Systemic blood distribution is an important factor involved in regulating cerebral blood flow (CBF). However, the effect of an acute change in central blood volume (CBV) on CBF regulation remains unclear. To address our question, we sought to examine the CBF and systemic hemodynamic responses to microgravity during parabolic flight. Twelve healthy subjects were seated upright and exposed to microgravity during parabolic flight. During the brief periods of microgravity, mean arterial pressure was decreased (−26 ± 1%, P < 0.001), despite an increase in cardiac output (+21 ± 6%, P < 0.001). During microgravity, central arterial pulse pressure and estimated carotid sinus pressure increased rapidly. In addition, this increase in central arterial pulse pressure was associated with an arterial baroreflex-mediated decrease in heart rate (r = −0.888, P < 0.0001) and an increase in total vascular conductance (r = 0.711, P < 0.001). The middle cerebral artery mean blood velocity (MCA Vmean) remained unchanged throughout parabolic flight (P = 0.30). During microgravity the contribution of cardiac output to MCA Vmean was gradually reduced (P < 0.05), and its contribution was negatively correlated with an increase in total vascular conductance (r = −0.683, P < 0.0001). These findings suggest that the acute loading of the arterial and cardiopulmonary baroreceptors by increases in CBV during microgravity results in acute and marked systemic vasodilation. Furthermore, we conclude that this marked systemic vasodilation decreases the contribution of cardiac output to CBF. These findings suggest that the arterial and cardiopulmonary baroreflex-mediated peripheral vasodilation along with dynamic cerebral autoregulation counteracts a cerebral overperfusion, which otherwise would occur during acute increases in CBV.
- arterial pressure
- cerebral blood flow
- cardiac output
previous studies have demonstrated that increases in central blood volume (CBV) directly increase cerebral blood flow (CBF) (4, 33). During spaceflight, acute transition from 1 g to microgravity causes a venous translocation of blood from lower segments of the body to the upper body along with increases in the volume of the closed chest cavity (3, 62), which results in an increase in CBV (29, 42, 55). These increases in CBV increase cardiac preload, stroke volume (SV), and cardiac output (CO) (27). Therefore, during rapid decreases and increases in CBV associated with parabolic flight, the acute changes in microgravity will modulate CBF regulation. Indeed, it is well known that the microgravity-induced cephalad shifts in blood volume causes facial puffiness (1). Moreover, Norsk et al. (28) recently suggested that the spaceflight-induced vision impairment syndrome is currently one of the major clinical concerns encountered following space flight.
Lower body negative pressure-induced decreases in CBV reduces CBF (31). However, techniques used to alter CBV in ground-based 1 g studies; water immersion (4), albumin infusion, and lower body negative pressure (33) require the establishment of steady-state increases or decreases in CBV before accurate measures of the change in CBF can be made. During the acute (1 to 10 min) transition from 1 g to the microgravity of low orbital space, central venous pressure decreases as a result of thoracic volume expansion, which causes larger increases in CBV, SV, and CO than those observed during microgravity in space (62). In addition, the ground-based simulation models have indicated that natriuresis and diuresis seek to return an initial increase in CBV back to preintervention volumes (18, 29). Therefore, the effect of acute changes (>20–30 s) in CBV on CBF regulation associated with the rapid changes between 1 g and microgravity obtained during parabolic flight remains unclear. Because an acute change in CBV distribution activates arterial and cardiopulmonary baroreflexes, identification of the CBF response to acute changes in CBV requires dynamic measurements of the changes in CBF and the use of linear dynamic analysis techniques to analyze the changes, instead of the steady-state measures used previously.
