Effects of vestibular nerve transection on the calcium incorporation of fish otoliths.

Previous investigations revealed that the growth of fish inner ear otoliths (otolith size and calcium-incorporation) depends on the amplitude and the direction of gravity, suggesting the existence of a (negative) feedback mechanism. In search for the regulating unit, the vestibular nerve was transacted unilaterally in neonate swordtail fish (Xiphophorus helleri) which were subsequently incubated in the calcium-tracer alizarin-complexone. Calcium incorporation ceased on the transacted head sides, indicating that calcium uptake is neurally regulated. Grant numbers: 50 WB 9533, 50 WB 9997.     

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.     

On the influence of altered gravity on the growth of fish inner ear otoliths

Inner ear stones (otoliths) of developing cichlid fish (Oreochromis mossambicus) were marked with the calcium tracer alizarin-complexone (AC) at 1g-earth gravity before and after a long-term (20 days) stay of the animals at moderate hypergravity conditions (3g; centrifuge). AC deposition at the otoliths resulted in two fluorescence bands, which enclosed the area grown during exposure to altered gravity. This area was measured with regard to size and asymmetry (size difference between the left and the right stones).

Both utricular and saccular otoliths (lapilli and sagittae, respectively) were significantly smaller after hyper-g exposure as compared to parallely raised 1g-control specimens. The asymmetry concerning the lapilli was pronouncedly decreased in comparison to the 1g-controls. These findings suggest, that the growth and the development of bilateral asymmetry of otoliths is guided by the environmental gravity vector.

Some of the hyper-g animals revealed a kinetotic behaviour at the transfer from hyper-g to normal 1g-earth gravity conditions, which was qualitatively similar to the behaviour observed in previous experiments at the transfer from 1g to microgravity in the course of parabolic aircraft flights. The lapillar asymmetry of kinetotic samples was found to be significantly higher than that of normally behaving experimental specimens. This result supports an earlier theoretical concept, according to which human static space sickness might be based on asymmetric utricular otoliths.     

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.     

Neurobiological responses of fish to altered gravity conditions: a review

In vertebrates (including man), altered gravitational environments such as weightlessness can induce malfunctions of the inner ears, based on an irregular dislocation of the inner ear otoliths from the corresponding sensory epithelia. This dislocation leads to an illusionary tilt, since the otolithic inputs are not confirmed by the other sensory organs, which results in an intersensory conflict. Vertebrates in the orbit therefore face severe orientation problems. In humans, the intersensory conflict may additionally lead to a malaise, commonly referred to as space motion sickness (SMS). During the first days at weightlessness, the orientation problems (and SMS) disappear, since the brain develops a new compensatory interpretation of the available sensory data. The present review reports on the neurobiological responses--particularly of fish--observed at altered gravitational states, concerning behaviour and neuroplastic reactivities.     

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.     

DARA vestibular equipment onboard MIR

In space, the weightless environment provides a different stimulus to the otolith organs of the vestibular system, and the resulting signals no longer correspond with the visual and other sensory signals sent to the brain. This signal conflict causes disorientation. To study this and also to understand the vestibular adaptation to weightlessness, DARA has developed scientific equipment for vestibular and visuo-oculomotoric investigations. Especially, two video-oculography systems (monocular--VOG--and binocular--BIVOG, respectively) as well as stimuli such as an optokinetic stimulation device have successfully been employed onboard MIR in the frame of national and European missions since 1992. The monocular VOG was used by Klaus Flade during the MIR '92 mission, by Victor Polyakov during his record 15 months stay onboard MIR in 1993/94 as well as by Ulf Merbold during EUROMIR '94. The binocular version was used by Thomas Reiter and Sergej Avdeyev during the 6 months EUROMIR '95 mission. PIs of the various experiments include H. Scherer and A. Clarke (FU Berlin), M. Dieterichs and S. Krafczyk (LMU Munchen) from Germany as well as C.H. Markham and S.G. Diamond from the United States. Video-Oculography (VOG) is a technique for examining the function of the human balance system located in the inner ear (vestibular system) and the visio-oculomotor interactions of the vestibular organ. The human eye movements are measured, recorded and evaluated by state-of-the-art video techniques. The method was first conceived and designed at the Vestibular Research Laboratory of the ENT Clinic in Steglitz, FU Berlin (A. Clarke, H. Scherer). Kayser-Threde developed, manufactured and tested the facilities for space application under contract to DARA. Evaluation software was first provided by the ENT Clinic, Berlin, later by our subcontractor Sensomotoric Instruments (SMI), Teltow. Optokinetic hardware to support visuo-oculomotoric investigations, has been shipped to MIR for EUROMIR '95 and has successfully been used in conjunction with VOG by ESA astronaut Thomas Reiter. Most recently, BIVOG aboard MIR will be reused in the frame of German/Russian joint experiment sessions employing two Russian cosmonauts from August 1997 to January 1998.     

