Otology, Neurotology and General ENT Expert Witness

Dr. Glenn Knox, MD - otolaryngology and neurotology

Aviation, Space, and Environmental Medicine x Vol. 85, No. 1 x January 2014

Motion Sickness: An Evolutionary and Genetic Basis for the Negative Reinforcement Model

KNOX GW. Motion sickness: an evolutionary and genetic basis for the negative reinforcement model. Aviat Space Environ Med 2013; 84:46–9.

It has been theorized that motion sickness evolved as a negative reinforcement system which terminates motion involving postural instability and/or sensory confl ict. A hypothetical example is provided by a "thought experiment" whereby protohominids are in a tree looking for food. Selection pressure results when the organisms that have an aversion to motionproducing sensory conflict do not venture out too far on the tree limbs and therefore tend to survive. In order to support an evolutionary model for motion sickness there must be evidence for genetic and/or heritable predisposition. The present study involves a retrospective literature review which reveals abundant evidence for genetic/heritable factors in motion sickness. Examples include genetic polymorphism of the alpha-2-adrenergic receptor, which has been shown to increase susceptibility to motion sickness, examination of family trees revealing heritable motion sickness susceptibility, evidence indicating that Asians are hyper-susceptible to motion sickness, and twin studies, just to mention a few. Thus, the theory of heritable negative reinforcement as a basis for motion sickness is supported by extensive evidence in the medical literature. This theory is compared and contrasted with other theories. Further areas for research are suggested.

LITTLE IS KNOWN about the factors that control individual differences in susceptibility to motion sickness. It has long been suspected that genetic and/or evolutionary factors govern motion sickness susceptibility. Treisman (33) and Money (23) have posited that motion sickness is a manifestation of a defense mechanism against ingested neurotoxins. Oman (24) recently cast doubt on this theory, noting that ingested toxins do not typically cause vertigo. Yates and Kerman ( 38 ) theorized that motion sickness is caused by inappropriate activation of the vestibulocardiovascular reflex. Ossenkopp et al. (25) found that motion sickness symptoms in the rat, such as reduction in body temperature and reduced spontaneous activity, require a functioning vestibular system. Watt et al. (36) postulated that motion sickness serves as a warning against inappropriate motor strategies that are causing undesired changes in vestibular function and subsequent disruption of normal sensorimotor integration. Bowins proposed that "motion sickness evolved as a potent negative reinforcement system designed to terminate motion involving sensory confl ict or postural instability" (4). Termination of such motion would obviously confer a survival advantage by avoidance of falls, injury, and/or death.

METHODS

The primary purpose of this paper is to provide a review of prior studies concerning genetic factors and motion sickness. In order to support an evolutionary model for motion sickness there must be evidence for genetic and/or heritable predisposition. The present study involves a retrospective literature review which reveals abundant evidence for genetic/heritable factors in motion sickness. The scope of review in this paper includes studies involving collection of primary data on susceptibility to motion sickness, correlated with any genetic factor. These studies include prospective motion sickness experiments on selected genetic subpopulations, analysis of motion sickness questionnaires, analysis of families with particular genetic markers, and twin studies involving some or all of the above measures.

The literature search was performed using the National Institutes of Health ' s PUBMED database. Keywords and phrases used in the search included "motion sickness," "genetic," "gene," "heritable," and "heredity." The search was restricted to articles published since 1960. The database was also searched for "related articles" for the most relevant articles. The literature identified through the database search was supplemented by relevant articles and reports cited in selected articles. Articles lacking any English translation and/or reporting individual cases and/or emphasizing auditory phenomena as opposed to vestibular factors were excluded.

Questionnaire Studies

Many studies were identified that utilized mail-in questionnaires. There were four twin studies that will be considered separately. Studies comparing gender effects will be considered separately. Williamson's group (29) found in their survey that if both parents were susceptible to motion sickness, then the child of such parents was five times as likely to be susceptible to motion sickness than the population at large. Diamond's (8) survey of British parents who drove noted that 41% of parents who were susceptible to motion sickness had a child who was also susceptible. Yanus et al. (37) found in a survey of 77 male graduate students that there was a significant correlation between males and their biological fathers in terms of motion sickness symptom severity.

Twin Questionnaire Studies

Four studies were identified that studied twin pairs via questionnaires. Sharma et al. (30) studied 200 twin pairs in India and found 100% concordance to motion sickness susceptibility. Bakwin (3) noted that monozygotic twins are 2.5 3 as likely as dizygotic twins to be concordant. Finally, Reavley et al. (28) noted in a study of 3652 monozygotic and dizygotic twins from the TwinsUK registry that the "pattern of responses indicated a significant genetic contribution." Abe et al. (2) examined 79 pairs of twins at age three and interviewed their mothers. There was a marked increased concordance among the monozygotic twins with respect to motion sickness susceptibility.

