Cerebral circulation during mild +Gz hypergravity by short-arm human centrifuge

Ken-ichi Iwasaki, Yojiro Ogawa, Ken Aoki, Ryo Yanagida

Abstract

We examined changes in cerebral circulation in 15 healthy men during exposure to mild +Gz hypergravity (1.5 Gz, head-to-foot) using a short-arm centrifuge. Continuous arterial pressure waveform (tonometry), cerebral blood flow (CBF) velocity in the middle cerebral artery (transcranial Doppler ultrasonography), and partial pressure of end-tidal carbon dioxide (ETco2) were measured in the sitting position (1 Gz) and during 21 min of exposure to mild hypergravity (1.5 Gz). Dynamic cerebral autoregulation was assessed by spectral and transfer function analysis between beat-to-beat mean arterial pressure (MAP) and mean CBF velocity (MCBFV). Steady-state MAP did not change, but MCBFV was significantly reduced with 1.5 Gz (−7%). ETco2 was also reduced (−12%). Variability of MAP increased significantly with 1.5 Gz in low (53%)- and high-frequency ranges (88%), but variability of MCBFV did not change in these frequency ranges, resulting in significant decreases in transfer function gain between MAP and MCBFV (gain in low-frequency range, −17%; gain in high-frequency range, −13%). In contrast, all of these indexes in the very low-frequency range were unchanged. Transfer from arterial pressure oscillations to CBF fluctuations was thus suppressed in low- and high-frequency ranges. These results suggest that steady-state global CBF was reduced, but dynamic cerebral autoregulation in low- and high-frequency ranges was improved with stabilization of CBF fluctuations despite increases in arterial pressure oscillations during mild +Gz hypergravity. We speculate that this improvement in dynamic cerebral autoregulation within these frequency ranges may have been due to compensatory effects against the reduction in steady-state global CBF.

  • gravitational load
  • centrifugation
  • cerebral blood flow

prolonged exposure to the microgravity environment in space leads to various physiological problems on returning to Earth. Periodic exposure to sustained mild +Gz (head-to-foot) hypergravity using a short-arm centrifuge has been proposed to prevent these physiological problems, including cardiovascular deconditioning, problems of bone-calcium metabolism, and muscle atrophy (5, 15, 18, 19, 37, 39). Although many reports have examined alterations of cerebral circulation during high +Gz load (22, 36, 41), the effects of mild +Gz hypergravity on cerebral circulation have yet to be established.

For human cerebral circulation, the autoregulatory system adjusts distal cerebral arterioles to maintain constant cerebral blood flow (CBF). Steady-state global CBF is maintained relatively independent from changes in cerebral perfusion pressure. Moreover, cerebral autoregulation acts to suppress transient changes or “dynamic” fluctuations in CBF induced by changes in arterial pressure as cerebral perfusion pressure (1). Continuous measurement of CBF velocity by transcranial Doppler in a large cerebral artery provides data with high temporal resolution, and reveals beat-to-beat fluctuations in CBF, similar to the arterial pressure oscillations (9, 43, 44). Such data also indicate linear correlations between two signals or transfer magnitude from arterial pressure oscillations to CBF fluctuations differ according to the frequency range. Although complete consensus has yet to be reached regarding the notion of “normal” and “impaired” dynamic cerebral autoregulation, numerous reports have shown common characteristics of frequency-dependent phenomena in healthy humans. For example, estimates of coherence function are increased at higher frequency ranges (>0.07 Hz), indicating increased linear correlations between these variables or dependence of CBF fluctuations on arterial pressure oscillations (7, 16, 17, 21, 25, 27, 43, 44). Moreover, several previous studies examining the effects of various interventions on dynamic cerebral autoregulation have shown that each intervention alters the dynamic relationships in specific frequency ranges (16, 17, 21, 27, 44). However, this new approach has not been applied to learning more situations under hypergravity conditions.

Even a mild degree of +Gz hypergravity might possibly augment venous pooling in the lower body and reduce cerebral perfusion pressure due to the altered hydrostatic pressure. These gravitational effects may impair cerebral circulation. We thus hypothesized that global CBF would be reduced and dynamic cerebral autoregulation would be impaired by mild +Gz hypergravity. To test this hypothesis, the present study evaluated the effects of sustained +1.5 Gz load on human cerebral circulation.

METHODS

Subjects.