Parabolic flight using jet aircraft permits the study of the earliest phase of the transition from ∼1.8 g to microgravity in humans (25). Parabolic flight-induced microgravity abolishes gravitational fluid-pressure gradients and, thus, induces increases in CBV as a result of the relocation of the blood from the lower limbs to an increased thoracic cavity (19, 25, 30, 61). It has been reported that during parabolic flight, left atrial diameter and transmural central venous pressure increased to values above those of the 1 g in the supine position (30, 61), while the decrease in intrathoracic pressure created a negative pressure around the heart and central vessels, resulting in an augmented cardiac filling (61). Johns et al. (19) evaluated cardiac filling and ejection properties of human subjects by Doppler echocardiography during parabolic flight and reported that right ventricular filling velocities rose significantly in the sitting position during microgravity, indicating a large and immediate augmentation of venous return to the right ventricle. In addition, the parabolic flight-induced changes in CBV affected hemodynamic factors, i.e., increases in heart rate (HR) and CO and decreases in arterial blood pressure (23–25, 43). In summary, parabolic flight provides a unique opportunity for investigators to rapidly change an individual's CBV. Previously, Bondar et al. (2) were the first to measure CBF velocity in humans during parabolic flight using transcranial Doppler (TCD). This previous work demonstrated the repeatability of TCD measurement during parabolic flight and identified that the phase lag in the TCD waveform induced by acceleration was affected by body position. Unfortunately, this previous study described the differences between CBF velocities at baseline and during microgravity without statistical analysis. Therefore, the influence of the earliest phase of transition to microgravity (acute central hypervolemia) on CBF remains to be identified. Since the acute increase in CBV during parabolic flight also loads the cardiopulmonary and arterial baroreceptors simultaneously during each parabola, as well as the loading of carotid baroreceptors by change in hydrostatic pressure, the CBF response to an acute hypervolemic condition is likely to be different from that observed during the steady-state central hypervolemic conditions reported previously (4, 33). We tested the hypothesis that the rapid and large increases in CBV and cerebral perfusion pressure would result in an overperfusion of the brain during the microgravity phase of each flight parabola.
MATERIALS AND METHODS
Twelve healthy men with a mean age of 26 ± 6 yr old (mean ± SD), height 176 ± 4 cm, and weight 72 ± 11 kg volunteered for this study. Each subject provided written, informed consent after all potential risks and procedures were explained. All experimental procedures and protocols conformed to the Declaration of Helsinki and were approved by the French Institutional Ethics Committee (Comité de Protection des Personnes Nord-Ouest 3). The subjects were considered physically active but not trained since they did not perform endurance training on a regular basis (<5 h/wk). In addition, they were free of any known cardiovascular and pulmonary disorders and were not using any prescribed medication. Prior to formal experimentation, each subject was familiarized with the techniques and procedures. They were requested to abstain from caffeinated beverages for 12 h and strenuous physical activity and alcohol for at least 24 h before the day of the experiment.
The study was performed during two parabolic flight campaigns supported by the French space agency (Centre National d'Etudes Spatiales or CNES; n = 12). Each campaign was conducted aboard the Airbus A300-ZERO G aircraft (Novespace) and consisted of three flights with one flight per day. The subjects were selected among volunteers less susceptible to motion sickness. Also, those not instrumented were kept in a supine position until the beginning of the experiment. However, some subjects were not able to continue recordings after four or five parabolas due to nausea. Although the sample size (n = 3) of sick subjects was small we “post hoc” compared the response of the MCA Vmean to microgravity of the sick subjects before feeling nauseous to those of the nonsick subjects. Each flight lasted 2.5 to 3 h and included 31 parabolas. Each parabola was composed of three phases of ∼20 s of hypergravity (1.8 g; pull-up phase), 20 s of microgravity (0 g; injection phase), and again 20 s of hypergravity (1.8 g; pull-out phase). Then, a return to normal gravity (1 g) was observed for 2 min before the following parabola. Two subjects per flight were studied. The first subject was tested during the first 15 parabolas. The second subject was instrumented between two parabolas, i.e., between the parabolas 15 and 16, and followed the same procedure as the first subject. During each test session, the subjects were seated upright, attached on a seat, and stayed relaxed with eyes closed. The average response of the hemodynamic variables measured during each subject's 15 parabolas was used to analyze the hemodynamic responses.
Arterial blood pressure (ABP) and HR were continuously measured using an automatic arterial pressure monitor using finger photoplethysmography (Finometer Pro, FMS, Amsterdam, Netherlands). The finger cuff was placed and adapted to the size of the middle finger on the right hand. This device was equipped with a hydrostatic height correction system placed between the finger cuff and the heart reference level. Moreover, an additional upper arm cuff circuitry was used to perform a “Return-to-Flow” calibration of the brachial waveform by measuring the systolic pressure in each individual subject. Pressure values provided by this type of device do not significantly differ from those taken directly from the radial artery in subjects in various physiological conditions (41), and there is good agreement in the evaluation of beat-to-beat variations (22).
