA/CBFV). Cerebrovascular autoregulation and CO2 reactivity were assessed in a supine position from an autoregressive moving average (ARMA) model of data obtained during a test where two breaths of 10% CO2 were given four times during a 5-min period. CBFV and Doppler pulsatility index were reduced during −20 mmHg lower body negative pressure, with no differences pre- to postflight. The postflight indicator of dynamic autoregulation from the ARMA model revealed reduced gain for the CVRi response to BPMCA (P = 0.017). The postflight responses to CO2 were reduced for CBFV (P = 0.056) and CVRi (P = 0.047). These results indicate that long duration missions on the ISS impaired dynamic cerebrovascular autoregulation and reduced cerebrovascular CO2 reactivity.
- transcranial Doppler ultrasound
- cerebral blood flow
- cerebrovascular resistance
the microgravity environment, which causes cephalic fluid shifts with increased arterial pressure at the level of the brain relative to normal daily life on Earth (17), might cause alterations in cerebrovascular structure and function. The impact of microgravity on human cerebrovascular function has primarily been examined during and after short-duration spaceflights (2, 5, 8, 20) with only a few measurements of cerebral blood flow velocity (CBFV) during or after long-duration flights (2, 33). During spaceflight, only modest changes in CBFV have been reported (2, 5) with small increases in cerebrovascular resistance after months in space that were speculated to reflect increased sympathetic vasoconstriction (2). Postflight CBFV in the supine posture was unchanged or slightly elevated from preflight (8, 20). Postflight measurements of dynamic cerebrovascular autoregulatory indexes, reflecting vascular smooth muscle responses to changes in arterial blood pressure, were slightly enhanced in one group of astronauts (20) but were reduced in astronauts with reduced postflight orthostatic tolerance (8).
Results from Earth-based analogs of spaceflight using head down–bed rest (HDBR) have revealed increases (21), decreases (2, 4, 14, 18, 32), or no changes (2, 3, 29, 38) in supine CBFV. After HDBR, some studies have shown a greater reduction in CBFV with lower body negative pressure (LBNP) (38) or assuming an upright posture (21), suggesting an impairment in the ability to regulate cerebral blood flow when faced with an orthostatic stress. However, other research has found no difference in cerebrovascular responses to tilt or LBNP (3, 4) or with rapid deflation of leg cuffs (29).
Animal models of spaceflight using hind limb suspension have provided convincing evidence of cerebrovascular structural and functional changes. Cerebral arteries from suspended rats have demonstrated vascular smooth muscle hypertrophy (24, 34, 36, 37) with a smaller luminal cross-sectional area (36) and increased basal myogenic tone (16, 24, 35). Further work has also shown that these changes are associated with reduced cerebral blood flow (34, 35) and greater vasoconstrictor responses possibly acting through nitric oxide–dependent (24, 30, 35) or renin-angiotensin system–dependent mechanisms (6).
To date, there have been no investigations of the cerebrovascular response to carbon dioxide (CO2) after spaceflight. Cerebrovascular CO2 reactivity reflects endothelial function through activation of the nitric oxide system (22, 23, 31) that was impaired in animals by hind limb suspension (24, 30, 35). In addition, cerebrovascular CO2 reactivity might also be altered as a consequence of elevated partial pressure of CO2 in the ambient air on the International Space Station (ISS) that could chronically influence arterial CO2 (Paco2) and cerebral acid-base balance.
We hypothesized in the current study that resting CBFV would be unchanged after long-duration spaceflight, but there would be greater decreases with LBNP. Furthermore, we hypothesized that postflight cerebrovascular autoregulation would be impaired and CO2 reactivity would be blunted as a consequence of chronic effects of the ISS environment.