The institutional review board of Nihon University School of Medicine (Itabashi-ku, Tokyo, Japan) approved this study. The procedures adhered to the tenets of the Declaration of Helsinki. All study participants provided written informed consent as well as a medical history and were screened based on a physical examination including electrocardiography and blood pressure measurements. Volunteers were excluded if CBF velocity signals in the middle cerebral artery (MCA) could not be obtained by transcranial Doppler ultrasonography. We investigated 15 healthy, normotensive men with a mean age (±SD) of 24 ± 2 yr (range, 20–28 yr), mean height of 171 ± 6 cm (range, 159–180 cm), and mean weight of 63.8 ± 6.7 kg (range, 48.6–77.7 kg). All participants fasted for ≥2 h before the experiments and refrained from heavy exercise and consuming caffeinated or alcoholic beverages for at least 24 h before the experiments. All participants were familiarized with the measurement techniques and experimental conditions before the study.

Data collection.

Participants were seated in the cabin of the centrifuge, in an environmentally controlled experimental room, at an ambient temperature of 23–25°C. Electrocardiography (Lifescope BSM-2101; Nihon Kohden, Tokyo, Japan) was performed. Capnography and partial pressure of end-tidal carbon dioxide (ETco2) were monitored using an infrared CO2 sensor (OLG-2800; Nihon Kohden). Continuous arterial pressure was measured in the left radial artery at the heart level using tonometry on a beat-to-beat basis, and calibrated by intermittent blood pressure measured using the oscillometric method with a sphygmomanometer cuff placed over the right brachial artery (JENTOW 7700; Colin, Aichi, Japan). CBF velocity in the MCA 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 a probe holder customized to fit the facial bone structure and ear of the individual (11). Signals were obtained according to standard techniques with the Doppler sample volume adjusted to the proximal segment of the MCA, optimizing the opportunity for obtaining true maximum velocities. All recordings were performed by the same experienced technician.

CBF velocity in the MCA was used as the index of global CBF, since the MCA supplies a much larger area than either the anterior or posterior arteries and carries ∼80% of the blood received by the cerebral hemispheres (40). Moreover, the diameter of the insonated MCA changes minimally under a variety of stimuli (10, 35) and CBF velocity in the MCA is directly proportional to global CBF (2, 23). However, we observed the changes in blood flow velocity at MCA rather than changes in CBF, and the velocity data as measures of flow must be interpreted with great caution.

Each waveform of continuous arterial pressure, CBF velocity (peak envelope of the TCD spectrum), electrocardiography, and capnography was recorded at a sampling rate of 1 kHz using commercial software (Notocord-hem 3.3; Notocord, Paris, France) throughout the experiment.

Baseline data (1 Gz) collection was performed for 6 min after ≥15 min of quiet rest in the chair of the centrifuge. Centrifugation was then started. Mild hypergravity data (1.5 Gz) collection was performed for 6 min from 15 min after beginning +1.5 Gz centrifugation (15–21 min of +1.5 Gz centrifugation).

Centrifugation.

Nihon University's short-arm human centrifuge (Daiichi Medical, Tokyo, Japan) was used for this study (Fig. 1). The subject was seated in a chair located in the enclosed cabin at a radius of 1.7 m. The chair was in the center of the cabin, facing the outside. The cabin was freely movable and the top tipped toward the center during centrifugation. The resultant vector of gravitational force of the earth and the force generated by centrifuge was directed along the longitudinal z-axis (head-to-foot) of the subject's body. A headrest stabilized the subject's head. Centrifuge acceleration and deceleration rates were 0.5 G/min. We maintained centrifugation at 24 rpm (1.5 Gz at heart level of the subject) for 21 min (Fig. 1). Arterial pressure, CBF velocity, electrocardiography, capnography, and ETco2 were monitored continuously. The condition of the on-board subject and the inside of the cabin were also continuously monitored using a CCD (charge coupled device) camera and a microphone. Centrifugation was terminated if signs and/or symptoms of presyncope developed, such as nausea, sweating, light-headedness, gray-out, bradycardia, or hypotension (sustained systolic blood pressure <80 mmHg). In the present study, all subjects completed the entire centrifugal protocol.

Fig. 1.

Schema of the short-arm human centrifuge at Nihon University. The subject is seated in a chair located at a radius of 1.7 m in an enclosed cabin. The chair was in the center of the cabin facing the outside. The cabin was freely movable and its top tips toward the center during centrifugation. The resultant vector of gravitational force for the earth (1 G) and centrifugal force was directed along the longitudinal z-axis of the subject's body. During 24 rpm of centrifugation, 1.5 Gz was loaded to the subjects at heart level.