Gender Questionnaire Studies, Subjective Reports, and Experimental Observations

Lentz et al. (19) surveyed 3618 college students and found that men had lower "susceptibility scores" than women. Park et al. (26) surveyed 485 subjects and found that women were more likely to report a history of motion sickness susceptibility than men. Many other studies involving survey questionnaires and/or subjective reports suggest that females are more susceptible to motion sickness than males. These include studies involving motion sickness and frostbite (1), seasickness (7, 10, 16), surveys on seasickness (17), airsickness (18, 35), motion sickness on railroad trains (12), loudness estimation and motion sickness (27), and postural ataxia (13). Some investigators, however, observed no significant differences between male and female motion sickness susceptibility. In a prospective analysis of transdermal scopolamine treatment of motion sickness, no signifi cant difference in motion sickness susceptibility between men and women was noted (20). A survey of train passengers also failed to show a gender difference in motion sickness susceptibility (34). Park and Hu (26) noted that women retrospectively reported greater incidence in motion sickness history. However, in prospective experiments, women did not differ signifi cantly from men in severity of motion sickness symptoms while viewing a rotating optokinetic drum. Jokerst et al. (11) also noted that women report more overall symptoms of motion sickness and GI symptoms than men. However, there were no significantly different increases in gastric tachyarrythmia during exposure to optokinetic stimuli such as a rotating drum. Cheung and Hofer (5) also noted a lack of gender difference in motion sickness severity induced by Coriolis cross-coupled exposure. These conflicting results can perhaps be explained by a possible increased level of motion sickness reporting by females. This is in spite of no apparent differences in prospective experimental measures of motion sickness susceptibility between the sexes. As a whole, the evidence suggests that genetic infl uences on motion sickness susceptibility are not sex-linked.

Analysis of Groups with Particular Genetic Markers

Liu et al. analyzed the gene sequence of the alpha-2 adrenergic receptor and found that the "gg" phenotype was 5.8 times more common in Chinese than in European Caucasians. Liu's group also found that the "gg" phenotype was 1.6 times more common in those susceptible to motion sickness (21). Sharma et al. noted that in 291 Indian teenagers, motion sickness susceptibility was twice as likely in those who have a supersensitive taste for phenylthiocarbamide (30). The phenotype for phenylthiocarbamide tasting ability is associated with chromosome 7q and 5p15. Choukèr et al. (6) studied 21 subjects who had blood drawn for endocannabinoid levels. Seven had low levels and high motion sickness susceptibility during parabolic flight. The endocannabinoid receptor is associated with Chr. 6q14-15 and Chr. 1P (6). Golding (9) noted that motion sickness is associated with migraine via the CACNA1 gene, and that motion sickness is also associated with hereditary cochleo-vestibular dysfunction via the COCH gene.

Prospective Motion Sickness Experiments on Selected Genetic Subpopulations

These studies are the most important since they involve prospective studies of genetically defined populations in a laboratory setting. Stern et al. (31, 32) used a rotating optokinetic drum to test for motion sickness susceptibility. Their group found that 80% of Chinese subjects were susceptible to motion sickness as compared to only 50% of European-Americans and African-Americans. Klosterhalfen et al. (14, 15) had similar results with a rotational chair plus head movements as the stimulus.

Lockette et al. (22) had a very comprehensive prospective study. They utilized 115 subjects exposed to a rotational chair plus head movements to "end-point malaise." Blood tests were then used to analyze the gene for the alpha-2 adrenergic receptor on Chromosome 10 for each subject. This gene can be 6.7 Kb or 6.3 Kb in size. Lockette's group found that subjects with a 6.7 Kb gene had chair tolerance time of 365 s on the average. This is compared with subjects with a 6.3 Kb gene who had an average chair tolerance time of 295 s (significant to P = 0.001). The importance of this work is that it is the first study to offer prospective experimental evidence of a link between motion sickness susceptibility and a specific gene. Finley et al. (9) studied 194 healthy subjects and measured autonomic responses to various forms of stress, including Coriolis stress. Their group found that there was "subjective and objective evidence of increased autonomic responsiveness...in those individuals harboring the 6.3 kb allele" as opposed to the 6.7 kb allele. Importantly, it is unclear whether the genetic marker findings represent a marker for motion sickness susceptibility, per se, or a general marker for autonomic sensitivity.

DISCUSSION

The questionnaire studies, including the twin studies, are of course merely suggestive of a link between heredity and motion sickness susceptibility, due to the inherent limitations of a retrospective questionnaire. They are helpful insomuch as they provide clues regarding the genetics of motion sickness susceptibility. For example, based on these studies, it may be worthwhile to further investigate these loci: Chromosome 6q14-15, Chr. 1p, Chr. 7q, and Chr. 5p15. In addition, the information regarding twin concordance is of interest. In particular, Choukèr's work (6) on endocannabinoids provides a theoretical target for pharmacotherapy. Endocannabinoid receptors have been investigated for weight reduction therapy. Finally, as mentioned earlier, the evidence suggests that genetic influences on motion sickness susceptibility are not sex-linked.