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.     

Development of space motion sickness in a ground-based human centrifuge

Adaptation of the vestibular system, specifically the otolith organs, to a non-terrestrial environment can result in space motion sickness-like symptoms when the human is reintroduced to the normal, 1 Gz, terrestrial environment. This premise was investigated by exposing nine subjects to 90 min of sustained 2 Gz acceleration in a human centrifuge and then observing and evaluating them at 1 Gz. Five of the subjects developed slight SMS symptoms, three developed moderate, and one developed frank sickness. Postural instabilities in two of the most affected subjects were also observed using the Equitest System post exposure. Long duration exposure to a non-terrestrial G(2Gz) appears to be a potential means for developing SMS-like symptoms in a ground-based human centrifuge.     

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.     

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.     

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.     

Voluntary head stabilization in space during trunk movements in weightlessness

The ability to voluntarily stabilize the head in space during lateral rhythmic oscillations of the trunk has been investigated during parabolic flights. Five healthy young subjects, who gave informed consent, were examined. The movements were performed with eyes open or eyes closed, either during phases of microgravity or phases of normal gravity. The main result to emerge from this study is that the head may be stabilized in space about the roll axis under microgravity conditions with, as well as without vision, despite the reduction of the vestibular afferent and the muscle proprioceptive inputs. Moreover, the absence of head stabilization about the yaw axis confirms that the degrees of freedom of the neck can be independently controlled, as it was previously shown [1]. These results seem to indicate that voluntary head stabilization does not depend crucially upon static vestibular afferents. Head stabilization in space may be in fact organized on the basis of either dynamic vestibular afferents or a postural body scheme.     

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.     

Space motion sickness preflight adaptation training: preliminary studies with prototype trainers

Preflight training frequently has been proposed as a potential solution to the problem of space motion sickness. The paper considers successively the otolith reinterpretation, the concept for a preflight adaptation trainer and the research with the Miami University Seesaw, the Wright Patterson Air-Force Base Dynamic Environment Simulator and the Visually Coupled Airborne Systems Simulator prototype adaptation trainers.     

The asymmetrical growth of otoliths in fish is affected by hypergravity.

Size and asymmetry (size difference between the left and the right side) of inner ear otoliths of larval cichlid fish were determined after a long-term stay at moderate hypergravity conditions (3g; centrifuge), in the course of which the animals completed their ontogenetic development from hatch to freely swimming. Both the normal morphogenetic development as well as the timely onset and gain of performance of the swimming behaviour was not impaired by the experimental conditions. However, both utricular and saccular otoliths (lapilli and sagittae, respectively) were significantly smaller after hyper-g exposure as compared to parallely raised 1g control specimens. The asymmetry of sagittae was significantly increased in the experimental animals, whereas the respective asymmetry con-cerning lapilli was pronouncedly decreased in comparison to the 1g controls. These findings suggest, that the growth and the development of bilateral asymmetry of otoliths is guided by the environmental gravity vector.     

Vestibular function in the space environment

Adaptation to the weightless state and readaptation after space flight to the 1-G environment on the ground are accompanied by various transitory symptoms of vestibular instability, kinetosis, and illusory sensations. Aside from the problem of how to treat and if possible prevent such symptoms, they offer a clue to a better understanding of normal vestibular functions. Weightlessness is a powerful new "tool" of vestibular research. Graybiel reported as early as 1952 that human subjects observed the illusion that a real target and the visual afterimage seemed to raise in the visual field during centrifugation when the subjects were looking toward the axis of rotation (oculogravic illusion). In aircraft parabolic-flight weightlessness, human subjects observed that fixed real targets appeared to have moved downward while visual afterimages appeared to have moved upward (oculoagravic illusion). It can be shown by electronystagmography as well as by a method employing double afterimages that part of this illusion is caused by eye movements that are triggered by the changing input from the otolith system. Another part of the illusion is based on a change of the subjective horizontal and must be caused by convergence of vestibular and visual impulses "behind" the eyes. This part was measured independently of the first one by using a new method. Eye movements could be prevented during these experiments by optical fixation with the right eye on a target at the end of a 24-in. long tube which was rigidly attached parallel to the longitudinal axis of an aircraft. At the same time the subject tried to line up a shorter tube, which was pivoting around his left eye, with the subjective horizon.     

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.     

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.     

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.