Analysis of steady-state indexes.

Steady-state mean arterial pressure (MAP), mean CBF velocity (MCBFV), heart rate, respiratory rate, and ETco2 were obtained by averaging the 6-min data segments. To determine MAP at the MCA level, distance from heart level to the eyes was measured and the hydrostatic equivalent of blood pressure was subtracted from the MAP obtained by tonometry. The hydrostatic pressure was calculated as this distance × 0.76 mmHg at 1 Gz and this distance × 0.76×1.5 mmHg at 1.5 Gz. Cerebral perfusion pressure was not calculated, since we did not measure intracranial pressure or cerebral venous pressure.

Spectral analysis.

The 6-min data for beat-to-beat MAP and MCBFV were linearly interpolated and resampled at 1 Hz for spectral analysis. The spectrum in MAP and MCBFV variabilities were obtained by fast Fourier transform. The transfer functions by the cross-spectrum method between these two variabilities were calculated to assess the dynamic relationship between arterial pressure and CBF velocity (Fig. 2). Data analysis was performed using DADiSP software (DSP Development, Cambridge, MA).

Fig. 2.

Group-averaged transfer function analysis between mean arterial pressure (MAP) and mean cerebral blood flow velocity (MCBFV). Gain, transfer-function gain between MAP and MCBFV variabilities; VLF, the very low-frequency range (0.02–0.07 Hz); LF, the low-frequency range (0.07–0.20 Hz); HF, the high-frequency range (0.20–0.35 Hz).

Transfer function H(f) between the two signals was defined as: H(f) = SPV(f)/SPP(f), where SPP(f) is the Fourier-transformed autocorrelation function (autospectrum) of changes in MAP and SPV(f) is the Fourier-transformed cross-correlation function (cross-spectrum) between MAP and MCBFV signals. Transfer function magnitude H(f) and phase spectrum Φ(f) were derived from the real part [HR(f)] and imaginary part [HI(f)] of the complex function H(f) as: H(f) = {[HR(f)]2 + [HI(f)]2}1/2 and Φ(f) = arctan[HI(f)/HR(f)].

Mean squared coherence (MSC) function MSC(f) was defined as: MSC(f) = SPV(f) 2/[SPP(f) SVV(f)], where SVV(f) is the autospectrum of MCBFV.

Spectral power of MAP and MCBFV variabilities, mean value of coherence function, transfer function gain, and phase were calculated in the very low (0.02–0.07 Hz)-, low (0.07–0.20 Hz)-, and high (0.20–0.35 Hz)-frequency ranges chosen to reflect previously reported frequency-dependent patterns of the dynamic pressure-flow relationship (43, 44).

Coherence function (strength of association) was calculated to assess the linear relationship between these two variables and reliability of the transfer function gain and phase. Coherence can range from 0 to 1. A perfect linear relationship is characterized by a coherence value of 1. Low coherence with shifts toward 0 has generally been attributed to tight autoregulation with suppressed influence of arterial pressure oscillations on CBF velocity fluctuations, or reduced signal-to-noise ratio. Another measure relevant to autoregulation is gain. Estimates of transfer function gain (magnitude of transfer) were used to quantify the amplitude of signal transmission from arterial pressure to CBF velocity. Phase was used to estimate the temporal relationship between these two variables. For example, improvement of dynamic cerebral autoregulation should lead to decreases in transfer function gain and/or coherence, reflecting the suppressed transfer and/or influence of arterial pressure oscillations on CBF velocity fluctuations.

Statistical analysis.

Data are given as means ± SD. Data were compared by using paired t-test. All statistical analyses were performed using SigmaStat software version 3.11 (Systat Software, Chicago, IL). A value of P < 0.05 was considered significant.

RESULTS

Changes in steady-state indexes are shown in Table 1. ETco2 was reduced with 1.5 Gz (−12%), but respiratory rate was unchanged. Heart rate increased significantly. Steady-state MAP did not change, but MCBFV was significantly reduced with 1.5 Gz (−7%). Mean arterial pressure at the MCA level was also significantly reduced with 1.5 Gz (−15%).

View this table:
Table 1.

