A new goldfish model to evaluate pharmacokinetic and pharmacodynamic effects of drugs used for motion sickness in different gravity loads.

This paper proposes a new goldfish model to predict pharmacodynamic/pharmacokinetic effects of drugs used to treat motion sickness administered in differing gravity loads. The assumption of these experiments is that the vestibular system is dominant in producing motion sickness and that the visual system is secondary or of small import in the production of motion sickness. Studies will evaluate the parameter of gravity and the contribution of vision to the role of the neurovestibular system in the initiation of motion sickness with and without pharmacologic agents. Promethazine will be studied first. A comparison of data obtained in different groups of goldfish will be done (normal vs. acutely and chronically bilaterally blinded vs. sham operated). Some fish will be bilaterally blinded 10 months prior to initiation of the experiment (designated the chronically bilaterally blinded group of goldfish) to evaluate the neuroplasticity of the nervous system and the associated return of neurovestibular function. Data will be obtained under differing gravity loads with and without a pharmacological agent for motion sickness. Experiments will differentiate pharmacological effects on vision vs. neurovestibular input to motion sickness. Comparison of data obtained in the normal fish and in acutely and chronically bilaterally blinded fish with those obtained in fish with intact and denervated otoliths will differentiate if the visual or neurovestibular system is dominant in response to altered gravity and/or drugs. Experiments will contribute to validation of the goldfish as a model for humans since plasticity of the central nervous system allows astronauts to adapt to the altered visual stimulus conditions of 0-g. Space motion sickness may occur until such an adaptation is achieved.     

Changes in the vestibular function during space flight

An analysis of observations and investigations carried out in space flight has shown that some cosmonauts and astronauts have experienced vestibular disorders during the transition to weightlessness. Vestibular-sensory disorders include: Spatial illusions (the feelings of falling down, being in an upside-down position, the sensations of rotation of the craft or the body) and vertigo occurring during the onset of the orbital flight and head movements; Feelings, similar to those experienced in response to Coriolis accelerations on the Earth, which occasionally develop in weightlessness during the spacecraft rotation upon abrupt head and body movements and restrained feet; Feelings "of the load on the vestibular analyser which is unlike any Earth-bound effects" upon abrupt head movements during the first hours of an orbital flight and "a prolonged movement" during the switch-off of thrusters in weightlessness. Vestibular-vegetative disorders comprise a complex of symptoms similar to those of motion sickness: loss of appetite, stomach awareness (12%), hypersalination, nausea (9.6%) and vomiting (4.8%). Soviet studies suggest that the vestibular tolerance to the flight effects depends on the natural stability and training to the cumulative effect of adequate vestibular stimuli. This has been used in the development of the system of vestibular selection. Changes in the vestibular function seem to play the major role in the development of motion sickness in weightlessness, extra-labyrinthine factors being contributory. The current hypotheses have not yet been adequately confirmed in experiments. A detailed physiological analysis allows the conclusion that the decisive factor in the development of motion sickness may be the disturbance of the function of analysers responsible for spatial orientation which take the form of sensory conflicts as well as an altered reactivity of the organism due to the hemodynamic rearrangement.     

Biomedical aspects of artificial gravity.

Artificial gravitv generated by spacecraft rotation may prove a universal countermeasure against adverse effects of weightlessness in the future. The paper summarizes the results of ground-based biomedical investigations of artificial gravity and flight experiments aboard Soviet biosatellites Cosmos-782 and Cosmos-936. It is believed that at the present stage the major goal of such investigations is to determine the minimum efficient value of artificial gravity in long-term flights which may eliminate adverse effects of prolonged weightlessness. In ground-bound studies the highest priority should be given to the development of methods on increasing human tolerance to the rotating environment.     

Artificial gravity: head movements during short-radius centrifugation.

Short-radius centrifugation is a potential countermeasure to long-term weightlessness. Unfortunately, head movements in a rotating environment induce serious discomfort, non-compensatory vestibulo-ocular reflexes, and subjective illusions of body tilt. In two experiments we investigated the effects of pitch and yaw head movements in participants placed supine on a rotating bed with their head at the center of rotation, feet at the rim. The vast majority of participants experienced motion sickness, inappropriate vertical nystagmus and illusory tilt and roll as predicted by a semicircular canal model. However, a small but significant number of the 28 participants experienced tilt in the predicted plane but in the opposite direction. Heart rate was elevated following one-second duration head turns. Significant adaptation occurred following a series of head turns in the light. Vertical nystagmus, motion sickness and illusory tilt all decreased with adaptation. Consequences for artificial gravity produced by short-radius centrifuges as a countermeasure are discussed. Grant numbers: NCC 9-58.     

