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. 2016 Feb 9;21(4):186–192. doi: 10.1007/s12199-016-0513-7

The relationship between widespread changes in gravity and cerebral blood flow

Yojiro Ogawa 1, Ryo Yanagida 1, Kaname Ueda 2, Ken Aoki 1, Ken-ichi Iwasaki 1,✉
PMCID: PMC4907926  PMID: 26860114

Abstract

Objectives

We investigated the dose–effect relationship between wide changes in gravity from 0 to 2.0 Gz (Δ0.5 Gz) and cerebral blood flow (CBF), to test our hypothesis that CBF has a linear relationship with levels of gravity.

Subjects and methods

Ten healthy seated men were exposed to 0, 0.5, 1.0, 1.5, and 2.0 Gz for 21 min, by using a tilt chair and a short-arm human centrifuge. Steady-state CBF velocity (CBFV) in the middle cerebral artery by transcranial Doppler ultrasonography, mean arterial pressure (MAP) at the heart level (MAPHeart), heart rate, stroke volume, cardiac output and respiratory conditions were obtained for the last 6 min at each gravity level. Then, MAP in the middle cerebral artery (MAPMCA), reflecting cerebral perfusion pressure, was estimated.

Results

Steady-state CBFV decreased stepwise from 0.5 to 2.0 Gz. Steady-state heart rate, stroke volume, estimated MAPMCA and end-tidal carbon dioxide pressure (ETCO2) also changed stepwise from hypogravity to hypergravity. On the other hand, steady-state MAPHeart and cardiac output did not change significantly. Steady-state CBFV positively and linearly correlated with estimated MAPMCA and ETCO2 in most subjects.

Conclusion

The present study demonstrated stepwise gravity-induced changes in steady-state CBFV from 0.5 to 2.0 Gz despite unchanged steady-state MAPHeart. The combined effects of reduced MAPMCA and ETCO2 likely led to stepwise decreases in CBFV. We caution that a mild increase in gravity from 0 to 2.0 Gz reduces CBF, even if arterial blood pressure at the heart level is maintained.

Keywords: Hypergravity, Hypogravity, Cerebral circulation, Transcranial Doppler ultrasonography, Centrifugation

Introduction

The human body, especially in a head-to-foot direction, is often exposed to changes in gravity in daily life, such as with postural change (0–1 Gz), on a roller coaster (transient 0–4 Gz due to acceleration), and during landing of an airplane (<1.3 Gz). The head-to-foot gravitational force (Gz) has a significant influence on cerebral circulation [1, 2]. In particular, gravity-induced decreases in cerebral blood flow (CBF) directly relate to (pre)syncope [3]. Many groups have investigated the effects of mild passive increases in gravity (0–0.5, or 0–0.8 Gz) on CBF using the head-up-tilt test [4, 5]. We also previously examined the effects of hypergravity (1.5 Gz) on cerebral circulation using centrifugation [1]. These previous studies reported that CBF decreases with increases in gravity [1, 4, 5], suggesting a dose–effect relationship between gravity and CBF. However, no study has investigated the relationship between a wide range of changes in gravity and CBF.

Therefore, we investigated the dose–effect relationship between a wide range of changes in gravity from 0 to 2.0 Gz (Δ0.5 Gz) and CBF, to test our hypothesis that CBF has a linear relationship with levels of gravity. CBF, assessed as “CBF velocity (CBFV) in the middle cerebral artery”, was measured by transcranial Doppler ultrasonography.

Methods

Subjects

The ethical committee of Nihon University School of Medicine (Itabashi-ku, Tokyo, Japan) approved this study (No. 20-26-1, 22 February 2011). The procedures adhered to the tenets of Declaration of Helsinki [6]. All study volunteers provided written informed consent as well as a medical history, and were screened based on a physical examination, including electrocardiography (ECG), arterial blood pressure and CBFV measurements. Exclusion criteria comprised failure to obtain CBFV signals in the middle cerebral artery by transcranial Doppler ultrasonography. A total of 10 healthy, normotensive males with a mean age of 23 years (range 20–28 years), height of 171 cm (range 159–184 cm), and weight of 65 kg (range 54–82 kg) were enrolled. All subjects were familiarized with the measurement techniques and experimental conditions before starting the study. A customized Doppler probe holder was made for each subject, using a polymer mold to fit individual facial bone structures and the right ear, to allow for repeated experiments, after the optimal angle of insonation with the highest velocity and best-quality Doppler signal had been identified in screening procedures [7].

