Yonago Acta medica 2003;46:1–8

Effects of Microgravity on Cerebral Hemodynamics
Yasuaki Kawai, Mitsuru Doi, Akira Setogawa, Reiko Shimoyama, Keigo Ueda,
Yasumasa Asai and Kyoko Tatebayashi
Division of Adaptation Physiology, Department of Functional, Morphological and Regulatory Science, School of Medicine, Tottori University Faculty of Medicine, Yonago 683-8503 Japan
After centuries of wonder, human being finally realized the decisive possibility of going to
the moon a little more than 50 years ago, and in 1969 this became a reality, no longer a
dream. The human body, however, is designed to live under 1 g as on Earth. Thus, it isimportant to understand what happens in the human body under microgravity in order tomake rapid progress in space development. One of the most serious problems produced by
microgravity is a fluid shift from lower to upper body. This cephalad fluid shift may change
the hemodynamics in the brain. In this review, effects of actual or simulated microgravity
on cerebral blood flow, intracranial pressure, formation of brain edema, and orthostatic
intolerance will be discussed. These studies provide us lots of information not only tomaintain the health of astronauts but also to treat senile persons who, on rare occasions, sit
or stand up.
Key words: brain edema; cerebral circulation; head-down tilt; intracranial pressure; microgravity

Advances in aerospace technology in the 20th
century provided human beings with an opportunity
to face a microgravitational (almost 0 g) environment, and this experience will further increase in
21st century. Astronauts experience weightlessness
during space flight. Since the human body is designed to live under 1 g as on Earth, exposure to
microgravity causes significant changes in bodyfunctions. Thus, it is important to understand what
happens to the human body under microgravity inorder to maintain health during space flight.
One of the most serious problems produced by
microgravity is a fluid shift toward the upper body.
This cephalad fluid shift is caused by changes in ahydrostatic pressure gradient and induces characteristic symptoms such as facial edema, nasal congestion and headache during space flight (Thornton
et al., 1987) as well as orthostatic intolerance onreentry to Earth gravity. Here we present a surveyof recent findings on hemodynamic changes in thebrain during and after microgravity. Effects of microgravity on the cardiovascular system can be simulated by head-down tilt (HDT) on Earth (Kakurin
et al., 1976; Nixon et al., 1979; Hargens et al., 1983).
In this review, therefore, effects of both actual andsimulated microgravity in humans and also in animals will be presented.

I. Cerebral Blood Flow
It has been speculated from early in the history of
space development that exposure to microgravity
alters cerebral blood flow (CBF). No reports, however, have shown the effect of microgravity on CBF
until the beginning of 1990s because of the limita-

Abbreviations: CBF, cerebral blood flow; CSF, cerebrospinal fluid; HDT, head-down tilt; ICP, intracranial pressure;
TCD, transcranial Doppler

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Y. Kawai et al.

tion in non-invasive technique for CBF measurement that is available for human study. The firstevidence was reported by Bondar, a Canadian astronaut, and colleagues (1991). They demonstrated a
30% increase in CBF velocity during parabolic
flight using a transcranial Doppler (TCD) techniquedeveloped by Aaslid (1982). Parabolic flight is anaircraft free fall and provides 20 s of an actual
microgravitational environment inside the plane.
Next, Bagian and Hackett (1991) measured CBF
velocity using TCD in a space shuttle and reported
that CBF velocity did not change significantly after
10 h of space flight compared with the preflightbaseline value. These findings led us to think thatthe time course of CBF changes should be moreclosely examined. It is difficult, however, to monitor CBF continuously during space flight because
the astronauts usually have to do so many tasks.
Thus, we planned to measure CBF velocity during
HDT, simulated microgravity, in collaboration withDr Hargens at NASA Ames Research Center.
First, we examined the effect of acute HDT on
blood flow velocity in the middle cerebral artery ofhumans. CBF velocity was measured using a 2
MHz pulse TCD. In 6 volunteers, exposure to 6˚
HDT for 5 min increased CBF velocity by 14 ± 3%
compared with the baseline value in an upright sitting posture (Kawai et al., 1992). An increase in
CBF velocity immediately after the onset of HDT
has been reported also from other laboratories (Freyet al., 1993; Savin et al., 1995). Next, we investigated CBF velocity before, during and after 24 h of
HDT. The mean CBF velocity increased from the
pre-HDT baseline value of 55.5 ± 3.7 cm/s to 61.5 ±3.3 cm/s at 0.5 h of HDT, reached a peak value of
63.2 ± 4.1 cm/s at 3 h of HDT, remained significantly above the baseline for 6 h, and then began to decrease toward the baseline after 9 h of HDT (Kawai
et al., 1993).
TCD is a useful technique for measuring CBF
velocity, but can not detect a change in vascular diameter. Since CBF is a product of CBF velocity
and the cross-sectional area of the blood vessel, an
increase in CBF velocity does not necessarily mean
an increase in CBF. Thus, in the next study, we examined brain oxygenation during postural changeusing near infrared spectroscopy. Brain oxygenation increased by 9.4 ± 1.1% and hemoglobin
concentration in the forehead increased by 4.9 ±
1.7% after going from an upright to a supine posture(Kawai et al., 1996). Together with the TCD findings, these results suggest that CBF increases at leastin the early phase of microgravity. On the other hand,
image analysis using single photon emission computer tomography demonstrated that a significant increase in CBF occurred in the basal ganglia and the
cerebellum during HDT, but not in the cerebral
hemisphere (Satake et al., 1994).
Direct measurements of CBF using a laser
Doppler flowmeter were carried out in animals.
Florence and colleagues (1998) showed that CBF
increased transiently during parabolic flight in rabbits. However, the increase in CBF was not observed in rabbits exposed to 45˚ HDT (Asai et al., 2002).
Further studies will be needed to clarify the controversy.

