Chapter 1

General introduction

1.1 Motion sickness; definition and symptoms

During many forms of transportation, people and animals can experience a kind of general malaise which is better known as motion sickness and which can have severe effects on normal day-life functioning. Motion sickness can be defined as a response to real or apparent motion to which an organism is not adapted or as a response to visual motion alone (Dobie and May, 1994). Types of motion sickness are named after the environment in which a subject is experiencing the motion sickness (sea-, air- or space motion sickness) or after the particular vehicle involved (car sickness).

Treisman (1977) suggested that motion sickness is the activation of a poison-response mechanism. The signs and symptoms of motion sickness, which can be considered as manifestations of the poison response, are always the same whet-her they are caused by transport vehicles or by visual motion. These symptoms are nausea (stomach awareness, increased salvation, and vomiting), pallor, cold sweating and headache. These symptoms are often accompanied by complex mental reactions including drowsiness, apathy, general discomfort, visual illusions, poor work-motivation and problems with spatial orientation (Thornton et al. 1987; Money, 1991a; Guedry, 1991a). Although the development of the symptoms occurs in a fixed order and over a varying period of time, the patterns of the motion sickness symptomatology may be dependent on the stimulus provoking these symptoms, on a persons susceptibility for the provocative motion stimuli or on the severity and duration of these stimuli (Guedry, 1991a; Dobie and May, 1994). The incidence and severity of motion sickness can further be influenced by age, mental activity, physical fitness or active control of the inducing motion (Guedry, 1991b).

1.2 Etiology of motion sickness and the related spatial orientation

One of the basic causes of motion sickness is changes in linear or rotatory accelerations which act on the peripheral vestibular apparatus. Adaptation to the effect of motion (linear as well as rotatory accelerations) can occur, leading to a disappearance of symptoms. A motion sickness response can appear again when the adapted organism returns to the normal motion environment (Dobie and May, 1994).

Several physiological explanations for the occurrence of motion sickness exist, but the most accepted one is that the symptoms occur because of conflicting sensory information arriving at the "Comparative Center" in the Central Nervous System (Kozlovskaya et al. 1990; Gue-dry, 1991a; Dobie and May, 1994). The visual, vestibular and proprioceptive systems are the principal sensory systems responsible for the normal behaviour of a subject with respect to spatial orientation as well as to motor and autonomic regulation. During sensory conflicts, signals coming from these systems may not only be conflicting at the "Comparative Center" but also be in disagreement with what this comparator expects to receive after a lifetime of experiences of everyday motion in Earth's gravity. Short periods of conflict result in immediate corrective muscle responses. But, sustaining conflicts alter the comparators internal model by adaptation.

Of these sensory systems, the vestibular system is the only one which is exclusively dedicated to detect head and/or body motions in reference to the earth and for generating motor reflexes to improve motion control (balance) while motion is in progress (Guedry, 1991b). Therefore, the vestibular system plays an important role in motion sickness. When its functioning is decreased or absent, partially damaged or completely destroyed (i.e. the semicircular canals and the otolith organs), motion sickness does not occur in humans or animals (Cole-hour, 1965, John-son et al. 1965; Igarashi et al. 1987; Morita et al. 1988). Motion sickness can also occur without a sensory conflict for example, during weightlessness when a signal is absent which is normally present.

1.3 Space Adaptation Syndrome and Sickness induced by long duration Centrifugation

A specific form of motion sickness is Space Motion Sickness or the Space Adaptation Syndrome (SAS) observed in 40% to 70% of the astronauts and cosmonauts subjected to weightlessness (or microgravity) during space flights. The symptoms of motion sickness and postural illusions, tumbling sensations and dizziness were experienced during the first days in orbit and especially appeared when the astronauts were making head or body movements (Homick, 1979; Young et al. 1986; Lin and Reschke, 1987; Kozlovskaya et al. 1990). Although symptoms are similar to those observed in motion sickness on Earth, space motion sickness seems to be a different form of motion sickness. No relationship was found between motion sickness experiences on earth and space motion sickness (Berry, 1970; Re-schke et al. 1984). Moreover, it is not possible to predict with ground-based tests, such as questionnaires, psychodynamics, vestibular function tests and tests in specific nauseogenic environments, who is susceptible for this type of motion sickness.

Orbital space flights expose the organism to a condition in which gravity is reduced to negligible magnitudes of 10-3 to 10-6 G resulting in alterations in the propriocep-tive and the vestibular system (Ross et al. 1987; Roll et al. 1990; Kozlov-skaya et al. 1990; Palo-ski et al. 1993, Dai et al. 1994). During those flights, the output from the semicircular canals (detectors of changes in rotatory accelerations) as well as from the visual system do not change while the output of the vestibular end-organs or otolith organs (detectors of changes in linear accelerations, i.e. the gravity-receptors) is decreased (Gray-briel, 1970). These contradictions in sensory output are responsible for the sensory conflict in the Central Nervous System (CNS) during weightlessness and results in symptoms of motion sickness and spatial disorientation which in turn decreases movement control (Thornton et al. 1987). After a few days the CNS adapts and these symptoms disappear (fig. 1).

Fig. 1. The response of the Central Nervous System (CNS) to altered gravity (adapted from Clément and Berthoz, 1994).

How this central adaptation takes place is un-known. Money (1991b) suggests three possible aspects of central adaptation:

1. Ignoring or suppressing otolith information.

2. Interpretation of all otolith input alterations as changes of linear acceleration rather than changes of tilt angle relative to gravity (sensory reinterpretation).