Cerebral hemodynamic data from long-duration spaceflight were collected as a part of the Cardiovascular and Cerebrovascular control on return from the International Space Station (CCISS) project. Methods and procedures were reviewed and approved by the Office of Research Ethics at the University of Waterloo and the Committee for the Protection of Human Subjects at Johnson Space Center. Each volunteer signed an approved consent form after receiving full verbal and written details of the experiment. The experiment conformed to the guidelines in the Declaration of Helsinki.
Seven astronauts (1 woman) with an average age of 48 ± 4 years participated. Preflight data were collected 36 ± 22 days before launch. Postflight data were collected from astronauts returning via the space shuttle within 3 to 4 h of landing (R + 0; n = 4) and, for astronauts returning via the Russian Soyuz spacecraft, the morning after landing (R + 1; n = 2) or two mornings after landing (R + 2; n = 1) for an astronaut whose return was delayed by weather. For R + 0 testing, the astronauts landed on the shuttle in a supine posture and remained in that posture for transportation to the research facility and until the experiment was completed. Experiments on days R + 1 and R + 2 were conducted first thing in the morning. The astronauts did not assume upright posture on test day before being transported to the laboratory in a supine posture in an attempt to minimize the effects of re-adaptation to Earth's gravitational environment. The astronauts spent an average of 147 ± 49 days in space ranging from 58 days to 199 days with all but one spending greater than 100 days on orbit.
Experimental protocol and instrumentation.
Preflight testing for the shuttle-launched astronauts and one Soyuz-launched astronaut took place at Johnson Space Center (JSC; Houston, TX). Three of the four shuttle astronauts completed postflight testing at Kennedy Space Center (KSC; Cape Canaveral, FL) with the other at Dryden Flight Research Center (Dryden; Edwards, CA). Preflight testing for two Soyuz launched astronauts and all postflight testing was completed at the Gagarin Cosmonaut Training Center (GCTC; Star City, Russia). Due to logistics of each location, slightly different equipment was used at each of the experimental sites.
Throughout the testing periods, astronauts were equipped with a standard three lead electrocardiogram [Finometer ECG Module (JSC, KSC, Dryden), Finapres Medical, Amsterdam, the Netherlands; Hewlett-Packard (GCTC)] for the assessment of heart rate. Arterial blood pressure (ABP) was continuously determined using finger photoplethysmography [Finometer (KSC, JSC, and Dryden), Portapres (JSC n = 1), and Finapres (GCTC), Finapres Medical, Amsterdam, the Netherlands] and height-corrected to heart level. The participants were also equipped with a nasal cannula for monitoring of expired CO2 [Ohmeda 5,200 CO2etCO2). Transcranial Doppler ultrasound [Multigon Industries, New York, NY (JSC); EZDop, DWL, Compumedics, Germany (KSC); MultiFlow, DWL GmbH, Sipplingen, Germany (Dryden); CardioLab, European Space Agency (GCTC)] was used for the assessment of CBFV in the MCA. In all locations TCD measures were conducted using a 2-MHz pulsed Doppler probe that was placed over the right temporal window to allow for the insonation of the M1 segment of the MCA and the assumption of a 0° angle of insonation. To minimize effects of angle variation from pre- to postflight, photographs were taken of probe placement in preflight testing and used as a reference for postflight tests. Throughout the testing, the probe was held in place using a headband.2 analyzer (Dryden)]. End-tidal CO2 values were converted to mmHg based on atmospheric temperature and pressure (P
2, and TCD signals. Data recorded at GCTC also utilized Chart software for the recording of ECG, ABP, and CO2. TCD data at GCTC were recorded on a separate system using CardioMed software (European Space Agency). Chart data were digitized at 1,000 Hz and CardioMed data at 100 Hz. Beat-by-beat data from the CardioMed system were aligned with Chart data by introducing a common marker signal and by pattern matching the between-beat intervals from R waves and TCD waves.
CO2 and LBNP tests.
