Special aspects of the cardiovascular system regulation and cerebral blood flow under gravitational influences. Review (part 2)

Evgeny Yu. Bersenev, Polina N. Demina, Diana E. Kaurova, Irina A. Berseneva, Rustem R. Kaspransky. Special aspects of the cardiovascular system regulation and cerebral blood flow under gravitational influences. Review (part 2). Cardiome-try; Issue 31; May 2024; p. 198-207; DOI: 10.18137/cardiome-try.2024.31.198207; Available from: https://www.cardiometry. net/issues/no31-may-2024/special-aspects-cardiovascular

Long-term research in the field of space medicine has established that space flight conditions have a multifactorial effect on the human body, the adverse effects of which can be traced at the level of functional and structural changes in almost every organ or system. These are mainly the effects of microgravity, cosmic radiation, hypokinesia and disruption of habitual circadian rhythms [1]. Due to the absence of a gravity vector, the insufficiency in hydrostatic pressure gradients occur; the shift of human fluids to the head is considered the main factor contributing to changes in hemodynamic parameters [2]. A set of characteristic neurological symptoms are observed at the initial stage of space missions, at the stage of adaptation, and also manifests itself upon return to Earth in the form of post-flight headache, dizziness, orthostatic instability with presyncope, impaired cognitive function, as well as the manifestation of syndromes of visual impairment and intracranial pressure (VIIP) [3-6] and space neuroocular syndrome (SANS) [7]. The previous review is shown the aspects of the reflex responses of the cardiovascular system to the effects of weightlessness and its modeling [9]. Continuing the theme, the authors hope to make interest about the information of the reactions of cerebral blood flow, features of orthostatic reactions and disturbances in the regulation of wakefulness-sleep cycles in microgravity conditions and its ground-based models.

WEIGHTLESSNESS AND GROUNDBASED MICROGRAVITY MODELLING

Under terrestrial conditions, the most common way to simulate changes in hemodynamic parameters under conditions of weightlessness is antiorthostatic hypokinesia or the more common international designation as head down bed rest (HDBR), which consists in positioning the human body on the bed at an angle of inclination of the head end of -6° [9-15]. To create conditions for different speeds of fluid shift of organism, the higher angles of inclination are used to the head: including -12° and -18°; however, an angle of -6° is used to simulate long-term microgravity modelling. It has been proven that this method allows one to effectively simulate and study hemodynamic changes in the human body over a long period of time (up to 1 year or more) [16-18].

Another way to simulate the effects of microgravity involves placing a person in a prone position, essentially in the so-called, at «embryo» position – «dry» immersion (DI). Versus to HDBR, the volunteers are immersed at armpit level in water with a constant temperature of 32-34°C. The human is separated from direct contact with moisture by a waterproof film, the area of which is several times greater than the surface area of the water. Thus, it is possible to conduct model studies from 1 to 30 days to quickly achieve the effects of microgravity simulation [19]. Despite the fact that under conditions of a DI the position of the body is close to horizontal, the forces of hydrostatic pressure on the body, «wrapped» by the volunteer’s film, equally «compress» all its parts (except the head and neck).

Both HDBR and DI, used to study the effects of microgravity, reproduce the effects of hypokinesia, even to a greater extent than space flight itself. The main difference between the two methods is the factor of combination of hypokinesia with redistribution of blood to the cranial region under conditions of HDBR and developing sensory deprivation under conditions of DI.

RESEARCH IN SPACE FLIGHT CONDITIONS, IN THE PRE-AND POST-FLIGHT PERIOD AND IN SIMULATED MICROGRAVITY CONDITIONS

Magnetic resonance imaging studies of the brain, angiography and cerebrospinal fluid dynamics

In recent years, a number of fundamental studies have been devoted to an in-depth study of the structural and functional changes in the human brain in weightlessness. Under microgravity conditions, the brain undergoes changes that result in a decrease in the volume of gray matter in some areas and an increase in the volume of white matter in others. Moreover, the brain structure is almost completely restored a year after the end of the flight [20]. Generally, a decrease in the amount of gray matter was observed in the temporal and frontal lobes, in contrast to a slight increase in white matter in the sensorimotor areas, which are associated with control of movement, maintaining balance, and perception of body position [21]. There was also movement of cerebrospinal fluid and an increase in the volume of the ventricles of the brain.