Equipment

Subjects were seated on the tilt chair or on the chair in the cabin of the centrifuge in an environmentally controlled experimental room at an ambient temperature of 23–25 °C. ECG monitoring (Lifescope BSM-2101; Nihon Kohden, Tokyo, Japan) was applied. A nasal cannula with an infrared carbon dioxide sensor was applied for recording of capnography (OLG-2800; Nihon Kohden). Arterial blood pressure was continually measured on a beat-to-beat basis in the left radial artery at the heart level using tonometry, and calibrated before each data collection by intermittent blood pressure measured using the oscillometric method with a sphygmomanometer cuff placed over the right brachial artery (JENTOW 7700; Colin, Aichi, Japan). These calibrations were performed to avoid potential changes in the sensitivity of the tonometric sensor by movement of the subjects, the passage of time, and changes in gravity. CBFV in the right middle cerebral artery was continuously measured by transcranial Doppler ultrasonography (WAKI; Atys Medical, St. Genislaval, France). A 2-MHz probe was placed over the temporal window and fixed at a constant angle with the customized probe holder made to fit individual facial bone structures and the right ear by an experienced technician [7]. Excellent reproducibility of CBFV in the middle cerebral artery measured by transcranial Doppler ultrasonography has been reported when careful attention is paid to probe placement [8]. Each waveform of ECG, capnography, continuous arterial pressure and CBFV was recorded at a sampling rate of 1 kHz using commercial software (Notocord-hem 3.3; Notocord, Paris, France) throughout the experiment.

Procedure

Exposure to each level of gravity was performed using a tilt chair (0–1.0 Gz) or a centrifuge (1.0–2.0 Gz). A single method could not be used to test all gravity levels since it is difficult to adjust the degree of tilt of the cabin in the centrifuge method. Hence, both a tilt chair and centrifuge were used in this study. At least 7 days were allowed between the tilt chair and centrifuge experiments.

In the tilt chair protocol, subjects were exposed to 0, 0.5, and 1.0 Gz by adjusting the degree of tilt of the chair. The subject was seated in the tilt chair. The degree of tilt of the chair was adjusted to the horizontal (0 Gz), 30-degree head-up (0.5 Gz), and 90-degree head-up (1.0 Gz) positions. Although the investigations at the three levels of gravity in the tilt chair were performed consecutively on a single day, the order of tilt angles was randomized in each subject. Data collection at each level of hypogravity (0, 0.5, and 1.0 Gz) was performed for 6 min from 15 min after initiation of exposure to each degree of tilt (15–21 min of 0, 0.5, or 1.0 Gz).

The centrifugation protocol was performed over two separate days. All subjects underwent both the 1.5 Gz experiment and the 2.0 Gz experiment. At least 7 days were allowed between the 1.5 and 2.0 Gz experiments. Details of Nihon University’s short-arm human centrifuge (Daiichi Medical, Tokyo, Japan) used in this study have been previously reported [1]. Centrifuge acceleration and deceleration rates were 0.5 Gz/min. We maintained centrifugation at 24.24 rpm (1.5 Gz at the heart level of the subject) or 30.17 rpm (2.0 Gz at the heart level of the subject) for 21 min. Also, we confirmed the target Gz by using an accelerometer. Baseline 1.0 Gz data were collected for 6 min after 15 min of quiet rest in the centrifuge chair, following which the centrifugation was begun. Data collection at each level of hypergravity was performed for 6 min from 15 min after exposure to 1.5 or 2.0 Gz centrifugation (15–21 min of 1.5 and 2.0 Gz hypergravity).

Thus, 1.0 Gz data were collected three times (during one tilt chair protocol and two centrifugation protocols) for each subject, and the average value of the three measurements was calculated as 1.0 Gz (average) data.

Data analysis

Beat-to-beat values of mean arterial pressure (MAP) at the subject’s heart level (MAPHeart), CBFV, and R–R interval on the ECG were obtained using PC-based Notocord-hem 3.3 software (Notocord). Respiratory rate and partial pressure of end-tidal carbon dioxide (ETCO2) were measured from capnography. Steady-state MAPHeart, CBFV, heart rate, respiratory rate, and ETCO2 were obtained by averaging data from the 6-min data segment. To determine MAP at the middle cerebral artery level (MAPMCA) as an index of cerebral perfusion pressure, the distance from the heart level to the temporal window (TCD probe) was measured and the hydrostatic equivalent of arterial blood pressure was subtracted from the MAPHeart obtained by tonometry at each level of gravity from 0 to 2.0 Gz. Stroke volume was calculated off-line from the arterial pressure waveform using a Modelflow program incorporated into Beatscope software (TNO-TPD; Biomedical Instrumentation, Amsterdam, Netherlands) [9]. Steady-state stroke volume data was obtained by averaging the 6-min data segment. Cardiac output was estimated as the product of heart rate and stroke volume.