Cerebral blood flow was assessed under two different conditions: LBNP and a CO2 challenge using the two-breath test of Edwards et al. (11). All testing took place with astronauts resting in a supine position. Two low levels of LBNP, −10 and −20 mmHg, were applied for ∼2 min at each level while the astronauts were sealed at the waist into an airtight box. Vacuum was applied to the box to produce negative pressure promoting a shift in blood volume toward the lower limbs.
The two-breath method (11) was used to assess both cerebrovascular autoregulation and cerebrovascular CO2 reactivity. During this test, the nasal cannula was removed and a mask was held in place over the nose and mouth. A valve was turned to control whether the astronaut inspired room air or a gas mixture consisting of 10% CO2, 21% O2, balance N2. Two breaths of the CO2 gas mixture were inspired every minute for a 5-min period.
The outer envelope of the TCD Doppler spectrum was averaged over each cardiac cycle to determine mean CBFV. Similarly, arterial blood pressure tracings were averaged over a cardiac cycle to provide an indication of beat-by-beat blood pressure at the level of the MCA (BPMCA). Mean CBFV and BPMCA were then used to calculate an index of cerebrovascular resistance (CVRi) as CVRi = BPMCA / CBFV. As an additional assessment of cerebrovascular resistance, the Gosling Pulsatility index was calculated as PI = (CBFVsys − CBFVdia)/CBFVmean (7).
During the LBNP section of the protocol, 30-s averages of cerebrovascular variables were taken starting 40 s before the end of each stage for the steady state assessment at rest, −10 mmHg, and −20 mmHg. The two-breath protocol was analyzed using autoregressive moving average (ARMA) analysis on the beat-by-beat data set as described previously (11). The ARMA model removes the mean value before computing gain for the input-output relationships. Pco2 was determined for each heart beat by taking the point on the linear interpolation for end-tidal Pco2 corresponding to each R wave on the electrocardiogram. Based on the best fit ARMA model parameters, the step gains were calculated as the values of CBFV and CVRi 45 s after the introduction of nominal inputs of 1-mmHg change in BPMCA and 1-mmHg change in Pco2 as described previously by Edwards et al. (11).
Technical problems reduced the sample size for certain comparisons. A CO2 analyzer did not function during one postflight test so the CO2 responses of this astronaut could not be included in the ARMA analysis. In one astronaut the mean value of the TCD signal differed by more than physiologically acceptable limits for pre- to postflight comparisons suggesting possible differences in equipment or vessel investigation. Even so, the variability of the signals appeared to be appropriate so this astronaut's data were included when the mean values were eliminated (e.g., ARMA analysis of CBFV) but were excluded when the absolute values were important (e.g., calculation of CVRi and its subsequent analysis by ARMA). The data set of one astronaut with a very low cardiac frequency would not solve with the ARMA algorithm. This data set was linearly interpolated to double the mean sampling frequency before analysis. Testing this approach on other data sets indicated no impact on model solution.
Two-way repeated-measures ANOVA was used to test pre- to postflight effects of LBNP (SigmaStat 3.5; Systat Software, Chicago, IL). The magnitudes of the impulse and step responses from the ARMA analysis were compared using a one-way repeated-measures ANOVA for pre- to postflight effects. Statistical significance was set at P < 0.05.
There were no differences in resting CBFV, CVRi, or PI from pre- to post-spaceflight during the LBNP phase of the study (Fig. 1). In response to LBNP, CBFV (Fig. 1A) and PI (Fig. 1C) were reduced at −20 mmHg with no changes in CVRi (Fig. 1B). BPMCA was not different (P = 0.142) from pre- to postflight at rest (92.9 ± 15.0 and 99.9 ± 8.4 mmHg) or at −20 mmHg of LBNP (92.2 ± 13.4 and 97.4 ± 8.8 mmHg). There were also no differences in PetCO2 (P = 0.737) at rest from preflight (42.3 ± 2.5 mmHg) to postflight (42.7 ± 1.2 mmHg) or at −20 mmHg LBNP from preflight (42.4 ± 3.0 mmHg) and postflight (41.8 ± 1.9 mmHg).