Steady-state indexes during spontaneous breathing

Changes in frequency analysis indexes are shown in Table 2. Variability in MAP in low- and high-frequency ranges increased significantly with 1.5 Gz (low frequency, +53%; high frequency, +88%), but variability in MCBFV within these frequency ranges did not change. Transfer function gain in low- and high-frequency ranges significantly decreased with 1.5 Gz (Fig. 2). In contrast, all of these indexes in the very low-frequency range were unchanged. Coherence and phase did not change in any frequency ranges.

View this table:
Table 2.

Frequency analysis indexes during spontaneous breathing

DISCUSSION

No previous studies have investigated steady-state global CBF and dynamic cerebral autoregulation during hypergravity. The present study found that CBF velocity in MCA was reduced with +1.5 Gz hypergravity. Moreover, MAP variability increased, but CBF velocity variability remained unchanged in the low- and high-frequency ranges. Associated with these changes, transfer function gains (magnitude of transfer) between MAP and MCBFV variabilities decreased in low- and high-frequency ranges. Transfer from arterial pressure oscillations to CBF fluctuations was thus suppressed in these frequency ranges. These results suggest that mild +Gz hypergravity reduced steady-state global CBF, but improved dynamic cerebral autoregulation with stabilization of CBF fluctuations despite increases in arterial pressure oscillations in these frequency ranges.

The results for reduced steady-state CBF would possibly be induced by reductions in cerebral perfusion pressure (4, 32). Many reports have discussed the effects of the mild passive increases in Gz on steady-state CBF using head-up tilt (4, 6, 14, 34). Increases in Gz differ between the present study (1 to 1.5 Gz) and those previous studies (i.e., 0 to 0.5 Gz, 0 to 0.8 Gz), and whether the effect of increases in Gz on steady-state CBF show a simple linear dose-effect relationship is uncertain. However, in agreement with those previous studies using head-up tilt, the increase in Gz reduced steady-state CBF velocity in the MCA in the present study. During increases in Gz, the cerebral arteries are positioned above the heart. Cerebral perfusion pressure may thus be reduced as in head elevation by altered hydrostatic pressure at the cranial level, if cerebral perfusion pressure equals “arterial pressure at the head” minus “intracranial pressure” (32). In fact, estimated MAP at the MCA level was reduced by the mild +Gz hypergravity, since MAP (at the heart level) did not change (Table 1). However, we cannot exclude the possibility that the intracranial pressure decreased similarly as “arterial pressure at the head” with increases in Gz, since intracranial pressure was not measured in the present study. Furthermore, the reduction in steady-state CBF would possibly be induced by reductions in arterial CO2 (PaCO2) (8, 29). Although doubts may exist regarding the accuracy of end-tidal carbon dioxide measurements, significant decreases in ETco2 were noted in the present study. Previous head-up tilt studies reported that reductions in PaCO2 may be partly attributable to the postural declines in CBF velocity within the MCA (4, 34). However, others have argued that the potential contribution of PaCO2 to postural reductions in CBF velocity within the MCA are only transient, not sustained (14). Whether this is the case in the present hypergravity is uncertain. Another possible explanation for reductions in global CBF may be the reduced cardiac output as observed at 2 or 3 Gz (30, 31). A relationship between CBF and cardiac output was found by demonstrating that both CBF velocity and cerebral oxygenation by near infrared spectroscopic topography decrease in association with the postural reduction in cardiac output (33). However, cardiac output was not measured in the present study and this explanation for reduced CBF during mild +Gz hypergravity remains purely speculative. Further work is needed to reveal whether this mechanism is involved. One mechanism underlying decreased CBF velocity would also involve sympathetic vasoconstriction in the brain, although the effects of sympathetic activity on CBF remain contentious (38).

