Symposium on the Role of the Vestibular Organs in Space Exploration (1970)

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Resume of Sessions on Motion Sickness HERBERT L. BORISON Dartmouth Medical School SUMMARY This is a review of the neurological elements responsible for coordinating the vomiting sequence and a discussion of the input and output components of the emetic reflex. Questions are raised as to the nature of the reflex arc in the vomiting of motion sickness, the cause for the long onset of the effects of motion sickness, and the mechanism by which anti-motion-sickness drugs act. REVIEW OF THE VOMITING MECHANISM If we go back into medical history, we find the ancient Egyptians depicted vomiting in a painting decorating a wall in a tomb of Thebes (fig. 1). Presumably the lady is disgorging herself between courses at a banquet. Another early reference to vomiting is in the form of a quotation attributed to a Christian physician of Bagdad, one Elluchasem Elimithar, who died in 1063. He said, "Vomiting is to be preferred when the moon is north of the house in conjunction with a receding planet." I have done some work in the footsteps of Dr. S. C. Wang on the vomiting mechanism. Figure 2 shows a specimen of the brainstem of the cat removed after in situ perfusion with formalin. Such an experimental preparation lacking both forebrain and cerebellum, but of course retaining its peripheral connections, is quite capable of executing the complete emetic process in response to appropriate stimuli —although certainly not to motion. Figure 3 is a drawing of the same surface of the brainstem as photographed in figure 2. The arrows point to the limits of a lesion on the margin of the fourth ventricle that abolishes selectively the emetic effectiveness of a variety of chemical agents without in any way dis- turbing the inherent control mechanism of vomiting. Wang and I described this phenome- non around 1948 and attributed the resulting emetic refractoriness to destruction of a special- ized receptive site that we labeled the medullary emetic chemoreceptor trigger zone (CTZ). We came to this conclusion for two main reasons, namely, that other reflex-induced emetic re- sponses were not attenuated and, most impor- tantly, we had localized the vomiting center itself more deeply, in the reticular formation of the medulla oblongata. Figure 4 is a phantom view of the medulla showing the spatial orienta- tion of various components of the neurological mechanism responsible for coordinating the complex sequential pattern of vomiting. I will not dwell on the experimental evidence for localization of the brainstem "centers." We have concluded from our studies that organization and integration of the emetic response must be accomplished in the reticular formation and that the CTZ on the medullary surface serves solely as a sensory organ —a chemical transducer, if you will —for specific agents in the bloodstream as well as in the cerebrospinal fluid. Figure 5 is a photomicrograph of a section through the region of the fourth ventricle (IV) at the level of the superficial chemoreceptor trigger zone and the deeper vomiting center (VC). It was only after we had developed our 117

118 THE ROLE OF THE VESTIBULAR ORGANS IN SPACE EXPLORATION concept of the emetic chemoreceptor mechanism that we came to know about the vascular epen- dymal organ, area postrema (AP), which coincides morphologically with our localization of the CTZ. FIGURE 1.—Egyptian lady vomiting. A review of the input-output relations of the emetic reflex follows: The chemoreceptor trigger zone is an input component sensitive to emetic substances in blood and cerebrospinal fluid. Vomiting center in bulbar reticular formation Input Output Chemoreceptor, miK'Osal, visceral, vestibular, and psychic elements. Gastrointestinal, secretory, respiratory, postural, and cardiovascular response. I call it "the" emetic reflex for all inputs because we can no longer accept the once-popular notion that the vomiting center itself could respond to emetic stimuli. Thus, by control-system analogy, we envisage a variety of inputs to the "controller" that, after suitable signal processing, delivers its commands to various outputs. On the output side, multiple forms of expres- sion are observed: gastrointestinal, secretory, respiratory, postural, and cardiovascular. There has been much discussion about the use of auto- nomic blockade in the treatment of motion sick- FIGURE 2.— Lower brainstem of the cat with fourth ventricle exposed by removal of the cerebellum. FlcURE 3.— Region of area postrema at "writing point" of fourth ventricle. Arrows indicate the limits of a lesion sufficient to destroy the emetic chemoreceptor trigger zone.