Blood flow velocity in the left MCA V was determined by TCD ultrasonography (WAKI, Atys Medical, Soucieu-en-Jarrest, France). A 2-MHz Doppler probe was placed over the temporal ultrasound window and fixed with an adjustable headband and adhesive ultrasonic gel (Tensive, Parker Laboratories, Orange, NJ). To gain an optimum Doppler signal, the position and angle of the TCD probe were initially adjusted at the same depth for all subjects; optimization of the gain and power intensity of the signal was then modified accordingly for each subject. Thoracic impedance was measured by using a tetra polar high-resolution impedance meter (THRIM 2994D, UFI, Morro Bay, CA) connected to two pairs of Ag/AgCl electrocardiogram electrodes. Injections electrodes were placed on the left sternocleidomastoid muscle and left foot, and measuring electrodes were placed inside the electric field, at the clavicular level and xiphoidal process, to assess the impedance across the thorax (40). The absolute values of thoracic impedance data are variable, as the individual's impedance value is related to the subject's body size, etc. However, the change in impedance between each gravitational condition quantifies the change in CBV. Because of the small number of subjects (n = 7), we elected to provide an average representative data set of all of the subjects, where the measurement was not compromised during the parabolic maneuvers. Expired air was sampled breath-by-breath, and end-tidal partial pressure of carbon dioxide (PetCO2) was measured with a gas analyzer system (Microcap, EtCO2, Oridion, Needham, MA) and a CO2 nasal cannula (Smart CapnoLine Plus, Covidien, Boulder, CO).
All data were sampled continuously at 1 kHz using an analog-to-digital converter interfaced with a computer using dedicated acquisition software (NOTOCORD-hem 3.5, NOTOCORD Systems, Croissy-sur-Seine, France). Beat-to-beat systolic, diastolic, and mean arterial pressures (SBP, DBP, MAP) and pulse pressure (PP) were acquired. Central arterial pressure was estimated from finger arterial pressure waveforms at the stable segment in the last 10 s of each phase of the parabola via a general transfer function (GTF) using the commercialized software (SphygmoCor software, AtCor Medical, Sydney, Australia) (58). Since this GTF was for the radial arterial pressure waveform, the validity of applicability was confirmed prior to this experiment. SV was calculated off-line from the arterial pressure waveforms using a Modelflow software program incorporated into BeatScope version 1.0 software (TNO-TPD, Biomedical Instrumentation, Amsterdam, The Netherlands). Cardiac output (CO) was calculated from the product of SV and HR. Total vascular conductance (TVC) was calculated as CO divided by MAP. Beat-to-beat mean MCA V (MCA Vmean) was obtained from MCA V waveform. The contribution of CO to CBF was expressed as MCA Vmean divided by CO (MCA Vmean/CO). Normalized MCA Vmean/CO and TVC was calculated as each value divided by the baseline value. The estimated cerebral perfusion pressure (CPP) at the MCA level or carotid sinus pressure (CSP) took into consideration the vertical distance from the fourth intercostal space in the mid-clavicular line (heart level) to the temple or carotid bifurcation level (i.e., hydrostatic pressure = the vertical length/1.36 × gravity). The 10 s preceding the onset of each parabola was averaged as baseline data. By design, the parabolic flight included the hypergravity periods before and after microgravity (for 20 s each). The response of hypergravity on CBF or systemic circulation may affect microgravity influences. To account for this interaction, the data of the final 10 s of the first and second hypergravity sequences were also analyzed as Hyper 1 and Hyper 2 conditions. The first (Micro 1) and last (Micro 2) 10 s of microgravity were analyzed separately. Recovery data were averaged from the initial 10 s immediately after the Hyper 2 period. The averaged data of selected trials (parabolas), which have the best MCA V signal, were used for data analyses.
Estimation of central arterial pressure.
58). Central arterial pressure waveforms computed from radial and digital arterial waveforms were calibrated with oscillometry-derived brachial systolic and diastolic pressures.
Validity of central arterial pressure estimation.
Central arterial systolic and diastolic, and PP computed from finger arterial pressure waveform strongly correlated with those obtained from simultaneously recorded radial arterial pressure waveforms in both sitting and standing positions (r > 0.99 for all). Average differences (± SD) of two measures were −1.0 ± 0.5 and −0.9 ± 0.6 mmHg in sitting and standing central arterial SBP, −0.4 ± 0.6 and −0.3 ± 0.7 mmHg in sitting and standing central arterial DBP, and −0.6 ± 0.7 and −0.6 ± 0.8 mmHg in sitting and standing central arterial PP. All individual plots ranged within 95% confidence intervals (i.e., ± 1.96 SD). These results suggest the superior applicability of the GTF on finger arterial pressure wave for predicting aortic hemodynamics.