The BPMCA and cerebrovascular responses to the two-breath test with intermittent increases of inspired CO2 are displayed for a typical subject in Fig. 2. The transient elevation in Pco2 reduced CVRi and resulted in increases in CBFV, whereas BPMCA maintained spontaneous variations without obvious effect of Pco2.
Group mean responses from the ARMA analyses are displayed as the time course of change to a unit input in BPMCA and Pco2 in Fig. 3 and individual step responses in Fig. 4. When BPMCA was considered as the input signal the averaged gain value for BPMCA CBFV was not different pre- to postflight (−0.225 ± 0.453 vs. 0.069 ± 0.119 cm·s−1·mmHg−1 BPMCA, P = 0.13; Figs. 3A and 4A), but the BPMCA CVRi gain was reduced 17% after spaceflight (0.035 ± 0.007 vs. 0.029 ± 0.005 units/mmHg BPMCA, P = 0.047; Figs. 3C and 4C). The indicators of CO2 reactivity from the responses of CBFV and CVRi revealed a strong trend for reduced CBFV response from pre- to postflight (2.113 ± 1.228 vs. 1.300 ± 0.595 cm·s−1·mmHg−1 Pco2, P = 0.056; Figs. 3B and 4B) and a reduction in the CVRi response (−0.038 ± 0.018 vs. −0.027 ± 0.012 units/mmHg Pco2, P = 0.017; Figs. 3D and 4D).
The major findings of this study showed that long-duration spaceflight was associated with reductions in the indexes of cerebrovascular dynamic autoregulation and CO2 reactivity with no differences seen in resting CBFV or responses to low levels of LBNP. These findings, following long-duration spaceflight on the ISS, were consistent with hypotheses that suggested cerebrovascular consequences from chronic elevation in cerebral blood pressure and chronic exposure to elevated atmospheric PCO2. Our results contrast with improved dynamic autoregulation after the short-duration Neurolab spaceflight mission (20) but are similar to findings in astronauts who presented with orthostatic intolerance after spaceflight (8).
Cerebrovascular indicators at rest and during LBNP.
We anticipated greater reduction in CBFV during LBNP after long-duration spaceflight, indicative of impaired cerebral blood flow regulation, but both at rest and during LBNP the CBFV, PI, and CVRi were unchanged from preflight. Resting CBFV is expected to reflect the metabolic demands of the brain (1, 27) as well as the constant influence of PaCO2 (26, 27). Our finding of no change in supine CBFV after spaceflight was consistent with other observations after short- (8, 20) and long-duration flights (33). The unchanged estimate of PaCO2 taken from the end-tidal Pco2 made it unlikely that alterations in CO2 had an effect on resting cerebral blood flow.
The potential effects of long-duration spaceflight on cerebrovascular structure and function have been inferred from HDBR studies with humans (2–4, 14, 18, 21, 29, 32, 38) and from animal models of hind limb suspension (16, 24, 34–37). The human HDBR studies reported variable results with increases, decreases, and no change in CBFV. Animal models have revealed reduced flow (34, 35) accompanied by significant structural changes with increased thickness of vessel walls (24, 34, 36, 37) and reduced internal dimensions (36). The animal models also suggested an involvement of renin-angiotensin system might in structural modifications with hind limb suspension (6, 15). An upregulation after 4 wk, but not after 7 days, of proteins involved in the synthesis of angiotensinogen and of angiotensin II type 1 receptors was observed in cerebral and carotid arteries, and these changes were associated with increased arterial wall thickness (6, 15). Based on these results from animal models, it is possible that human cerebral arteries might also undergo structural change with prolonged exposure to microgravity. At the moment, it is not possible to rule out the possibility that, although CBFV was unchanged, cerebral blood flow might have been reduced as a function of a smaller MCA. This can only be tested in future studies by quantitative measurements of cerebral blood flow or measures of MCA dimensions.