Statistical analysis

We confirmed normality of the data using the Shapiro–Wilk test. Thereafter, the variables were compared using one-way repeated-measures analysis of variance (ANOVA) (between 0, 0.5, 1.0, 1.5, and 2.0 Gz). To determine where significant differences occurred, the Student–Newman–Keuls post hoc test was used for all pair-wise comparisons as test of the difference according to the levels of gravity. A P value of <0.05 was considered statistically significant. Since respiratory rate was not normally distributed, the Friedman repeated-measures ANOVA on ranks was performed. All analyses were performed using PC-based software (SigmaPlot12; Systat Software, Inc., San Jose, CA, USA). Data are presented as mean ± standard error of the mean (SEM).

Results

Demographic characteristics of study participants are presented in Table 1. Steady-state hemodynamics and respiratory conditions at each level of gravity from 0 to 2.0 Gz are presented in Table 2. Percentage changes in group-averaged CBFV, MAPMCA, and ETCO2 are presented in Fig. 1. Steady-state CBFV showed a stepwise decrease from 0.5 to 2.0 Gz (ANOVA, P < 0.001). Steady-state MAPHeart did not change, whereas steady-state MAPMCA decreased stepwise from 0 to 2.0 Gz (ANOVA, P < 0.001). Steady-state heart rate increased stepwise from 0.5 to 2.0 Gz (ANOVA, P < 0.001), whereas steady-state stroke volume showed a stepwise decrease from 0.5 to 2.0 Gz (ANOVA, P < 0.001). Steady-state cardiac output and respiratory rate did not change, whereas ETCO2 showed a stepwise decrease from 1.0 to 2.0 Gz (ANOVA, P < 0.001).

Table 1.

Demographic characteristics of study participants

Age (years) 23 ± 3
Body mass index 22 ± 1
SAP (mmHg) 117 ± 2
DAP (mmHg) 59 ± 1
Heart rate (bpm) 80 ± 3
Diabetes 0/10
Hyperlipidaemia 0/10
Smoking 1/10
Problem drinkers 0/10a
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Values are means ± SEM

SAP systolic arterial pressure in the sitting position, DAP diastolic arterial pressure in the sitting position

aAll subjects refrained from alcoholic beverages for at least 24 h before the experiments

Table 2.

Steady-state hemodynamics and respiratory conditions

0 Gz 0.5 Gz 1 Gz (average) 1.5 Gz 2.0 Gz ANOVA
CBFV (cm/s) 65 ± 3 65 ± 3 60 ± 2*,# 58 ± 2*,# 51 ± 2*,#,†,‡ <0.001
MAPHeart (mmHg) 79 ± 2 77 ± 3 78 ± 1 79 ± 3 86 ± 4 0.246
MAPMCA (mmHg) 79 ± 2 65 ± 3* 54 ± 1*,# 43 ± 3*,#,† 38 ± 4*,#,† <0.001
Heart rate (bpm) 55 ± 1 56 ± 1 64 ± 1*,# 65 ± 2*,# 75 ± 2*,#,†,‡ <0.001
Stroke volume (ml) 86 ± 3 88 ± 4 80 ± 3*,# 72 ± 4*,#,† 60 ± 3*,#,†,‡ <0.001
Cardiac output (L/min) 4.7 ± 0.2 4.9 ± 0.2 5.3 ± 0.2 4.7 ± 0.3 4.5 ± 0.2 0.089
Resp-R (breath/min) 15 ± 1 14 ± 1 14 ± 1 15 ± 0 16 ± 1 0.142
ETCO2 (Torr) 41 ± 1 41 ± 1 39 ± 0 36 ± 0*,#,† 32 ± 0*,#,†,‡ <0.001
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Values are means ± SEM

CBFV cerebral blood flow velocity, MAP Heart mean arterial pressure at the heart level, MAP MCA mean arterial pressure at middle cerebral artery, Resp-R respiratory rate, ETCO 2, end-tidal carbon dioxide pressure, ANOVA analysis of variance

* P < 0.05 (vs. 0 Gz), # P < 0.05 (vs. 0.5 Gz), † P < 0.05 (vs. 1 Gz), ‡ P < 0.05 (vs. 1.5 Gz)

Fig. 1.