Analyses were conducted using SigmaStat (Jandel Scientific Software, SPSS, Chicago, IL). One-way repeated-measures ANOVA was used to determine the effect of condition (Baseline, Hyper 1, Micro 1, Micro 2, Hyper 2, and Recovery) on the responses. In the case of a significant F value, a post hoc Student-Newman-Keuls test was used to identify significant differences. Correlational analysis was performed to determine the relation between two variables of interest. In addition, the comparison in MCA Vmean response between sick and nonsick subjects was performed by using Mann-Whitney rank sum test. Data are expressed as means ± SD. Statistical significance was set a priori at P < 0.05.
Hemodynamic responses to brief periods of microgravity.
Thoracic impedance, as an index of CBV, was decreased during microgravity (Fig. 1A), indicating that microgravity acutely caused central hypervolemia. Also, the thoracic impedance-averaged data (n = 7) was reduced from control (337 ± 40 Ω) to Micro 1 (326 ± 40 Ω, P = 0.089) or Micro 2 (324 ± 39 Ω, P = 0.06). Similarly, SV, CO, and central PP, other indices of central blood volume, were also increased by microgravity (0 Gz) (Figs. 2 and 3). These data identify that the repeated flight parabolas are a profile of reproducible changes in CBV.
The change in CBV that occurs in the parabolic flight's period of microgravity (0 Gz) increased TVC, while HR and MAP were decreased from Hyper 1 (Table 1 and Figs. 1–3). These changes were emphasized with time during microgravity (from Micro 1 to Micro 2), except for HR. In addition, peripheral and central arterial PP increased largely at Micro 1 and decreased to baseline values at Micro 2 (Fig. 3), while the MCA Vmean and PetCO2 were unchanged throughout microgravity (Micro 1 and 2). The lower PetCO2 value of the present study was probably associated with the hypobaric condition inside the aircraft, as the inside pressure of aircraft (cabin pressure) during flight was maintained at 835 mbar (∼1600 m altitude level). Since microgravity reduces the hydrostatic pressure gradients within an upright seated position, the estimated CPPs and CSPs were acutely increased (Figs. 1 and 3). However, the contribution of CO to MCA Vmean was gradually decreased during the period of microgravity. The central-peripheral PP ratio increased throughout microgravity and returned to baseline values at Hyper 2. In the present study, three subjects who complained of nausea were unable to continue after the fourth or fifth parabola. Before feeling nauseous, the change in CBF from baseline to Micro 1 in the sick subjects was not different (P = 0.5), but from baseline to Micro 2 was different (−18 ± 3%) compared with the nonsick subjects (+2 ± 4%) (P = 0.062).
Cerebral and systemic blood flow responses to brief periods of microgravity.
The changes in central arterial PP from Hyper 1 to Micro 1 related to the corresponding decreases in HR (r = −0.888, P < 0.0001, Fig. 4). The change in central arterial PP from Hyper 1 to Micro 1 were not significantly correlated with the corresponding change in TVC from Hyper 1 to Micro 1 (r = 0.397, P = 0.202) but was significantly correlated with the change in TVC from Micro 1 to Micro 2 (r = 0.711, P < 0.001). The TVC gradually increased during microgravity along with an increasing CO. However, during Micro 2, the increase in TVC was much larger than that of CO (P < 0.001, TVC vs. CO; +44 ± 8% vs. +20 ± 6%, respectively; Figs. 2 and 5). In addition, the contribution of CO to MCA Vmean was negatively correlated with the increase in TVC throughout microgravity during parabolic flight (r = −0.683, P < 0.0001, Fig. 5).