II. Intracranial Pressure
Total volume of brain tissue, cerebrospinal fluid(CSF), and blood in the cranial vault is usually well
regulated at a constant value. However, an increasein volume results in an elevation of intracranialpressure (ICP) because the cranium is rigid andpoorly distensible. Therefore, the cephalad fluid
shift due to microgravity may increase the ICP.
When the ICP rises, it compresses the blood vessels
and increases vascular resistance, causing a reduction of cerebral blood flow. Keil and coworkers(1992) reported that ICP elevated from –6.3 mmHg
in an upright sitting posture to 5.3 mmHg at 6˚ HDTin anesthetized monkeys. Murthy et al. (1992)
showed an increase in ICP by 15.5 mmHg during theacute phase of 6˚ HDT in humans by a non-invasive
tympanic membrane displacement technique(Marchbanks, 1984). These reports demonstrated
an elevation of ICP within several minutes after the
onset of HDT.
We designed animal experiments using rats
and rabbits to investigate the time course of ICP
during HDT. Rats were tilted head-down to 45˚ in a2

Microgravity and brain circulation(mmHg)

*

15

*

10

Fig. 1. Change in intracranial pressure(ICP) in anesthetized rabbits before, during and after 8 h of 45° head-down tilt
(HDT) ( , n = 8). The ICP increased during the first 4 h of HDT and dropped below the baseline value after cessation of
HDT. Rabbits in the control group ( , n= 8) remained in the horizontal prone position throughout the experimental period(from Doi et al., 1998).

ICP

*

5

0

pre

*

45˚ HDT

*
post

–5
–2

0

2

4

6

8

10

(h)

time
hand-made jacket and remained in this position for
8 h. The ICP increased by 2 mmHg immediately
after the onset of HDT (Kawai et al., 1997). This
increase in ICP is attributable to both the shift of
CSF from the spine toward the head (Friden and
Ekstedt, 1983) and the increase of blood volume inintracranial veins (Kotani et al, 1993). After the initial elevation, the ICP decreased toward the baseline over the next 3 h. This decrease is probably due
to the absorption of CSF through arachnoid villi.
After 3 h of HDT, ICP began to rise again. We
speculated that the second rise in ICP might be due
to edema formation in the brain since capillarypressure in the head increased during HDT(Parazinski et al., 1991). The increase in ICP in rats
is small (Maurel et al., 1996) because of the little
effect of hydrostatic pressure resulting from theanimal’s small body size. Thus, in the next study,
we used rabbits to examine the effect of greaterhydrostatic pressure than in rats. In rabbits, ICP
elevated from 4.6 ± 0.7 mmHg at horizontal prone
position to 13.7 ± 1.0 mmHg immediately after the
onset of 45˚ HDT and gradually reduced toward thebaseline value over the next 8 h (Fig.1) (Doi and
Kawai, 1998). A second rise in ICP was not observed in rabbits. These measurements were carried out
using anesthetized animals. In the next study, wemeasured ICP in conscious rabbits. The ICP wasmeasured through a catheter chronically implanted

into the subarachnoid space throughout the HDT
period. It increased from 4.8 ± 0.9 mmHg to 9.2 ±1.6 mmHg immediately after the onset of 45˚ HDT,
reached a peak value of 12.8 ± 2.5 mmHg at 12 h of
HDT, and then decreased towards the pre-HDT
baseline value during 7 days of HDT (personal communication).

III. Brain Edema
Facial edema is a symptom commonly observed in
astronauts during space flight and also in subjects
exposed to HDT. However, little is known of edema formation in the brain during microgravity.
Parazynski and colleagues (1991) demonstrated elevation of capillary pressure in the head and reduction of colloid osmotic pressure in human subjects
during HDT. Wen and coworkers (1994) showeddisruption of the blood-CSF barrier because ofelevated arterial pressure during 90˚ HDT in rabbits. These findings suggest that HDT may increase
capillary filtration and produce brain edema. A
morphological study showed vessel dilatation andperivascular edema in the monkey brain after 7 daysof 6˚ HDT (Kaplansky et al., 1985).
We investigated brain edema in rabbits exposed to 8 days of HDT using physicochemical andhistological techniques (Shimoyama et al., 2000).
3Y. Kawai et al.