Fig. 1

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Percentage changes in group-averaged cerebral blood flow velocity (CBFV), estimated mean arterial pressure at the level of the middle cerebral artery (MAPMCA), and end-tidal carbon dioxide pressure (ETCO2) at each level of gravity, with 0 Gz (horizontal) = 100 % as a reference. *P < 0.05 (Bonferroni post hoc test for comparisons with 0 Gz value)

The relationships between CBFV and MAPMCA and between CBFV and ETCO2 are presented in Fig. 2. Steady-state CBFV positively and linearly correlated with MAPMCA in all but one subject. Also, steady-state CBFV positively and linearly correlated with ETCO2 in all subjects.

Fig. 2.

Fig. 2

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Linear relationship between cerebral blood flow velocity (CBFV) and estimated mean arterial pressure in the middle cerebral artery (MAPMCA) (A), and between CBFV and end-tidal carbon dioxide pressure (ETCO2) (B) using individual subject’s data

Discussion

The present study demonstrated stepwise gravity-induced changes in steady-state CBFV, estimated MAPMCA, heart rate, stroke volume and ETCO2, whereas steady-state MAPHeart and cardiac output remained unchanged with increasing levels of gravity. Positive linear relationships were found between CBFV and MAPMCA and between CBFV and ETCO2.

Many previous studies have also reported that CBF decreases with increase in gravity [1, 4, 5]. The decrease in CBF is possibly induced by reduction in cerebral perfusion pressure [4, 5]. An increase in gravity would result in altered hydrostatic pressure at the cranial level, as with head elevation, which, in turn, would decrease cerebral perfusion pressure. In fact, in the present study, estimated MAPMCA, which reflects cerebral perfusion pressure, showed a stepwise decrease from 0 to 2.0 Gz. Further, CBFV and estimated MAPMCA had a positive linear correlation (Fig. 2A). On the other hand, cerebral autoregulation maintains steady-state CBF by adjusting cerebral arteriolar caliber in the face of sustained cerebral perfusion pressures between 60 and 150 mmHg [10]. Since the estimated MAPMCA (i.e., cerebral perfusion pressure) at 0 and 0.5 Gz in the present study were probably situated on the plateau of the autoregulation curve, steady-state CBFV at 0 and 0.5 Gz remained unchanged. Also, the estimated MAPMCA at over 1.0 Gz might be less than the lower limit on the autoregulation curve, leading to stepwise decreases in CBFV. Thus, the relationship between CBFV and the estimated MAPMCA fit in with the characteristics of the autoregulation curve, and the reduced cerebral perfusion pressure would be one of the main reasons for the stepwise decrease in steady-state CBFV with levels of gravity from 0.5 to 2.0 Gz.

Possibly, the decrease in CBFV could also be induced by reduction in arterial carbon dioxide pressure, because arterial carbon dioxide pressure is one of the strongest influences on CBF [11, 12]. The present results demonstrated a stepwise decrease in ETCO2 and an unchanged respiratory rate, especially with levels of hypergravity, probably implying increases in tidal volume [13, 14]. The increased tidal volume would contribute to decreases in arterial carbon dioxide pressure, leading to decreases in CBFV. In this study, the relationship between CBFV and ETCO2 was also positive and linear (Fig. 2B). Thus, the potential reductions in arterial carbon dioxide pressure with increases in gravity would also affect a stepwise decrease in steady-state CBFV with levels of hypergravity.

A previous study reported that the relationship between changes in cardiac output and CBF are linear and highly significant [15]. In the present study, steady-state heart rate showed a stepwise increase, whereas steady-state stroke volume showed a stepwise decrease from hypogravity to hypergravity. The stepwise increase in steady-state heart rate in the present study probably compensated for the decrease in stroke volume caused by increases in gravity, resulting in maintenance of steady-state cardiac output. Therefore, the impact of cardiac output on decreases in CBFV in the present study was probably small. On the other hand, the unchanged cardiac output might likely have led to maintenance of steady-state arterial blood pressure at the heart level.

Thus, potential reductions in cerebral perfusion pressure and arterial carbon dioxide pressure together are likely to induce the stepwise decrease in CBFV with increasing levels of gravity from 0.5 to 2.0 Gz. Moreover, a previous study showed that a 1-mmHg reduction in cerebral perfusion pressure decreased CBF by approximately 0.82 % [16]. In the present study, the percentage reduction of CBFV against cerebral perfusion pressure was approximately 1.21 % per 1 mmHg. The difference might relate to the additive action of potential reductions in arterial carbon dioxide pressure in the present study.