In the current study, CBFV was reduced during −20 mmHg of LBNP, but there was no difference in this response from pre- to postflight. These results contrast with observations after the short-duration Neurolab mission (20) where there was a smaller reduction in CBFV during LBNP as well as during upright tilt compared with preflight. Our LBNP results after long-duration spaceflight were consistent with observations from cosmonauts after 6 mo in space; however, at greater levels of LBNP, cosmonauts showed a trend toward greater reductions in CBFV after flight (33). In the current study, it is therefore possible that −20 mmHg LBNP was not sufficient to challenge cerebral blood flow regulation, since these same astronauts only showed small changes in postflight baroreflex function in the seated posture (19); therefore, it is still possible that changes in CBFV might have occurred with greater levels of LBNP or in assuming an upright posture. Reduced PI during LBNP might have reflected a relative reduction in cerebrovascular resistance under the conditions of constant PetCO2 in the current study (7), but there were no apparent pre- to postflight differences in this indicator of static cerebrovascular autoregulation.
Dynamic cerebrovascular autoregulation.
Dynamic cerebrovascular autoregulation, in contrast with static autoregulation (1, 28), is an index of the rapid responses of the cerebrovascular system to acute changes in BPMCA (28). Because an inverse relationship exists between the dynamic autoregulatory index and Pco2 (10), it was important that resting Pco2 was not different from pre- to postflight and further that the simultaneous effects of BPMCA and Pco2 were accounted for by the ARMA model. The 17% reduction in gain for CVRi relative to the change in BPMCA provided an index of impaired dynamic cerebrovascular autoregulation after spaceflight. Similarly, there was a trend toward a reduced CBFV response to a change in BPMCA (P = 0.128). Reduced cerebrovascular dynamic autoregulation after long-duration spaceflight was consistent with some (38) but not all (29) findings after HDBR and with astronauts who had orthostatic intolerance after short-duration spaceflights (8). Altered postflight cerebrovascular control might reflect the structural and functional changes observed in the animal models of spaceflight (24, 34, 36, 37).
Cerebrovascular reactivity to CO2.
No previous investigation has examined cerebrovascular CO2 reactivity after spaceflight. Animal studies showing reductions in nitric oxide–dependent dilation of cerebral arteries after hind limb suspension (24, 30, 35) suggested that the CO2 response might be altered due to the link between CO2–induced dilation of human cerebral arteries and nitric oxide–dependent mechanisms (12, 23, 31). CO2 reactivity was investigated in the current study by the two-breath method (11), which accounts for the spontaneous variability in Pco2 that can complicate interpretation of cerebrovascular responses (11, 27). The reduced gain for the CBFV and CVRi responses computed with respect to the input of Pco2 support the hypothesis that the nitric oxide–dependent dilatory mechanisms of the cerebrovascular system might be impaired by long-duration spaceflight.
The environment of ISS had an average inspired Pco2 of 3.34 mmHg during the experiments described in this study. This value is over 10-fold greater than ambient conditions on Earth. Data from a clinical population suggest that chronic exposure to hypercapnia leads to blunting of cerebrovascular CO2 reactivity (9); however, it is unclear if chronic exposure to increased atmospheric Pco2, as seen on ISS, produces reductions in cerebrovascular CO2 reactivity in a healthy population. Slightly elevated inspired CO2 might have had a chronic effect on PaCO2 and arterial acid-base, which could in turn affect cerebrovascular resistance. To date, no arterial blood samples have been taken on ISS to determine whether changes in PaCO2 have occurred.
Individual variability and potential implications.