Male and female characteristics in vestibular testing: a step toward the selection of the best participants for space flight

Vestibular disturbances in connection with space flight were reported by a majority of participating astronauts and cosmonauts. These include motion sickness symptoms in the first few days of the space flight, as well as standing, gait and orientation disturbances after the return to Earth. The Aerospace Medical Community has been trying to select those people that are particularly adapted to the above stresses or that can be further adapted through training programs. As the circle of selectees extends to women, the problem arises as to whether differences between men and women exist under the conditions of space flight. In seeking answers to this question we studied a group of 42 women and 44 men, who were further subdivided according to their subjective motion sickness sensitivity, as determined by a questionnaire. Using this material, 26 men and 22 women were designated as motion sickness resistant, and 18 men and 20 women were designated as nonresistant. The vestibular test battery given these test subjects consisted of caloric, rotatory, optokinetic, vestibulo-spinal and vestibulo-vegetative testing. Because of the mixed orthostatic and vestibular problems seen after space flights, we also studied the response of the vestibular apparatus during peripheral blood pooling as induced by lower body negative pressure. The collected historical and test data are analyzed in this paper with emphasis on the relationship to motion sickness tendency.     

Space motion sickness

Space motion sickness, presumably triggered by sudden entry into a weightless environment, occurred with unexpected frequency and severity among astronauts who flew the Skylab missions. Recovery from symptoms was complete within 3-5 days, and as revealed by the Skylab M131 Human Vestibular Function Experiment, all crewmembers were immune to experimentally induced motion sickness after mission day 8. This syndrome has been recognized as a possible threat to the early mission well-being and operational efficiency of at least some individuals who will fly space missions in the future. The causes of space motion sickness are not clearly understood, nor have satisfactory methods been identified to date for its prediction, prevention and treatment. In order to minimize the potential impact of this syndrome on Space Shuttle crew operations the National Aeronautics and Space Administration has organized a broad program of inter-disciplinary research involving a large number of scientists in the United States. Current research on the etiology of space motion sickness is based to a large extent on the so called sensory conflict theory. Investigations of the behavioral and neurophysiological consequences of intralabyrinthine, as well as intermodality sensory conflict are being performed. The work in this area is being influenced by the presumed alterations that occur in otolith behavior in weightlessness. In addition to sensory conflict, the possible relationship between observed cephalad shifts of body fluids in weightlessness and space motion sickness is being investigated. Research to date has failed to support the fluid shift theory. Research underway to identify reliable test methods for the prediction of susceptibility to space motion sickness on an individual basis includes attempts to (a) correlate susceptibility in different provocative environments; (b) correlate susceptibility with vestibular and non-vestibular response parameters, the latter including behavioral, hemodynamic and biochemical factors and (c) correlate susceptibility with rate of acquisition and length of retention of sensory adaptation. Controlled studies are also being performed during parabolic flight as a means of attempting to validate predictive tests for susceptibility to this syndrome. Research to develop new or improved countermeasures for space motion sickness is underway in two primary areas. One of these involves anti-motion sickness drugs. Significant achievements have been realized with regard to the identification of new highly efficacious drug combinations, dose levels and routes of administration. Although pronounced individual variations must be accounted for in selecting the optimum drug and dose level, combinations of promethazine plus ephedrine or scopolamine plus dexidrine are presently the drugs of choice. Work is also underway to identify side effects associated with anti-motion sickness drug use and to identify new drugs which may selectively modify activity in central neural pathways involved in motion sickness. In addition to research on drugs, efforts are being made to develop practical vestibular training methods. Variables which influence rate of acquisition of adaptation, length of retention of adaptation and transfer of protective adaptation to new environments are being evaluated. Also, included in this area is the use of biofeedback and autogenic therapy to train individuals to regulate autonomic responses associated with motion sickness. While valuable new knowledge is expected to evolve from these combined research programs, it is concluded that the final validation of predictive tests and countermeasures will require a series of controlled space flight experiments.     

An appraisal of the value of vitamin B12 in the prevention of motion sickness

Unpublished reports have suggested that hydroxycobalamin (B12, i.m.) prevents motion sickness. Some biomedical evidence supports this contention in that B12 influences the metabolism of histidine and choline; dietary precursors to neurotransmitters with established roles in motion sickness. Susceptibility to motion sickness was evaluated after B12 (1000 micrograms, i.m.). Subjects initially completed vestibular function and motion sickness susceptibility tests to establish normal vestibular function. The experimental motion stressor was a modified coriolis sickness susceptibility test. Subjects executed standardized head movements at successively higher RPM until a malaise III endpoint was reached. Following two baseline tests with this motion stressor, subjects received a B12 injection, a second injection two weeks later, and a final motion sickness test three weeks later. No significant differences in susceptibility were noted after B12. Hematological parameters revealed no B12 deficiency before injection. The possibility that patients with B12 deficiencies are more susceptible to motion sickness cannot be ruled out.     

Neurohumoral mechanism of space motion sickness.

This paper reviews existing hypotheses concerning the mechanisms of adaptation of the vestibular apparatus and related somatosensory systems to microgravity with reference to the flight data. Having in view theoretical concepts and experimental data accumulated in space flights, a conceptual model of the development of a funtional system responsible for the termination of vestibular dysfuntion and space motion sickness manifestations is presented. It is also shown that changes in the hormonal status during motion sickness induced by vestibular stimulation give evidence that endocrine regulation of certain functions can be involved in adaptive responses.     

Function-morphological investigations of fish inner ear otoliths as basis for interpretation of human space sickness

In man, altered gravity may lead to a vestibular dysfunction causing space motion sickness. A hypothesis was developed, according to which asymmetric inner ear statoliths might be the morphological basis of space sickness. The animal model, fish, revealed further information: inner ear "stone" (otolith) growth is dependent on the amplitude and the direction of gravity, regulated by a negative feedback mechanism. The present study was focused on the question, where the regulation centre of adaptive otolith growth may be situated. Therefore, the vestibular nerve was unilaterally transected in neonate swordtail fish (Xiphophorus helleri). As growth marker, the calcium tracer alizarin-complexone was used. It was found that otolith growth had ceased on the operated head sides indicating that the brain is significantly involved in regulating otolith growth. About 2 weeks after nerve transection, otoliths had regained normal growth, probably due to nerve regeneration. Concerning fish, it has now to be tested, if this regeneration is affected by altered gravity, e.g. in a long-term experiment on the International Space Station. Regarding mammals, it has to be proved if asymmetric statoliths are the basis of kinetosis and whether or not the mammalian brain has an effect on statolith growth in the course of compensating altered gravity.     

Biomedical problems of EVA support during manned space flight to Mars

Current projects of manned missions to Mars are aimed to their realization in the second-third decades of this century. The purpose of this paper is to determine and review the main biomedical problems, that require a first and foremost decision for safety support of extravehicular activity (EVA) carried out by crewmembers of the Mars expedition. To a number of such problems the authors of the paper attribute a creation of adequate EVA equipment intended, first, for assembly of interplanetary spacecraft on the Earth orbit, performance of maintenance operations and scientific researches on the external surface of spacecraft during interplanetary flight and, secondly, for work on the Mars surface. New generation of space suits with low weight, high mobility and acceptable risk of decompression sickness must be as a central component of EVA equipment. The program for preparation to a Mars expedition also has to include special investigations in order to design the means and methods for a reliable protection of crew against space radiation, to elaborate the approach to medical monitoring and primary medical care during autonomous space mission, to maintain good health condition of crewmembers during EVA under the Mars gravity (0.38 g) after super long-term flight in weightlessness.     

深空探测重力模拟飞行器方案设想

为解决失重环境对航天员生理健康的影响,在调研国内外重力飞行器研究现状的基础上,结合重力模拟飞行器的原理及人造重力舒适度影响因素,提出了一种通过自旋产生人造重力的深空探测飞行器方案设想。最后给出了重力模拟飞行器建设的实施规划、总体方案、在轨组装流程及技术难点。深空探测重力模拟飞行器稳定运转可为空间工作生活的航天员提供与地面无异的重力环境,将为执行深空探测任务提供必要的环境保障。     

Individual differences in susceptibility to motion sickness among six Skylab astronauts

One of the Skylab experiments dealt with motion sickness, comparing susceptibility in the workshop aloft with susceptibility preflight and postflight. Tests were conducted on and after mission-day 8 (MD 8) by which time the astronauts were adapted to working conditions. Stressful accelerations were generated by requiring the astronauts, with eyes covered, to execute standardized head movements (front, back, left, and right) while in a chair that could be rotated at angular velocities up to 30 rpm. The selected endpoint was either 150 discrete head movements or a very mild level of motion sickness. In all rotation experiments aloft, the five astronauts tested (astronaut 1 did not participate) were virtually symptom free, thus demonstrating lower susceptibility aloft than in preflight and postflight tests on the ground when symptoms were always elicited. Inasmuch as the eyes were covered and the canalicular stimuli were the same aloft as on the ground, it would appear that lifting the stimulus to the otolith organs due to gravity was an important factor in reducing susceptibility to motion sickness even though the transient stimuli generated under the test conditions were substantial and abnormal in pattern. Some of the astronauts experienced motion sickness under operational conditions aloft or after splashdown, but attention is centered chiefly on symptoms manifested in zero gravity. None of the Skylab-II crew (astronauts 1 to 3) was motion sick aloft. Astronaut 6 of the Skylab-III crew (astronauts 4 to 6) experienced motion sickness within an hour after transition into orbit; this constitutes the earliest such diagnosis on record under orbital flight conditions. The eliciting stimuli were associated with head and body movements, and astronaut 6 obtained relief by avoiding such movements and by one dose of the drug combination 1-scopolamine 0.35 mg + d-amphetamine 5.0 mg. All three astronauts of Skylab-III experienced motion sickness in the workshop where astronaut 6 was most susceptible and astronaut 4, least susceptible. The higher susceptibility of SL-III crewmen in the workshop, as compared with SL-II crewmen, may be attributable to the fact that they were based in the command module less than one-third as long as SL-II crewmen. The unnatural movements, often resembling acrobatics, permitted in the open spaces of the workshop revealed the great potentialities in weightlessness for generating complex interactions of abnormal or unusual vestibular and visual stimuli. Symptoms were controlled by body restraint and by drugs, but high susceptibility to motion sickness persisted for 3 days and probably much longer; restoration was complete on MD 7. From the foregoing statements it is clear that on and after MD 8 the susceptibility of SL-II and SL-III crewmen to motion sickness under experimental conditions was indistinguishable. The role played by the acquisition of adaptation effects prior to MD 8 is less clear and is a subject to be discussed.     

Nausogenic properties of various dynamic and static force environments.

Motion sickness can occur when an accelerating force acting on the human body repeatedly changes amplitude and direction or both. It also can occur without any motion after transfer into a constant force field significantly different from Earth-gravity. Dynamic and static causes of motion sickness can be distinguished accordingly. Space sickness, too, has dynamic as well as static aspects. Dynamic space sickness might depend on increased bilateral differential sensitivity of the peripheral and central vestibular apparatus, whereas static space sickness may be caused by erroneous compensation of bilaterial asymmetries of the otolith-system in the microgravity environment. Experiments in airplanes, cars and on a vestibular sled have shown that the susceptibility to motion sickness is highest for changes of acceleration in the negative X-axis (as compared to the other axes) of the body. During reciprocating linear accelerations on the vestibular sled, standstill periods of movement and the direction of movement cannot correctly be indicated, because the peripheral vestibular apparatus lacks true motion detectors.     

Summary of experiments onboard Soviet biosatellites.

Physiological, morphological and biochemical studies of mammals flown onboard biosatellites of the series Cosmos revealed changes in their cardiovascular, musculoskeletal, endocrine and vestibular systems. Space flight resulted in moderate stress reactions, intralabyrinthine conflict information during movements and changes in fluid-electrolyte metabolism. Exposure to artificial gravity (1 g) decreased the level of myocardial, musculoskeletal and excretory changes, but disturbed the function of equilibrium. Studies with combined weightlessness and ionizing radiation demonstrated that weightlessness did not produce a significant modifying effect on radiation damage and postradiation recovery. Consistent changes in certain systems of animals and humans in weightlessness confirm the practical importance of biosatellite studies, which also contribute to the solution of general biology, problems associated with gravity effects on life processes.     

Does gravity play an essential role in the asymmetrical visual perception of vertical and horizontal line length?

The eye perceives the length of vertical and horizontal lines with an inherent asymmetry. A vertical line having the same length as a horizontal one is usually perceived to be longer. In this experimental investigation we tested the hypothesis that gravity has a direct role in producing the observed perceptual asymmetry. To this end we performed experiments in weightlessness during long-orbital space flights onboard the MIR station. Subjects performed a psychophysical task in which the length of a visually-presented vertical line was adjusted to match the length of a horizontal reference. On Earth, almost all subjects produce errors in adjusting the length of the vertical line, consistently under-estimating the length of the horizontal reference. The asymmetry of perception of the line lengths persisted in weightlessness. From these results we conclude that the phenomena of asymmetry of perception of the lengths of vertical and horizontal lines is not dependent on gravity, but is instead defined by properties of the system of internal representation. Grant numbers: 99-04-48450.     

Animals in biomedical space research

The use of experimental animals has been a major component of biomedical research progress. Using animals in space presents special problems, but also provides special opportunities. Rat and squirrel monkeys experiments have been planned in concert with human experiments to help answer fundamental questions concerning the effect of weightlessness on mammalian function. For the most part, these experiments focus on identified changes noted in humans during space flight. Utilizing space laboratory facilities, manipulative experiments can be completed while animals are still in orbit. Other experiments are designed to study changes in gravity receptor structure and function and the effect of weightlessness on early vertebrate development. Following these preliminary animals experiments on Spacelab Shuttle flights, longer term programs of animal investigation will be conducted on Space Station.     

On the planar inertial motion of a system of three coupled bodies

Numerous papers are devoted to studying the motion of a system (coupling) of two bodies in the Earth’s satellite orbit ([1–4] and others). The problem on the planar inertial motion of three bodies, coupled by a non-extensible weightless string having the form of an unfastened chain, is considered in the paper. Such a configuration can be represented, for example, by a system of two coupled spacecraft rotating around their common center of mass (in order to simulate the gravity force) in long-term space missions, when the third body (the lift) is located on a connecting cable. The bodies are considered to be the material points (particles).     

Future investigations onboard Soviet biosatellites of the Cosmos series.

Many rat experiments onboard Cosmos biosatellites have furnished information concerning the effects of weightlessness, artificial gravity, and ionizing radiation combined with weightlessness on structural and biochemical parameters of the animal body. The necessity to expand the scope of physiological investigations has led to the project of flight primate studies. It is planned to carry out the first primate experiments onboard the Cosmos biosatellite in 1982. At present investigations of weightlessness effects on the cardiovascular and vestibular systems, higher nervous activity, skeletal muscles and biorhythms of two rhesus monkeys are being developed and tested. It is also planned to conduct a study of weightlessness effects on embryogenesis of rats and bioenergetics of living systems onboard the same biosatellite. Further experiments onboard Cosmos biosatellites are planned.     

Effect of weightlessness on sympathetic-adrenomedullary activity of rats.

Three cosmic experiments were performed in which rats spent 18-20 days in space on board the biosatellites "COSMOS 782", "COSMOS 936" and "COSMOS 1129". The following indicators of the sympathetic-adrenomedullary system (SAS) activity were measured: tissue and plasma catecholamines (CA), CA-synthesizing enzymes--tyrosine hydroxylase (TH), dopamine-beta-hydroxylase (DBH), phenylethanolamine-N-methyltransferase (PNMT)--as well as CA-degrading enzymes-monoamine oxidase (MAO) and catechol-O-methyltransferase (COMT). Adrenal epinephrine (EPI) and norepinephrine (NE) as well as CA-synthesizing and degrading enzymes were not significantly changed in the animals after flight on COSMOS 782. On the other hand, a significant increase was found in heart CA, the indicator which is usually decreased after stress. 26 days after landing all values were at control levels. The results obtained, compared to our previous stress experiments on Earth, suggest that prolonged weightlessness does not appear to be a pronounced stressful stimulus for the SAS. Heart and plasma CA, mainly NE, were increased both in the group living in the state of weightlessness and the group living in a centrifuge and exposed to artificial gravitation 1 g (COSMOS 936), suggesting again that prolonged weightlessness is not an intensive stressful stimulus for the SAS. The animals exposed after space flight on COSMOS 1129 to repeated immobilization stress on Earth showed a significant decrease of adrenal EPI and an expressive increase of adrenal TH activity compared to stressed animals which were not in space. Thus, the results corroborate that prolonged state of weightlessness during space flight though not representing by itself an intensive stressful stimulus for the sympathetic-adrenomedullary system, was found to potentiate the response of "cosmic rats" to stress exposure after return to Earth.     

Vestibular tests in the selection of cosmonauts.

Vestibulo-vegetative disorders in cosmonauts and astronauts occurring during space flight compel otolaryngologists to search for vestibular tests enabling a precise evaluation of the activity of the vestibular apparatus and showing disposition to motion sickness. Otoneurological investigation of Polish candidates for cosmonaut status consisted of the following vestibular tests: caloric, rotatory, optokinetic, swinging torsion, statokinesimetric and vestibulo-vegetative. The value of various vestibular tests for aviation and space medicine is presented in this paper, taking into account the results of investigations of the equilibrium system with the group of pilots selected for space flight as well as extensive experience with candidates for the air service and also trained pilots and patients. The relatively frequent lack of correlation between the results of the applied tests, which renders difficult the proper evaluation of the equilibrium system, is emphasized in the paper. Finally, the results of investigations of acute habituation of the vestibular apparatus are discussed.