Syncope accounts for 1.2–3.5 % of all emergency transport [17, 18]. In the Framingham study, approximately 3 % of humans reportedly experience at least one time of syncope during 26 years of follow-up survey [19]. The other previous study reported that the incidence of syncope is 0.8–0.93/1000 peoples/years [20]. In daily life, orthostatic (pre)syncope often occurs by increased gravity on a head-to-foot direction. Orthostatic hypotension is one of the main mechanisms for (pre)syncope [2, 3]. However, based on the present observations, CBF is likely to decrease due to reductions in cerebral perfusion pressure and arterial carbon dioxide pressure secondary to increases in gravity, even if arterial blood pressure at the heart level is maintained. Occurrence of orthostatic (pre)syncope relates importantly to reduction in CBF [21]. Then, the present results imply that even mild increases in gravity (Gz), such as standing up, stepping out at a bath, and/or motions of a vehicle (i.e., airplane, car, or roller coaster), would reduce CBF. We therefore caution that even mild increases in gravity without hypotension increase the risk of (pre)syncope via reduced CBF in everyday life.

In the present study, transcranial Doppler ultrasonography was used for non-invasive estimation of CBF. This approach is based on the assumption that changes in flow are proportional to changes in velocity only if the diameter of the middle cerebral artery remains constant. Also, the blood flow velocity in the middle cerebral artery can reflect global CBF rather than local CBF [22, 23]. On the other hand, a previous study reported that the diameter of the middle cerebral artery can change over a wide range of ETCO2 (approximately 23–46 Torr) [24]. Therefore, it is possible that the middle cerebral artery was constricted by the hypocapnia, leading to under-estimation of the decrease in CBFV caused by gravity in the present study. Thus, the true decrease in CBFV induced by changes of gravity from 0 to 2.0 Gz might be larger than indicated by the present results.

A primary limitation of the present study is the environmental difference between the tilt chair protocol and the centrifugation protocol. In the centrifugation protocol, a gondola-type cabin rotates to generate hypergravity. Although the rate of rotation was constant during data measurement of mild hypergravity, the possibility that vestibular stimulation affects the systemic circulation through vestibulo-autonomic reflexes cannot be ruled out. Likewise, changes in the tilt angle in the tilt chair protocol might also stimulate the vestibular system, which would have affected the present results, although a rest period of 15 min was allowed at each level of gravity before measurements were made.

There are some other limitations to the present study. Possible changes in intracranial pressure might affect the present results. In general, cerebral perfusion pressure equals “MAPMCA” minus “intracranial pressure”. Although we did not measure intracranial pressure in this study, a previous study reported that intracranial pressure is reduced by postural change from the horizontal (0 Gz) to sitting (1.0 Gz) position [25]. Probably, intracranial pressure decreases further during hypergravity. To confirm this effect in detail, a future study that investigates the effects of changes in intracranial pressure on cerebral perfusion pressure during a wide range of changes in gravity will be needed. Another limitation was the small sample size. However, the post hoc powers (α = 0.05) in CBFV, stroke volume, MAPMCA, and ETCO2 were all 1.00. Hence, the main finding of the stepwise gravity-induced changes in steady-state CBFV from 0.5 to 2.0 Gz is not likely to have been affected by small sample size. On the other hand, the post hoc power in MAPHeart was below 0.80. Therefore, there is a possibility that the present study could not show significant increases in the MAPHeart at 2.0 Gz, implying type II error. In addition, the reproducibility of CBFV measured in the middle cerebral artery by transcranial Doppler is most important in the present study. When careful attention is paid to probe placement, the reproducibility of CBFV especially has been confirmed to be good, indicated by the high intraclass correlation coefficient of ~0.9 [26] and small coefficient of variation (10 %) in repeated measurements [27] for CBFV. Thus, we believe that the reproducibility of present findings is likely to be high, although the future study with many subjects will be needed to confirm the actual reproducibility.

In conclusion, the present study investigated the dose–effect relationship between steady-state CBF and levels of gravity from 0 to 2.0 Gz (Δ0.5 Gz). We found that steady-state CBFV was reduced stepwise by increases in gravity from 0.5 to 2.0 Gz. Moreover, the present study found that steady-state CBFV positively and linearly correlated with MAPMCA and ETCO2. The combined effects of reduced MAPMCA and ETCO2 would lead to the stepwise decrease in CBFV. Based on the present findings, we caution that mild increases in gravity could possibly reduce CBF despite unchanged arterial blood pressure at the heart level.

Acknowledgments

This study was supported by The Uehara Memorial Foundation on conducting the experiments, and by JSPS KAKENHI Grant Number 15H05939 on editing the manuscript. This report was previously presented, in part, at “The 85th Annual Meeting of The Japanese Society for Hygiene”.

Compliance with ethical standard

Disclosures

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

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