The responses of dynamic autoregulation and CO2 reactivity, and the pre- to postflight differences, varied between astronauts. Finding a range of preflight baseline CBFV and CVRi responses to the input of BPMCA (Fig. 4, A and C) is similar to previous observations (11). Likewise, differences between subjects in CO2 reactivity (Fig. 4, B and D) are expected and might be related to differences in nitric oxide-dependent dilation, but this was not directly tested. Of interest in the current study is the magnitude of change following spaceflight. One individual (solid circle, Fig. 4) had the largest change from pre- to postflight in both CBFV and CVRi responses to BPMCA along with one of the larger changes in response to Pco2. The other astronauts had relatively consistent changes. The functional consequences of these changes cannot be identified from the current study; however, a recent study (8) noted that reductions in dynamic cerebrovascular autoregulation were associated with orthostatic intolerance. No tilt tolerance tests were performed by the astronauts in the current study.
Implications of individual variability in the changes in cerebrovascular dynamic autoregulation and CO2 reactivity beyond orthostatic tolerance are not known. However, NASA has recently identified idiopathic intracranial hypertension as a risk factor for postflight visual problems (13, 25). The current data showing a range of changes in postflight cerebrovascular responses might provide impetus to investigate the potential for transcranial Doppler measurements to yield information on risk for these visual problems.
The sample size in the current study was small. We had seven astronauts participate in the study but technical limitations reduced our main comparison of CVRi responses to n = 5. CO2 was not available in one astronaut (this astronaut's data were eliminated from all ARMA analyses but were included in the LBNP portion of the study), and there were marked differences between pre- and postflight CBFV in another astronaut, suggesting that different arteries might have been investigated (this astronaut's data were eliminated from CVRi results but maintained for CBFV since the Δ response was assumed similar independent of artery). Furthermore, it is acknowledged that with data collection in several different locations, different equipment was used for data collection possibly contributing to variability in the results. However, the consistent pattern of response between astronauts suggests that equipment did not influence the main findings of this study.
There were also differences in the timing of the postflight testing. Figure 4 indicates the individual astronauts according to their landing site, which dictated whether tests were conducted on R + 0 (all shuttle landings, n = 3 for this figure) or were on R + 1 or R + 2 (Soyuz landings). For shuttle landings, all astronauts were tested within 3 to 4 h of landing, and they had not been in an upright position for more than a few seconds during transitions between the shuttle and crew transport vehicle. For Soyuz landings, crew were upright at some times on landing day during their return to Star City, but were transported the morning after their arrival to the laboratory without assuming an upright posture for longer than toilet requirements. This provided a situation as similar as possible to the shuttle crew. These preparations contributed to the similar responses observed for most astronauts.
The current studies have shown a consistent impairment of dynamic cerebrovascular autoregulation and CO2 reactivity in astronauts following long-duration spaceflight; however, there were between-person differences in the magnitude of impairment. It is unclear at the moment whether these changes have pathophysiological significance associated with the complications in vision attributed to idiopathic intracranial hypertension (13, 25). Future studies should investigate pre- to postflight changes in transcranial Doppler indexes of cerebral blood flow and CO2 reactivity to determine whether they are predictors of pathophysiological complications resulting from long-duration spaceflight.
This research was supported by the Canadian Space Agency (9F007-02-0213) and Centre National d′Etude Spatiale (CNES 480000546).
No conflicts of interest, financial or otherwise, are declared by the author(s).
Author contributions: K.A.Z., P.A., J.K.S., A.P.B., D.K.G., and R.L.H. performed experiments; K.A.Z., D.K.G., D.X., and R.L.H. analyzed data; K.A.Z., J.K.S., A.P.B., D.X., and R.L.H. interpreted results of experiments; K.A.Z. and R.L.H. prepared figures; K.A.Z. drafted manuscript; K.A.Z., P.A., J.K.S., A.P.B., D.K.G., D.X., and R.L.H. approved final version of manuscript; P.A., J.K.S., A.P.B., D.K.G., D.X., and R.L.H. edited and revised manuscript; J.K.S. and R.L.H. conception and design of research.
- Copyright © 2012 the American Physiological Society