During the brief periods of microgravity (20 s) induced by parabolic flight, the acute decrease in the hydrostatic pressure gradients resulted in increases in CBV and, thus, CO in upright seated humans. This result is consistent with the previously reported parabolic flight studies (19, 24, 29, 30, 43, 61). However, an unexpected finding was that the acute and large increase in central hypervolemia did not increase MCA Vmean throughout parabolic flight, indicating that the CBF responses were different from those observed to the increased CBF during steady-state central hypervolemia (4, 33). On the other hand, the large decreases in MAP and increases in TVC that occurred during microgravity were a result of marked peripheral vasodilation. In addition, the large increase in TVC was significantly correlated with the increase in central arterial PP during microgravity, indicating that the acute microgravity-induced increases in CO, as a result of the increases in CBV, were preferentially distributed more to the dilated systemic vasculature via arterial and cardiopulmonary baroreflex-mediated changes in peripheral vascular tone. Interestingly, the contribution of Q to MCA Vmean was gradually decreased during microgravity and were negatively correlated with the increase in TVC throughout microgravity during parabolic flight (r = −0.683, P < 0.0001, Fig. 5). These findings suggest that the rapid onset of systemic vasodilation via arterial and cardiopulmonary baroreflex activity, as well as dynamic cerebral autoregulation during the brief periods of microgravity prevents the cerebral overperfusion that is usually associated with rapid increases in CBV and CPP in the 1 g environment.
In the human, increases and decreases in steady-state CBV and/or CO in the 1 g environment result in increases and decreases in CBF, respectively (33). In addition, in the 1 g environment, increases and decreases in steady-state CBV decrease and increase central sympathetic outflow (5) and modulate arterial baroreflex regulation of ABP via the loading and unloading of the cardiopulmonary baroreceptors (32, 40). In the short period of microgravity obtained during parabolic flight, the resultant increases in left atrial diameter and transmural central venous pressure identifies an augmented filling of the heart (43, 61). These data confirm that the parabolic flight-induced microgravity environment employed in our investigation would have resulted in an acute increase in ventricular transmural wall pressure. Indeed, in the present study, peripheral and central arterial PP increased largely at Micro 1 despite a decrease in MAP (Fig. 3). It is well established that this increase in transmural wall pressure of the heart stimulates cardiopulmonary baroreceptors, resulting in peripheral vasodilation (9, 10). Usually the loading of the cardiopulmonary baroreceptors does not alter HR (20, 32, 40, 60), but in the present study, the microgravity condition induced a decrease in HR and was significantly associated with the increase in central arterial PP (Fig. 4). Thus, the parabolic flight induced acute central hypervolemia most likely stimulated the arterial baroreceptors simultaneously with the cardiopulmonary baroreceptors. The presence of a significant correlation between the increase in central arterial PP and the increase in TVC supports the concept of a microgravity-induced loading of the arterial and cardiopulmonary baroreceptors, inhibiting central sympathetic outflow (7). Importantly, the aortic baroreceptors respond to changes in mean pressure only, whereas the carotid baroreceptors respond to both mean and pulse pressure (17). Therefore, these significant associations between changes in central arterial PP and HR or TVC may only identify changes associated with carotid baroreflex function.
In addition, during acute microgravity, the estimated CSP was acutely increased by microgravity-induced reductions in hydrostatic pressure (Fig. 3). Thus, the reductions in hydrostatic pressure at the carotid sinus, as well as the increased loading of the aortic and cardiopulmonary baroreceptors, result in the observed peripheral vasodilation. The peripheral vasodilation associated with the changes in CBV appear to be similar to the changes in myogenic tone identified by Sheriff et al. (54) during rapid tilting-induced changes in CBV. Thus, in the present study, acute and large increases in CO along with an increase in CO's contribution to TVC appears to have an important impact on the contribution of the myogenic responses of the peripheral vasculature.
Cerebral blood flow.