There is [22-23] an increase in the volume of cerebrospinal fluid at the border of the lateral and third ventricles after space flight. With these changes, according to scientists, significant neurocognitive impairments do not occur, since with a very large amount of work carried out by cosmonauts and astronauts on board, cognitive functions do not suffer significantly. The data obtained on the emergence of neural connections between several motor areas of the brain during long-term expeditions to the International Space Station (ISS) allow us to focus on the development and creation of means for the prevention of movement disorders. On the other hand, there are a number of risk factors unrelated to this problem that cosmonauts experience starting from the stage of acute adaptation to space flight conditions, within six-month orbital missions and, in the future, during long-term interplanetary flights.

Results from studies of fMRI data before, after, and 8 months after long-duration spaceflight in 13 Russian cosmonauts, published by Jillings, S., et al. in 2023, show persistent decreases in connectivity in the posterior cingulate cortex and thalamus and persistent increases in the right angular gyrus [24]. Connectivity in the bilateral insular cortex decreased after spaceflight, but this effect was no longer observed at follow-up. The study shows that the altered gravitational environment affects longitudinal functional connectivity in multimodal brain centers, reflecting adaptation to unfamiliar and conflicting sensory information in microgravity.

Studies of fluctuations in endogenous blood oxygenation using fMRI and infrared spectroscopy have shown that endogenous, non-neural fluctuations in hemodynamic parameters account for 30% of the variation in gray matter [25]. In this regard, to study hemodynamic parameters of cerebral blood flow, it makes sense to conduct a hypercapnic test during fMRI.

A model of the existence of coherent relationships between the heart and brain is described; it describes structural and functional networks that neurofunctional connect the nuclei of the brain stem, solitary tract, hypothalamus and amygdala, as well as areas of the prefrontal cortex that ensure the functioning of the cardiovascular system, probably in interaction with the respiratory system, as well as with other body systems (for example, reflection of vestibulo-sympathetic coordination) [26-30].

Orthostatic tolerance before- and after space flight and on-ground models

The muscle tone is the one of the most important mechanisms that plays role in providing both orthostatic and postural stability. The weak of in muscle tone, which develops in the very first minutes of weightlessness, can make a significant contribution to the development of both one and the other phenomenon [31, 32]. According to G.A. Fomina, changes in the lumen of the venous bed in the lower extremities, in terms of their time characteristics, completely coincide with the dynamics of changes in muscle tone [33]. A sharp decrease in tone and deactivation of postural muscles undoubtedly also make a significant contribution to the development of postural disorders, which are observed in the early stages after exposure to simulated weightlessness [34] and are expressed after short flights, essentially the same as after long ones. However, changes in the mechanisms regulating vascular activity undoubtedly make a certain contribution to violations of orthostatic stability [35].

Decreased orthostatic intolerance is a common disorder associated with spaceflight. A number of authors [36-38] report the presence of orthostatic intolerance in 9-30% of astronauts after short-term flights (4-10 days). Fritsch-Yelle et al. (1994) noted either difficulties during independent attempts to exit the spacecraft, or pre-syncope symptoms during tilt-test in 25% of astronauts after flights lasting 8-14 days [39].

The pathophysiology of microgravity-induced orthostatic intolerance is still poorly understood. Orthostatic intolerance occurs: 1) when cardiac output and stroke volume are excessively reduced and/or 2) when ineffective compensatory neurohumoral responses lead to an inability to maintain adequate cerebral perfusion in an upright position [40].

According to [36], after a short-term (from 9 to 14 days) space flight, 9 out of 14 (64%) crew members were unable to pass a 10-minute orthostatic test, while the pre-flight test was negative for all astronauts, i.e. Everyone passed the tilt-test. Supine hemodynamic characteristics were similar before and after flight, with the exception of slightly higher preflight systolic and mean arterial pressures in astronauts who completed the test. After the flight, the astronauts who completed the test and those who did not complete the test had a similar decrease in stroke volume and postural tachycardia. Cardiac output during the test was also within similar values. However, astronauts with a «negative» test had higher total peripheral vascular resistance in the standing position, which characterizes the vasoconstrictor effect. The authors conclude that, with similar reactions of the components of the cardiovascular system to the tilt-test, the main factor responsible for ortho-resistance is the postural vasoconstrictor reaction.