Analysis of groups with particular genetic markers and prospective motion sickness experiments on selected genetic subpopulations provide more convincing results. As noted previously, Lockette et al. (9, 22) demonstrated that motion sickness susceptibility correlates with the genome of the alpha-2 adrenergic receptor on Chromosome 10 for each subject. This gene can be 6.7 Kb or 6.3 Kb in size. Lockette's group found that subjects with a 6.7 Kb gene had signifi cantly higher tolerance to motion sickness. Stern's group (31, 32) repeatedly demonstrated that Chinese individuals are hypersusceptible to motion sickness. Remarkably, Liu et al. (21) provides a link between Stern's work and Lockette's findings. That is, Liu found that the alpha-2 adrenergic receptor "gg" phenotype ("gg" equals the 6.3 Kb gene) was found 5.8 times as often in Chinese individuals than non-Chinese individuals. Also, Liu found that the "gg" phenotype occurred 1.6 times as often in those individuals susceptible to motion sickness. We now have a testable theory linking Lockette's work with Stern's results.

Bowins (4) theorized that motion sickness evolved as a negative reinforcement system which terminates motion involving postural instability and/or sensory conflict. He noted that "aberrant motion of this form would have greatly increased the risk of injury or signaled weakness and vulnerability to predators, thereby reducing evolutionary fitness" (4). A hypothetical example is provided by a "thought experiment" whereby protohominids are in a tree looking for food. Selection pressure results when the organisms that have an aversion to motion-producing sensory conflict do not venture out too far on the tree limbs and therefore tend to survive. This does not account for lower nonprimate mammals that demonstrate evidence of motion sickness in the laboratory. These phenomena are perhaps explained by convergent evolution. Perhaps these animals are subject to the same evolutionary considerations and selection pressure.

Motion sickness susceptibility appears to have a genetic basis such as an evolutionary adaptation to avoid dangerous situations. Further research on twins and ethnic groups could focus on the alpha-2 adrenergic receptor gene (Chromosome 10). Other loci could easily be involved (Chromosome 6q14-15, Chr. 1p, Chr. 7q, Chr.5P15). Chinese hypersusceptibility to motion sickness may be explained by the genetics of the alpha-2 adrenergic receptor phenotypes. Such research can guide future pharmacotherapy.

ACKNOWLEDGMENT

Author and affiliation: Glenn Knox, M.D., J.D., Department of Surgery, Division of Otolaryngology, University of Florida Health, Jacksonville, FL.

REFERENCES

  1. Abe K, Amatomi M, Kajiyama S. Genetical aspects of susceptibility to motion sickness and frost bite. Hum Hered 1970; 20:507–16.
  2. Abe K, Oda N, Hatta H. Behavioural genetics of early childhood: fears, restlessness, motion sickness and enuresis. Acta Genet Med Gemellol (Roma) 1984; 33:303–6.
  3. Bakwin H. Car-sickness in twins. Dev Med Child Neurol 1971; 13:310–2.
  4. Bowins B. Motion sickness: A negative reinforcement model. Brain Res Bull 2010; 81:7–11.
  5. Cheung B, Hofer K. Lack of gender difference in motion sickness induced by vestibular Coriolis cross-coupling. J Vestib Res 2003; 12:191–200.
  6. Chouker A, Kaufmann I, Kreth S, Hauer D, et al. Motion sickness, stress, and the endocannabinoid system. Retrieved 1 August 2012 from PLoS ONE 2010; 5(5):e10752.
  7. Cooper C, Dunbar N, Mira M. Sex and seasickness on the Coral Sea. Lancet 1997; 350(9081):892.
  8. Diamond Insurance Company Press Release. Nation's children sick of car journeys. Retrieved 1 August 2012 from http://www.diamond.co.uk/pressReleases/04082011/Nation%27s%20%20children%20sick%20of%20journeys.
  9. Finley JC, Jr., O'Leary M, Wester D, MacKenzie S, Shepard N, et al. A genetic polymorphism of the alpha2-adrenergic receptor increases autonomic responses to stress. J Appl Physiol 2004; 96:2231–9.
  10. Griffi n MJ. Sea Sickness. Motion Sickness: Significance in Aerospace Operations and Prophylaxis, in: AGARD Lecture Series 175, Advisory Group for Aerospace Research and Development, Neuilly-sur-Seine: France, pp. 7.10-7.20.
  11. Jokerst MD, Gatto M, Fazio R, Gianaros PJ, Stern RM, Kock KL. Effects of gender of subjects and experimenter on susceptibility to motion sickness. Aviat Space Environ Med 1999; 70:962–5.
  12. Kaplan I. