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Unpublished reports have suggested that hydroxycobalamin (B12, i.m.) prevents motion sickness.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.     

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.     

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.     

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.     

Motion sickness susceptibility during rotation at 30 rpm in free-fall parabolic flight

Free fall per se whether in parabolic or orbital flight may be regarded as a "partial" motion environment with respect to eliciting motion sickness, requiring an additional component to render this environment "complete" or stressful. Parabolic flight in toto falls in the category of a "complete" motion environment in that some persons became motion sick with head fixed and eyes closed. In the present experiment we selected subjects who were symptom free or nearly symptom free in the KC-135 with head fixed. All tests were conducted with the subject rotating at 30 rpm in a rotating litter chair, and comparisons were made between head-fixed and head-moving conditions (right-left) in the free-fall phase of parabolic flight and under simulated free-fall phases in the laboratory. With head fixed most subjects were insusceptible; with head moving left-right susceptibility was slightly higher in the laboratory than aloft. An additional comparison was made correlating susceptibility in the free-fall phases of parabolic flight with susceptibility to experimental motion sickness in Skylab. In both situations cross-coupled angular accelerations were generated by executing head and body movements out of the plane of rotation. In parabolic flight 9 of 15 subjects reached an endpoint just short of frank motion sickness. In the Skylab workshop all eight of the astronauts tested were symptom free at the end of the test. The explanation for the difference in susceptibility rests in two factors: (1) Basic susceptibility in free fall is lower than on the ground, and (2) in Skylab the astronauts who needed to adapt had achieved this goal prior to the first test on Mission-Day 8.     

Spacelab experiments on space motion sickness

Recent research results from ground and flight experiments on motion sickness and space sickness conducted by the Man Vehicle Laboratory are reviewed. New tools developed include a mathematical model for motion sickness, a method for quantitative measurements of skin pallor and blush in ambulatory subjects, and a magnitude estimation technique for ratio scaling of nausea or discomfort. These have been used to experimentally study the time course of skin pallor and subjective symptoms in laboratory motion sickness. In prolonged sickness, subjects become hypersensitive to nauseogenic stimuli. Results of a Spacelab-1 flight experiment are described in which four observers documented the stimulus factors for and the symptoms/signs of space sickness. The clinical character of space sickness differs somewhat from acute laboratory motion sickness. However SL-1 findings support the view that space sickness is fundamentally a motion sickness. Symptoms were subjectively alleviated by head movement restriction, maintenance of a familiar orientation with respect to the visual environment, and wedging between or strapping onto surfaces which provided broad contact cues confirming the absence of body motion.     

Relative efficacy of the proposed Space Shuttle antimotion sickness medications

Space motion sickness has been estimated as affecting between 1/3 and 1/2 of all space flight participants. NASA has at the moment proposed a combination of promethazine and ephedrine (P/E) and one of scopolamine and dextroamphetamine (S/D), both given orally, as well as a transdermally applied scopolamine (TAS), as preventive and ameliorative measures. The reported double-blind study, tests the early phase actions and efficacy of the transdermal scopolamine (Transderm (TM)-V of ALZA Corporation) and compares these in detail to the oral medications. Motion sickness resistance was tested by standardized head movements while accelerating at 0.2 degree/sec2 to a maximum rotation of 240 degrees/sec, with an intermediate plateau of 10 min at 180 degrees/sec. To permit weighting motion sickness protection against other system influences, cardiovascular, psychological (subjective and objective), and visual parameter changes were documented for the three therapeutic modes. The relative impact of the various modalities on operational and experimental components of space missions is discussed. A comparison to intramuscularly administered promethazine (a backup therapeutic mode suggested for Space Shuttle use) is also included.     

Vestibular factors influencing the biomedical support of humans in space

This paper will describe the biomedical support aspects of humans in space with respect to the vestibular system. The vestibular system is thought to be the primary sensory system involved in the short-term effects of space motion sickness although there is increasing evidence that many factors play a role in this complex set of symptoms. There is the possibility that an individual's inner sense of orientation may be strongly coupled with the susceptibility to space motion sickness. A variety of suggested countermeasures for space motion sickness will be described. Although there are no known ground-based tests that can predict space motion sickness, the search should go on. The long term effects of the vestibular system in weightlessness are still relatively unknown. Some preliminary data has shown that the otoconia are irregular in size and distribution following extended periods of weightlessness. The ramifications of this data are not yet known and because the data was obtained on lower order animals, definitive studies and results must wait until the space station era when higher primates can be studied for long durations. This leads us to artificial gravity, the last topic of this paper. The vestibular system is intimately tied to this question since it has been shown on Earth that exposure to a slow rotating room causes motion sickness for some period of time before adaptation occurs. If the artificial gravity is intermittent, will this mean that people will get sick every time they experience it? The data from many astronauts returning to Earth indicates that a variety of sensory illusions are present, especially immediately upon return to a 1-g environment. Oscillopsia or apparent motion of the visual surround upon head motion along with inappropriate eye motions for a given head motion, all indicate that there is much to be studied yet about the vestibular and CNS systems reaction to a sudden application of a steady state acceleration field like 1-g. From the above information it is obvious that the vestibular system does have unique requirements when it comes to the biomedical support of space flight. This is not to say that other areas such as cardiovascular, musculo-skeletal, immunological and hematological systems do not have their own unique requirements but that possible solutions to one system can provide continuing problems to another system. For example, artificial gravity might be helpful for long term stabilization of bone demineralization or cardiovascular deconditioning but might introduce a new set of problems in orientation, vestibular conflict and just plain body motion in a rotating space vehicle.     

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.     

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.     

Artificial gravity--head movements during short-radius centrifugation: influence of cognitive effects

Short-radius centrifugation is a potential countermeasure against the effects of prolonged weightlessness. Head movements in a rotating environment, however, induce serious side effects: inappropriate vestibular ocular reflexes (VOR), body-tilt illusions and motion sickness induced by cross-coupled accelerations on a rotating platform. These are well predicted by a semicircular canal model. The present study investigates cognitive effects on the inappropriate VOR and the illusory sensations experienced by subjects rotating on a short-radius centrifuge (SRC). Subjects (N=19) were placed supine on a rotating horizontal bed with their head at the center of rotation. To investigate the extent to which they could control their sensations voluntarily, subjects were asked alternatively to "fight" (i.e. to try to resist and suppress) those sensations, or to "go" with (i.e. try to enhance or, at least, acquiesce in) them. The only significant effect on the VOR of this cognitive intervention was to diminish the time constant characterizing the decay of the nystagmus in subjects who had performed the "go" (rather than the "fight") trials. However, illusory sensations, as measured by reported subjective intensities, were significantly less intense during the "fight" than during the "go" trials. These measurements also verified an asymmetry in illusory sensation known from earlier experiments: the illusory sensations are greater when the head is rotated from right ear down (RED) to nose up (NU) posture than from NU to RED. The subjects habituated, modestly, to the rotation between their first and second sequences of trials, but showed no better (or worse) suppression of illusory sensations thereafter. No significant difference in habituation was observed between the "fight" and "go" trials.     

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.     

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.     

The effects of space travel on the nervous system

The translation of man from terrestrial to an extra terrestrial environment is accompanied by an upset in the servo-control of movement engendered by the removal of the normal gravitational signal. Unfortunately the "natural" response of the nervous system, to ocular and vestibular confusion, is to cause varying degrees of sickness which can only be avoided by choice of suitable space travellers i.e., those who are least upset by gravitational chaos. This will remain so until much more is learned about the fundamental physiological mechanisms whereby man maintains a correct head/trunk, head/eye, trunk/limb and eye/limb positional coordination and why if these are upset man's natural response is to vomit.     

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.     

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.     

Coping with space motion sickness in Spacelab missions.

A substantial number of persons, around 75%, making their first transition into orbital flight will need to adapt to this unique environment. The two most powerful instruments in the prevention of space motion sickness reside in the selection process and in acquiring adaptation-prelaunch. Today, neither of these means is practical. One logical alternative is to administer preventative medication to all or none. One candidate drug is a high-potency transdermal therapeutic system (TTS)-scopolamine. This is marketed in the nature of a patch that is affixed to the skin behind the ear 12 hr before need and delivers scopolamine into the blood stream for three days. We are systematically evaluating all claims for its high potency and low side effects. We are also evaluating new antimotion sickness remedies and new combinations of homergic drugs.     

Effects of long-duration space flight on target acquisition

The purpose of the study was to explore the effects of long-duration space flight on the acquisition of specific visual targets in the horizontal plane. Seven cosmonauts (4 high performance pilots and 3 non-pilots) who had flown between 186–198 days on Mir served as subjects. Baseline testing was performed 4 times prior to launch and 4 times following landing at different intervals totrack recovery. During testing the subjects were required to acquire targets that were randomly presented with both a head and eye movement using a time optimal strategy. Prior to flight two unique head movement strategies, related primarily to piloting experience, were used for target acquisition. Non-pilots employed a Type-I strategy consisting of high velocity head movements with large peak amplitudes, while high performance pilots used primarily low velocity, small amplitude head movements (Type-II) to acquire the targets (p<0.02). For both strategies peak head velocities increased as the angular distance to the target increased (p<0.01) resulting in greater discrimination between strategies for the 60° targets. While preflight eye velocity between strategies did not reach statistical significance, postflight testing revealed a decrease in eye velocity for Type-I compared with their preflight performance (p<0.02) for the 60° targets. Postflight, the Type-I group showed a decrease in head velocity (p<0.20) while the Type-II group compensated by increasing head velocity (p<0.02). Variability for both of the head and eye parameters tended to increase postflight for both types of strategies.     

Gravity and perceptual stability during translational head movement on earth and in microgravity

We measured the amount of visual movement judged consistent with translational head movement under normal and microgravity conditions. Subjects wore a virtual reality helmet in which the ratio of the movement of the world to the movement of the head (visual gain) was variable. Using the method of adjustment under normal gravity 10 subjects adjusted the visual gain until the visual world appeared stable during head movements that were either parallel or orthogonal to gravity. Using the method of constant stimuli under normal gravity, seven subjects moved their heads and judged whether the virtual world appeared to move “with” or “against” their movement for several visual gains. One subject repeated the constant stimuli judgements in microgravity during parabolic flight. The accuracy of judgements appeared unaffected by the direction or absence of gravity. Only the variability appeared affected by the absence of gravity. These results are discussed in relation to discomfort during head movements in microgravity.     

Dexamethasone mimicks the antimotion sickness effects of amphetamine and scopolamine

Based on preliminary suggestions that individual differences in susceptibility to stressful motion might be related to physiological differences in responses of the hypothalamic-pituitary-adrenal axis, we tested the efficacy of dexamethasone and metyrapone in subjects exposed to cross-coupled accelerative semicircular canal stimulation on a rotating chair. Subjects given 0.5 mg of dexamethasone every 6 h for 48 h could endure 80% more stressful motion (P = 0.03) in a within-subjects design study, whereas, no improvement followed treatment with 750 mg of metyrapone[correction of metryapone] every 4 h for 24 h. The efficacy of dexamethasone might be explained in terms of its neurochemical actions on several neurotransmitter systems which are also modulated by such classical antimotion sickness drugs as amphetamine and scopolamine. Because dexamethasone induces adaptive changes within the central nervous system it may prove superior to scopolamine and amphetamine which possess significant side effects, are short acting, and rapidly tolerated.