A

B

Fig. 2. Macroscopic appearances of the brain obtained
from (A) the control rabbit, (B) the 2 day HDT rabbitand (C) the 8 day HDT rabbit. Dilatation of the pial vessels is observed in the brain of HDT rabbits (B, C). Bar= 1 cm (from Shimoyama et al., 2000).

We hypothesized that edema formation increases
water content in the brain tissue. However, the results showed that the water content in the brain tissue of rabbits exposed to HDT did not increasesignificantly compared with that of control animals.
Neither Evans blue staining nor immunohistochemical examination demonstrated extravasationof plasma constituents in the brain. Although marked congestion was observed in the brain (Fig. 2),
hematoxilin and eosin staining showed no edematous changes. In addition, transmission electron
microscopy revealed that tight junctions of the capillary endothelium were intact in the HDT rabbits(Fig. 3). These findings suggest that either HDT up
to 8 days does not produce brain edema in rabbits orit induces only a slight brain edema that is hard to demonstrate by only measuring water content or histological examinations. Regulation of microcirculation
seems to be well maintained in the brain of rabbits
exposed to 45˚ HDT. A recent study of ours show-Ced that exposure to 8 days of HDT increased thethickness of the medial layer in the rabbit basilar
artery and decreased the intraluminal cross-sectional
area (Fig. 4) (Ueda, 2001). Such morphologicalchanges may play a beneficial role in preventing
edema formation during HDT in rabbits. In addition, although it is commonly accepted that there
are no lymphatics in the brain of most animals, asmuch as half of the drainage of CSF is through thelymph in rabbits (Bradbury et al., 1981). Ohhashi

4Microgravity and brain circulation

Fig. 3. Transmission electron microscopy revealed that the tight junctionof capillary endothelium
was intact and the featuresof brain edema, such aspinocytotic vesicles, were
not seen in the HDT group(from Shimoyama et al.,2000).

A

B

50 µm

C

50 µm

D

100 µmFig. 4. Typical cross-sectionalviews of rabbit arteries.
A: basilar, control.
B: basilar, HDT.
C: popliteal, control.
D: popliteal, HDT.
(from Ueda et al., 2001)

100 µmand colleagues (1993) revealed that venous valves
were found in rabbit jugular veins but not in thoseof monkeys. These differences may explain thediscrepancy between our result and that in monkeys
reported by Kaplansky and coworkers (1985). Thus,
we have to take account of species differences inanalyzing the effect of HDT.

IV. Orthostatic Intolerance
Astronauts frequently experience orthostatic intolerance after coming back to Earth from space.
Symptoms have ranged from increased heart rate tofrank syncope. In Gemini crewmembers after 14days of space flight, tilting them from a supine con-5

Y. Kawai et al.

trol posture to a 70˚ head-up tilt position increased
heart rate by about 50 beats/min, and the test wasaborted because of presyncopal symptoms (Berryand Catterson, 1967). Syncope is presumably attributable to decreased CBF. In our previous study,
CBF velocity decreased to 87% of the pre-HDT
baseline value during upright seated recovery after
24 h of HDT (Kawai et al., 1993). Although presyncope or syncope was not observed in the study,
decreased CBF velocity is likely to increase the riskof syncope during stand test or lower body negative
pressure which is commonly used to quantify orthostatic deconditioning.
Several factors are involved in brain ischemia.
First, diminished blood volume during space flightplays a significant role in orthostatic intolerance(Hoffler, 1977; Johnson, 1979). Bungo and colleagues (1985) showed an efficacy of fluid loadingwith 1 L of normal saline to prevent symptoms of
intolerance. The efficacy of this countermeasure,
however, varies with flight duration. It seems toprotect orthostatic tolerance only for short spaceflight. Second, Thornton and Hoffler (1977) suggested that an increase of vascular compliance inthe lower extremities might play a certain role. It
increases accumulation of blood in the legs and decreases venous return, resulting in decreased cardiac output. Third, a disturbance in the baroceptor
reflex has been proposed to be involved in themechanism for orthostatic intolerance caused byexposure to microgravity (Convertino et al., 1990;
Eckberg et al., 1992; Fritsch et al., 1992).

knowledge will provide us with a lot of informationin other aspects of medicine such as treatment ofsenile persons who, on rare occasions, sit or standup.

Acknowledgments: Some of our studies referred in thisarticle were carried out as a part of “Ground Research
Announcement for Space Utilization” promoted by theJapanese Space Forum.

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Received December 25, 2002; accepted January 10, 2003
Corresponding author: Yasuaki Kawai

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