3. Substitution of other sensors (visual and proprioceptive systems) for the previously used vestibular ones.

Upon return to Earth, the CNS has to readapt to normal gravity, causing again motion sickness, postural and locomotor instabilities during the first days in normal gravity (Dai et al. 1994). Black et al. (1995) found that astronauts showed increased reliance on visual and somatosensory information up to 8 days after landing, which supports the suggestion of Money (1991 b) that the output of the other sensory systems become more important.

Disturbances in spatial orientation were also observed when humans were subjected to increased gravity forces (hyper-gravity). Astronauts exposed to hypergravity in a centrifuge (3 G for 1.5 hours) experienced postural instability and symptoms of motion sickness after return to normal gravity which were similar as the ones they experienced during spaceflight (Bles et al. 1989). In another article Bles and de Graaf (1993) exposed normal subjects to 3 G for 1.5 hours. They found that subjects tried to immobilize their head upon returning to normal gravity because head movements caused symptoms of motion sickness. Furthermore, it became clear that the subjects became more dependent of other sensory systems than the vestibular system.- Therefore, it is suggested that there is a correlation between space motion sickness (SAS) and the hyper-gravity induced motion sickness (Sickness induced by long duration Centrifugation or SIC) experienced upon return to normal-- gravity (Ockels et al. 1990; Bles and de Graaf, 1993).

Experiments with human subjects in space or during a centrifuge-run have the disadvantage that these studies can not cover a extended period of time. For example, centrifuge experiments lasted only for 1.5 hours (Bles and de Graaf, 1993). Furthermore, it is not possible to study the anatomy of the peripheral vestibular end-organs after exposure to micro- or hyper-gravity to assess structural alterations. Animal research allows us to study the effect of sustained altered gravity forces both on structure and on function of the vestibular system and the role of the peripheral vestibular system in the genesis of motion sickness. However, animal research in space is both expensive and difficult. Experiments in a centrifuge are relatively easy to perform and the results of these hyper-gravity experiments can be extrapolated to space research and be used to study the vestibular functioning in general. Up to the present day, most hypergravity research concentrated on its effect- on the morphology and function of parts of the body, such as the cardiovascular system, the muscular system and the bone structure (Oyama and Zeitman, 1967; Martin, 1978; Wunder et al. 1987; Burkovskaya and Krasnov, 1991). Only a few studies were performed studying the effects of hyper-gravity on the vestibular end-organs and the behaviour of animals during hyper- and normal gravity (Clark, 1974; Lim et al. 1974; Krasnov, 1991; Fox et al. 1992). Animal research concentrated on disturbances in spatial orientation, because the classical symptoms of motion sickness (sweating, pallor and vomiting) do not occur in small rodents (Mitchell et al. 1977; Morita et al. 1988). In these studies, the animals were tested after the hypergravity period over a period of 2 weeks. Histological research of the peripheral vestibular system was not included, thus making it impossible to couple behavioural results to structural alterations.

1.4 The scope of the thesis

The experiments presented in this thesis contain both functional and structural studies of the effect of long-term hypergravity on the vestibular system in hamsters. Two introductory chapters precede the chapters in which the experiments are discussed. Chapter 2 gives a short introduction to the vestibular system with the emphasis on the peripheral vestibular system, which consists of the otolith organs (utricle and saccule) and the semicircular canals. The genesis and physiology of the gravity sensing end-organs, especially the otoconial layer, will be discussed in detail. Furthermore, a brief overview is presented of the central vestibular system.

During presentations at congresses a frequently asked question dealt with the effect of hypergravity on various parts of the animals' anatomy. Therefore, the effects of hyper-gravity on body weight, bones and muscles, cardiovascular system, reproduction and the vestibular system are evaluated in chapter 3. Also in chapter 3, extra attention was given to the effects of hyper-gravity on the behaviour of animals after return to normal gravity.

Four experiments were performed during September 1992 and December 1995. The results of these experiments are discussed in chapters 4 to 9. During the start of the experiments in September 1992, no data were available about which tests were useful in studying the effects of hypergravity on vestibular evoked behaviour, especially concerning problems with spatial disorientation, locomotion and swimming. New tests had to be developed or existing tests had to be modified- in order to study the behaviour of the hamsters exposed to prolonged hyper-gravity. The usefulness of these tests were assessed during a pilot experiment. The results of this experiment will be discussed in chapter 4.

Table 1: Schedule of the experiments in this thesis:

The first longterm experiment started in September 1993 with studying the behaviour of 21-day old hamsters which were subjected to 2.5 times normal gravity (2.5 G). The behavioural part of this experiment lasted 10 months (6 months hyper-gravity, 4 months normal gravity). Afterwards, a histological examination of the morphology of the otoco-nial layer of the otolith organs was performed. The results of the histological part of this experiment will be discussed in chapter 5. The consequences of sustained hypergravity on the behaviour of these hamsters and control hamsters is presented in chapter 6.

The effect of hypergravity on behaviour and otoconial morphology in hamsters subjected to the increased gravity forces after maturation is presented in chapter 7. The offspring of these hamsters were used for the last experiment: investigation of the behaviour and structure of the otoconial layers of hamsters conceived, born and raised in hypergravity. The differences in otoconia morphology that were found between hamsters born in hypergravity and control hamsters born in normal gravity are presented in chapter 8. The behavioural differences between these groups are discussed in chapter 9. Furthermore, during this experiment hamsters were placed in the center of the centrifuge and were thereby subjected to rotatory accelerations without the increased G-load, which mainly affected their semicircular canals. The effect of this rotation on the behaviour of these hamsters is also discussed in chapter 9.

A final conclusion concerning the effects of hypergravity before birth, after birth and during adulthood on the function and structure of the peripheral vestibular system is presented in chapter 10 together with recommendations for further research.