In humans, a change in posture from the upright to the supine position in the 1-g environment increases cerebral blood flow (CBF) (38, 47). In addition, decreases and increases in CO decrease and increase CBF, respectively, in the semirecumbent posture (33). On the other hand, during orthostatic stress in the 1-g environment, unloading of the cardiopulmonary and arterial baroreceptors induces vasoconstriction in the peripheral vasculature and counteracts the expected decrease in CBV and, thereby, prevents syncope (40). These findings indicate that CBF is significantly affected by mechanisms involved in systemic vascular regulation, especially resulting from changes in CBV that invoke baroreflex alterations of CO and TVC. Bondar et al. (2) were the first to have measured CBF velocity in humans during parabolic flight using TCD measurement. In the present study, during the microgravity-induced increases in CO and CPP, we expected to observe an increase in the MCA Vmean similar to the CBF response to infusion of human serum albumin (33). Our data were similar to that described by Bondar et al. (2), who observed that at the onset of microgravity, there was a large increase in CBF (Fig. 1). However, our data additionally indicate that the CBF quickly decreased back to baseline and maintained its value to the end of the period of microgravity. Thus, the 10-s average of the MCA Vmean was unchanged (Fig. 2). This unexpected CBF response to the parabolic flight profile was most likely a result of the large increase in TVC. The increase in TVC was significantly correlated with changes in central arterial PP (Fig. 4). These findings strongly indicate that the larger systemic peripheral vasodilation resulting from the acute loading of the arterial and cardiopulmonary baroreceptors was a result of the increased CBV. The percent increase in TVC was markedly larger than that of CO (Fig. 5). In addition, the contribution of CO to MCA Vmean was gradually decreased during microgravity, and this response was correlated negatively with the increase in TVC throughout microgravity (r = −0.683, P < 0.0001, Fig. 5). Therefore, these findings of the present study indicate that redistribution of the blood volume into the peripheral vascular beds (baroreflex-mediated change in systemic blood volume distribution) is one physiological mechanism that prevents the cerebral overperfusion. However, in the present study, the increases in CO were much smaller than that caused by the infusion of human serum albumin (33). Thus, we cannot rule out the possibility that the small increases in CO were insufficient to affect MCA Vmean during microgravity. In contrast during water immersion, similar increases in CO (+20%), as those observed in the present study occurred, and yet during water immersion, the CBF was significantly increased (4).
In contrast to our findings, Schneider et al. (49) demonstrated that microgravity resulted in an increase in the oxyhemoglobin of the near-infrared spectroscopy (NIRS) signal during parabolic flight and suggested that microgravity increased arterial blood flow to the brain. However, many recent investigations (14, 15, 37, 39, 56, 57) indicate that a major limitation of the NIRS signal identifying changes in intracranial blood flow is confounded by the NIRS signals being affected by changes in skin blood flow. Indeed, the microgravity-induced cephalic shift in blood volume causes facial puffiness (1). Interestingly, Ogoh et al. (37) demonstrated that changes in external blood flow affected intracranial blood flow regulation; thus, if the microgravity period of the parabola increased external carotid blood flow, it also would have prevented overperfusion of the brain.
Recent evidence indicates that α1 adrenergic receptors (34, 44) and muscarinic receptors (51) play a functional role in regulating CBF during orthostasis and exercise. These findings indicate that it is the cerebral vascular tone that determines CBF responses to cerebral hyperperfusion or hypoperfusion conditions. Therefore, the differential response observed between the cerebral and systemic vasculature in the present study may be explained by the greater autoregulatory (myogenic) and adrenergic receptor vasoconstrictive properties of the cerebral blood vessels compared with systemic blood vessels (46). In the present study, the estimated cerebral perfusion pressure at the MCA was acutely and largely increased during microgravity despite a decrease in MAP (Figs. 1 and 3). Recently, it has been demonstrated that cerebral autoregulation is not impaired during acute changes in CBV (63). Therefore, dynamic cerebral autoregulation would respond rapidly to the acute changes in CPP and subsequently maintain MCA Vmean constant during the brief periods of microgravity. Another possible explanation of the unchanged MCA Vmean during microgravity is that the vestibular system, which is known to affect the sympathetic activity (26, 45), is activated differently during orthostatic stress compared with that observed in the change from 1 g to the microgravity environment.
It is important to understand the response of CBF to acute and chronic changes in CBV (e.g., nausea, the vision impairment syndrome, etc.) in space medicine. For example, the findings of a previous study (53) indicated that cerebral hypoperfusion provides early warning of the onset of nausea in susceptible individuals. The investigators demonstrated that reductions in CBF precede the development of nausea. Similarly, in the present study, the three nauseous subjects had a greater reduction in CBF during microgravity compared with the nine nonnauseous subjects. These data appear to indicate that subjects with systemic vasculatures sensitive to rapid changes in CBV may be more likely to suffer from motion sickness during microgravity. Indeed, the TVC response to microgravity was higher in the nauseous subjects than the nonnauseous subjects (+50% vs. +39%). Confirmation of this hypothesis will require a greater number of subjects to be exposed to the rapid changes in gravitational forces.