Adaptation to weightlessness or its simulation is reflected by a decrease in total blood volume [41], which is manifested by a decrease of the cardiac chambers fulfill in the supine position and a decrease in stroke volume in the orthostasis. The peripheral filling of the veins of the legs increases, associated with an increase in the distensibility of the latter (and, possibly, the veins of the abdominal cavity), which can also contribute to a decrease in stroke volume in a vertical position.

At the HDBR condition, Gaffney et al. [42] report that orthostatic intolerance is associated with several mechanisms, including a decrease in intravascular volume (blood volume decreased by 8% in subjects with a head down tilt of -5° for 20 hours). They hypothesized that HDBR may cause disruption of reflex mechanisms responsible for maintaining blood pressure and tissue perfusion in an upright position. Neural mechanisms may also be involved in cardiovascular responses to HDBR exposure.

Cerebral blood flow before and after space flight and model experiments

In both spaceflight and ground-based microgravity models, most short-term studies show preservation or even improvement of cerebral blood flow (CBF). However, after long flights, CBF values changed. Firstly, for negative changes may depend on the initial orthostatic stability. It has been shown that crew members resistant to orthostasis have preserved or even increased CBF. In contrast, cosmonauts and astronauts with orthostatic intolerance will experience CBF abnormalities [4]. There is an opinion that the existing differences should be attributed to the methods used to assess the CBF and the interpretation of each indicator should be carried out with caution [43]. Moreover, according to authors Armstead (2016) and Zhang and Hargens (2018) [44, 45], there are no effective methods for accurately measuring CBF velocity. CBF scores seems to be sex-related differences. Several studies have shown gender differences in CBF velocity [46, 47], cerebral vasomotor activity [48], and cerebrovascular reactivity [49], CBF in both young and older adults [50, 51]. When assessing CBF, regional differences between the anterior and posterior cerebral circulation should be taken into account [52]. L.G. Petersen and S. Ogoh (2019) expressed the opinion that gravitational loads can make a difference between the arterial blood pressure at brain level and the intracranial pressure due to which dynamic CBF may be overestimated or underestimated [53]. In detail all these facts in the review are presented [54].

Theoretically, disruption of cerebral autoregulation, which maintains blood flow over a wide range of blood pressures, could seriously affect orthostatic stability after spaceflight. A recent review of the topic included various methodological approaches to defining static and dynamic cerebral autoregulation [55, 56]. Interestingly, certain changes in cerebral vasoconstriction and cerebral hypoperfusion during parabolic flights with brief and rapid gravity transitions contribute to the prediction of orthotic stability disorders [57].

In six astronauts who participated in a short-term flight within the framework of the Space Shuttle program, the characteristic dynamics of changes in the autoregulation of CBF before, during and after space flight at rest and under orthostatic stress were determined. Notable that after a short-term orbital flight the cerebral autoregulation was improved [58]. During long-duration flights, the rate of CBF is inversely proportional to the of blood hemoglobin level [60]. The authors hypothesized that the increase in blood flow could compensate for the decrease in the blood’s ability to carry oxygen. CBF velocities during additional testing with negative lower body pressure (LBNP) were lower compared to HDBR [61]. It is marked that the not significantly changes in brain autoregulation occur, especially during longer missions, but there is no evidence of consistent or profound impairment.

The experiments with -6º HDBR are carried out and managed by Z. B. Wang showed that the systolic and mean blood flow velocity in the right middle cerebral artery decreased significantly compared to the initial values, while the systolic and mean blood flow velocity in the left middle cerebral artery increased at the beginning of the experiment, decreasing with over time [62]. A decrease in the blood flow velocity of the cerebral arteries was noted at -6º by HDBR and other authors [63, 64]. An increase in cerebral vascular resistance and a decrease in cerebral blood flow were observed by C. B. Yang et al. during a 21-day experiment with HDBR -6° [65]. There was also a decrease in venous inflow, and signs of venous congestion in the cervicocephalic region were observed [66, 67].