RESUME OF SESSIONS ON MOTION SICKNESS 119 ness. It is, however, irrational to separate cen- tral autonomic from somatic coordination. In- deed, there is no justification for speaking of an autonomic center as such. That is to say, it is impossible to select those neuronal components in the central nervous system, particularly in the reticular formation, that are concerned with auto- nomic as opposed to somatic expression. For our immediate interest, somatic activity is no less important, if not more so, than is autonomic activity in the execution of vomiting. Thus, it is an unprofitable course to seek protection against motion sickness through attempts at autonomic drug blockade of controller and motor functions. While I have had considerable experience with the physiology and pharmacology of vomiting per se, I must confess that my research contact with motion sickness has been strictly limited. In Salivation Forced inspiration Spasmodic respiratory movement Vomiting FIGURE 4. — Phantom view ofhemi-medulla oblongata showing the location of the vomiting center and related integrative loci. FIGURE 5. — Histologic cross section through area postrema (AP) on the surface of the fourth ventricle (IV). center (VC) is situated ventrolaterally. fact, I can tell you about the only really pertinent experiment, if you can call it that, which I have done on the problem. This relates to a cat that resided in my laboratory, which we took one day to visit a country school in the rolling hills of New Hampshire. I was going to show the chil- dren some simple reflex responses to enliven my talk on the subject, "Your Brain Protects You." On our way to the school the cat vomited in the back seat of the car, which is not a very unusual occurrence on the roads of New Hampshire, except that this cat was one of our experimental animals possessing a lesion of the chemoreceptor trigger zone. It had been with us for a long time and had been tested repeatedly in demonstrations to the medical students of its refractoriness to emetic drugs. This raises a real problem with regard to the suspected role of area postrema in motion sickness, as was so thoroughly analyzed by Dr. Money. It is easy to suggest that species difference may account for research discrep- ancies, but I would prefer to think that the role of the chemoreceptor trigger zone in the emetic pathway for motion sickness has still not been fully elucidated. Indeed, the larger question of the involvement of a humoral factor in motion- induced vomiting requires most serious consideration. QUESTIONS REGARDING FURTHER STUDY We have heard much discussion about a highly complex constellation of effects. If we are to make any further progress, we must make sure that we are all talking about the same thing. There must be no equivocation in communica- tion. "Vomiting" is oftentimes avoided or simply implied in speaking about motion sickness. Yet it is the only all-or-none unmistakable con- comitant, as well as the most incapacitating. We all know what vomiting means in relation to motion sickness, but if this is not explicitly stated as part of the response pattern, it cannot be an assumed criterion. The next question that must be raised is whether we are in fact dealing with a single spectrum of effects pro- duced by different stimuli arising from the various types of motion capable of initiating

120 THE ROLE OF THE VESTIBULAR ORGANS IN SPACE EXPLORATION physiological disturbance. This is another source of difficulty in extrapolating laboratory experiments —these elegant laboratory experi- ments on humans —to the real thing that occurs in the field. We are also dealing, in human experimentation, with the same situation faced in clinical pharmacology: namely, with the ever-present hazard of subjective interpretation. Going on to more specific questions: First, what is the essential reflex arc in the vomiting of motion sickness? We know that structures of primary importance include the labyrinthine apparatus and the cerebellum. The whole forebrain can be excluded, which takes care of a huge lineup of secondary effects that in good measure are mediated by the hypothalamus. Second, what accounts for the long onset of effect? This suggests cumulation of a trans- mitter, a neurohumoral substance. In looking at Dr. Graybiel's work with stepwise adaptation, this might be explained by some process such as enzyme induction, which implies that the hypothetical transmitter is destroyed faster than it is being made. Something of this sort could possibly account for adaptation, but where does the process occur? This is, of course, the key problem that poses our third question. At the present time, the two most likely sites of transmitter action for motion- induced vomiting, which should also be con- sidered vulnerable points for therapeutic attack, are the labyrinth itself and the CTZ. Our lack of understanding of the discrete mechanism however, is underscored by the empiric and large- ly ineffective therapy of motion sickness that has availed itself to date. As a result of extensive investigative efforts we are faced with the fact that anti-motion-sickness drug efficacy bears no correlative relationship to other types of anti- emetic drug activity. Thus, antiemetic drugs that are effective antagonists of substances that act on the CTZ are not effective in preventing motion sickness. So where are the anti-motion- sickness drugs acting? We observe many side effects of drug therapy that cast suspicion on actions unrelated to the specific neural pathways participating in motion sickness, at least for the vomiting component. To get to the root of the problem, I think it becomes necessary to work with the stripped animal, that is an animal with- out its forebrain — one that is free of the psychic complications that confound the underlying physiological disturbance. Nothing I have said diminishes the marvelous work being done in humans, with its broad psychological implications. I wish only to inject a note of caution that we may lose sight of the forest because of the trees, and that both ap- proaches are really required. We still have no means of making educated guesses on drug efficacy in motion sickness. The role of our chemoreceptor trigger zone remains an enigma. In the final analysis, it appears that we should be looking for agents that act directly on the labyrinth or, with less likelihood of success, in the cerebellovestibular circuit. I have not spoken specifically of the fine critiques given today on such matters as sensory conflict and the dynamics of motion as a physio- logical stimulus. I hope, in any case, that I have touched most of the bases and beg to be excused for my oversights.

SESSION V Chairman: BO E. GERNANDT INaval Aerospace Medical Institute