The present hypergravity conditions also altered the dynamic relationship between arterial pressure oscillations and CBF velocity fluctuations in the low- and high-frequency ranges, but not in the very low-frequency range. Two main mechanisms may underpin the increased oscillations of arterial pressure during mild +Gz hypergravity. First, increases in vasomotor sympathetic activity may augment arterial pressure oscillation in the low-frequency range (0.07–0.2 Hz), since Mayer waves in arterial pressure have a frequency ∼0.1 Hz. Second, increases in respiratory tidal volume may augment arterial pressure oscillation in the high-frequency range. Arterial pressure oscillation at respiratory frequency is primarily induced by the mechanical effect of respiratory intrathoracic pressure changes on the heart and large thoracic vessels (28). A reduction in lung perfusion and a gravitational blood pressure gradient over the lung would increase ventilation (12). In fact, a previous report from our research project using the same centrifuge showed a 1.4- to 1.7-Gz load increased tidal volume and pulmonary minute ventilation, but not respiratory rate (20). In contrast to increases in arterial pressure oscillations, CBF velocity fluctuations remained unchanged in the low- and high-frequency ranges. Thus, contrary to our hypothesis, the effect of damping the transfer from arterial pressure oscillations to CBF velocity fluctuations would be ameliorated in these frequency ranges during mild +Gz hypergravity. In fact, transfer function gain as the index of magnitude of transfer from arterial pressure to CBF velocity decreased with unchanged coherence in these frequency ranges. Decreases in arterial carbon dioxide may exert positive influences on dynamic CBF autoregulation (1, 7, 25). If mild +Gz hypergravity reduced PaCO2 as indicated by reduced ETco2, lower PaCO2 may induce the decreases in transfer function gain in the present study. Rosenhamer's report (31) of reduced PaCO2 at 3 Gz supports this possibility. However, it is also possible that the result at high frequency is partially achievable under the influence of respiratory changes to CBF fluctuations without changes in dynamic cerebral autoregulation. For example, fluctuations in intracranial pressure mechanically induced by respiration may cause CBF fluctuation at the respiratory frequency independent of arterial pressure oscillations. No clear conclusions can be drawn, since the present study did not attempt to elucidate the mechanisms underlying changes in dynamic cerebral autoregulation. However, we speculate that improvements in dynamic cerebral autoregulation may have been due to compensatory effects against reductions in steady-state CBF during mild +Gz hypergravity. Improved or normal rather than impaired dynamic cerebral autoregulation is possibly a common phenomenon to compensate for gravitational declines in steady-state CBF as observed in nonsyncopal astronauts (3, 16).

Limitations.

Transcranial Doppler ultrasonography was used for noninvasive and beat-to-beat estimation of CBF in the present study. This approach is based on the assumption that the diameter of the insonated MCA changes minimally and CBF velocity in the MCA is directly proportional to the global CBF. The results obtained using this technique should thus be interpreted with caution, since we observed the changes in blood flow velocity at MCA rather than changes in cerebral blood flow. However, previous studies have confirmed that changes in CBF in MCA velocity are actually proportional to global CBF as measured by single-photon emission computed tomography scanning (23) or 131Xe clearance technique (2) or internal carotid artery flow using an electromagnetic flowmeter (24, 26). Moreover, the large cerebral arteries are like a conduit rather than a resistance artery (13) and a constant diameter in the proximal segment of the MCA has been confirmed during hypocapnia with hyperventilation (35, 42), hypo- and hypertension (23), or other stimuli (10, 35). Another limitation of the present study was the use of ETco2, which is not perfectly equivalent to PaCO2 (29). We cannot exclude the possibility of overestimated or false decreases in ETco2 due to increases in physiological dead space (both of anatomical and alveolar dead space) following footward shifts in the thoracic diaphragm and lung blood flow.

In conclusion, the present result of reduced MCBFV indicates that the steady-state global CBF was reduced even during mild +Gz hypergravity. The reduction in global CBF may be induced by reduced cerebral perfusion pressure, cardiac output, and/or arterial CO2 during centrifugation. Since even a mild degree of hypergravity can reduce global CBF, careful monitoring of the subject is necessary for these experiments or countermeasures against post-flight deconditioning. Contrary to the decreased MCBFV, the present results of spectral and transfer function gain between MAP and MCBFV indicate that dynamic cerebral autoregulation was improved with stabilization of CBF fluctuations despite increases in arterial pressure oscillations in low- and high-frequency ranges. Reductions in steady-state global CBF may thus be partially compensated for by improvements in dynamic cerebral autoregulation during mild +Gz hypergravity.

GRANTS

This study was supported by The Uehara Memorial Foundation.

DISCLOSURES

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

AUTHOR CONTRIBUTIONS

Author contributions: K.I. conception and design of research; K.I., Y.O., K.A., and R.Y. performed experiments; K.I. and Y.O. analyzed data; K.I. and Y.O. interpreted results of experiments; K.I. prepared figures; K.I. drafted manuscript; K.I., Y.O., K.A., and R.Y. edited and revised manuscript; K.I., Y.O., K.A., and R.Y. approved final version of manuscript.

ACKNOWLEDGMENTS

We thank Drs. J. Kato and S. Ogawa for their support during the project.

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