Analysis of the fluid shift at zero gravity and microgravity simulation models

In space, weightlessness immediately causes an upward shift of fluid [62]. This fluid shift initiates subsequent changes in the cardiovascular system, including changes in arterial and venous hemodynamics and vascular tone [63]. Fluid redistribution also includes a decrease in plasma volume [64]. Research by Thornton WE (1987) noted that in space, in the absence of gravity, body fluids with a volume of just under two liters move to the upper body from the lower extremities [65], which accounts for 11.6% of changes in the total volume fluids, both intravascular and extravas-cular. This fact was later confirmed by participants in the Space Shuttle program. [68]. The rapid intravascular movement of fluid to the head during spaceflight is also quickly restored upon return to Earth. However, most of the intravascular volume shift is reversed within 90 minutes after landing [65, 68].

When conducting bioimpedance analysis on board the International Space Station (ISS), data was obtained showing a decrease in total body fluid, as well as the volumes of extracellular and cellular fluid, but the lowest values were recorded at the end of the flight. The amount of lean body mass also decreased, while the amount of fat component, on the contrary, increased. The results obtained allow us to conclude that the volume of fluid spaces in the human body decreases during space flight while the amount of muscle mass decreases [73].

Research into the architecture of night sleep, autonomic regulation of the heart and blood pressure during space flight and modeling of space mission conditions

It has been established that under conditions of weightlessness, the sleep-wake cycle, the quantitative and qualitative characteristics of night sleep, its duration and efficiency undergo a number of significant transformations. The values of encephalographic activity associated both breathing and the average duration of sleep are decreases and the structure of cycles and phases of sleep are changes [74-76]. Polysomno-graphic studies in weightless conditions have shown changes in sleep architecture: rapid eye movement (REM) sleep latency has become shorter and slow wave sleep (SWS) has been redistributed from the first to the second sleep cycle [75, 77]. Presumably, these factors may also depend on the quality of hemodynamics.

Previously it was shown that microgravity affects to deep changes in most physiological systems, including disorders of the sensorimotor, skeletal and muscular systems and, above all, changes in the cardiovascular system [78, 79]. Therefore, cardiovascular disorders caused by weightlessness may be one of the predisposing factors for sleep disturbances, possibly from central to autonomic regulation include modified cerebral-cardiac connectivity’s.

The connections between functional brain networks and cardiac autonomic regulation were analyzed in studies by Otsuka et al. In one study, the authors reported that spaceflight for 6 months improved cardiac autonomic regulation [80]. Another study documented increased circadian periodicity of HRV, improved sleep quality, and increased parasympathetic modulatory influences at night [81]. According to the authors, these data indicate unconscious activation of a functional brain network during long-term space travel and contribute to slowing down the aging of regulatory mechanisms.

Disturbances in sleep architecture and sleep-wake cycles can affect diurnal blood pressure fluctuations. A study conducted on cosmonauts aboard MIR during 24-hour monitoring (short-term orbital flights) revealed an increase in systolic blood pressure during sleep («night peaker») with unchanged mean systolic blood pressure [82]. However, during long-term missions to the ISS, NASA astronauts experienced a nighttime dipper in blood pressure, characteristic of terrestrial conditions [83]. The differences are likely due to insufficient adaptation time to weightlessness, but the level of psychological stress is known to be particularly high during short-term space flights [84]. Direct recordings of sympathetic nerve activity using microneurography and measurements of norepinephrine release during short-duration missions reveal increased sympathetic activity [85] in contrast to those obtained during long-duration flights.

When simulating conditions of being in weightlessness - HDBR, sleep studies showed that prolonged stress of a forced reduction in physical activity causes not only a change in night sleep, but also the emergence of a stable need for daytime sleep. The duration of the REM and NREM sleep phases changes. Also, in 202 | Cardiometry | Issue 31. May 2024

model simulation experiments with long-term isolation of testers in a closed volume («MARS-500»), an increase in the effect of daytime sleepiness is noted, which can affect the nature of the operator’s activity, especially during responsible duty.

It is known that deprivation, i.e. forced complete or partial sleep deprivation for a period of up to several days most seriously manifests itself approximately on the third day of research. The subjects fall into a halfasleep state, irritability increases, which is replaced by apathy, absent-mindedness, inhibition and inability to make clear, correct decisions [86]. In simulated microgravity, the study of quantitative and qualitative characteristics of night sleep, its duration and architecture are of great scientific interest.