There are some technological considerations that merit clarification. First, a potential limitation of estimating CBF using transcranial Doppler ultrasonography is that vasoconstriction of the insonated vessel increases MCA Vmean at any given volume of flow. Some previous human studies (50, 52) have demonstrated that the MCA diameter appears to remain relatively constant under a variety of autonomic neural challenges. In contrast, a recent report (8) identified that transcranial Doppler-determined cerebral blood velocity underestimates changes in CBF by 7–18%. In the present study, we contend that measured MCA Vmean may reflect the CBF response because there was no change in MCA Vmean during parabolic flight. In addition, acute microgravity-induced body movements may have caused movement artifacts that affect the transcranial Doppler signals. However, many previous studies (33, 35, 36, 48) measured transcranial Doppler signals accurately during heavy dynamic exercise-induced whole body movements. Moreover, throughout the parabolic flight, the waveform of MCA V was well maintained (Fig. 1B), indicating that the effect of the subject's movements were negligible. Another concern that needs to be considered is that the Modelflow's estimation of SV may be subject to error, as it has been reported that the average Modelflow value of SV during head-up tilt when the change in SV is small is variable (13). However, the Modelflow-estimated cardiac outputs have been shown to be significantly correlated with simultaneous Doppler-estimated CO (59). In addition, a previous report (16) used the relative changes in Modelflow-estimated CO to identify the effect of cardiac output on MCA Vmean during exercise. Some studies (11) estimated CO by Modelflow during parabolic flight. In addition, Limper et al. (21) compared CO between different methods (rebreathing, impedance, pulse contour methods) and suggested that the pulse contour method can be validly used to track cardiac output dynamics during parabolic flight. These findings suggest that relative changes in Modelflow-estimated CO during parabolic flight provided reliable information regarding the changes in CO. However, a more recent study (12) reported that Modelflow underestimated stroke volume during acute increase in TVC induced by infusion of vasoactive drug (isoprenaline). If Modelflow underestimates the change in stroke volume during microgravity, the actual change in TVC is much larger in the present study. Also, to compute aortic blood pressure, the established GTF (i.e., aorta-radial artery) was applied on finger arterial pressure waveforms measured by photoplethysmography, which was conducted for the stable recording of arterial pressure. The superior applicability of the GTF on finger arterial pressure waveform for predicting aortic hemodynamics was confirmed by the validation study prior to this experiment. The validity of general transfer function for estimation of central arterial pressure from radial arterial pressure waveforms has been confirmed not only at steady state but also during hemodynamic transients (e.g., Valsalva maneuver, abdominal compression, nitroglycerin, vena caval obstruction) (6). Prior to this study, we confirmed the validity of aortic pressure estimation from finger arterial pressure in both sitting and standing positions. However, its accuracy during hemodynamic transients has never been examined. Finally, in the present article, we focused on the effect of microgravity-induced central hypervolemia on CBF and observed that the parabolic flight profile caused hypergravity before microgravity. Therefore, we cannot rule out the possibility that the changes in circulation during 0 Gz after exposure to ∼1.8 Gz are different or not different from the changes observed during 0 Gz after 1 Gz.
Perspectives and Significance
In contrast to our hypothesis, MCA Vmean was unchanged during the brief periods of microgravity despite an increase in the CO. Because there was a significant correlation between the increase in central arterial PP and the increase in TVC or decrease in HR during microgravity, we conclude that the increase in TVC was a result of the increased CBV associated with microgravity loading the arterial and cardiopulmonary baroreceptors. Since the contribution of CO to MCA Vmean was gradually decreased during microgravity and this response was correlated negatively with the increase in TVC throughout microgravity, we concluded that these changes in systemic blood volume distribution, as well as dynamic cerebral autoregulation prevents hyperperfusion of the brain during brief periods of microgravity in humans when seated upright.
No conflicts of interest, financial or otherwise, are declared by the authors.
Author contributions: S.O. and H.N. conception and design of research; S.O., A.H., J.S., and H.N. analyzed data; S.O. interpreted results of experiments; S.O. prepared figures; S.O. drafted manuscript; S.O., P.B.R., P.D., J.S., and H.N. edited and revised manuscript; S.O., A.H., P.B.R., T.R., P.D., R.L., J.S., and H.N. approved final version of manuscript; T.R., P.D., R.L., and H.N. performed experiments.
The authors appreciate the time and effort invested by the volunteers. The research leading to these results has received funding from the People Programme (Marie Curie Actions) of the European Union's Seventh Framework Programme FP7/2007-2013/under REA grant agreement no. 318980. This work was supported by Centre National d'Etudes Spatiales.
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