The results obtained under conditions of 5-day «dry» immersion, indirectly reflecting the characteristics of night sleep and its effectiveness, were obtained in 2016-2018 [87]. It was noted that on days 3-4, subjects get used to the conditions of a long stay in a forced posture (mainly on the back and less often on the right or left side), limited mobility, while the need for physical activity also decreases, they complain less about pain and other discomfort, report better quality night sleep [87, 88]. Using portable polysomnographic equipment and 24-hour blood pressure monitoring devices, studies were carried out under conditions of 21-day «dry» immersion. Data were obtained before and after the dive, during SI: on the 3rd, 10th and 19th days of the 21-day experiment. Data analysis has shown that changes in sleep architecture are associated with an increase in REM sleep and a drop in blood pressure, which could potentially affect arterial elasticity [89].

SUMMARY AND CONCLUSION

Concluding a brief report on the effect of microgravity on some cardiometric characteristics that ensure cerebral obedience, self-regulation of cerebral circulation, features of orthostatic stability and hemodynamic changes in sleep conditions in weightlessness or during its simulation, the authors come to the following opinion:

• •    staying in space flight conditions remains dangerous for humans without the use of developed preventive measures;

• •    microgravity has a multifactorial effect on the human body, the adverse consequences of which can be traced at the level of functional and structural changes in almost every organ or system;

• •    one of the main adaptive systems that takes the main influence is the cardiovascular system.

• 1.    Studies of fMRI data, particularly after long-duration spaceflight, have shown persistent decreases in connectivity in the posterior cingulate cortex and thalamus and persistent increases in the right angular gyrus. Connectivity in the bilateral insular cortex decreased after spaceflight, but this effect was no longer observed at follow-up. These studies also showed that the altered gravitational environment affects longitudinal functional connections in multimodal brain centers, reflecting adaptation to unfamiliar and conflicting sensory information in microgravity conditions. However, the ventricles of the brain, enlarged in microgravity, acquire their original size over time and cerebral blood flow returns to normal within the next six months in conditions of Earth gravity.

• 2.    Orthostatic intolerance is a more common spaceflight-associated condition. There are a large number of reports of orthostatic intolerance in 9-30% of astronauts after short-term flights. It has also been reported that 25% of astronauts have difficulty attempting to exit the spacecraft on their own or experience symptoms of fainting during the tilt table test. Orthostatic stability after being in weightlessness is ensured by several factors: the presence of muscle tone, vascular and neural components. Accordingly, detraining of the gravitational muscles, vasodilation of the arteries and relaxation of the large veins of the lower extremities, in conjunction with the altered structure of the autonomous regulation of blood circulation, are provoking factors for orthostasis disorders.

• 3.    Research has shown that in both spaceflight and ground-based microgravity models, most short-term studies show maintenance or even improvement of cerebral blood flow. Under experimental conditions simulating microgravity effects, blood flow in the right middle cerebral artery and left middle cerebral artery changed in the opposite direction. A decrease in cerebral artery blood flow velocity has been noted at -6° HDBR in several publications. An increase in vascular resistance of the cerebral arteries was observed with a decrease in cerebral blood flow. Researchers note a decrease in venous inflow and signs of venous congestion in the cervicocephalic region.

• 4.    The shift of body fluids to the upper part of the body entails a cascade of reactions from almost all systems, including cerebral blood flow, cardiovascular and respiratory systems. Autonomic regulation chang-

• es. In addition, it has been shown that not only the water-salt balance, but also a decrease in active cell mass in the body composition, due to a decrease in muscle tissue, is another unfavorable factor in the influence of weightlessness.

• 5.    Disturbances in sleep architecture and sleepwake cycles can influence diurnal fluctuations in blood pressure. Surprisingly, circadian hemodynamics change to a greater extent in the first 14-21 days of flight. This is followed by a period of adaptation, but the daily rhythms of blood pressure differ from those on Earth. Sleep disturbances actually provoke changes in 24-hour blood pressure patterns, as demonstrated in microgravity models. Simulated microgravity also makes its own corrections to the formation of the sleep-wake structure.

FUNDING

The material was prepared as a part of the research work on the topic “Structural and functional changes in the human brain and their impact on operator activity at various periods of adaptation to the conditions of simulated microgravity” (code “Cerebrum-A”) of the state task of the Federal State Budgetary Institution “FNKTs KM” FMBA of Russia for 2023 and for the planning periods of 2024 and 2025.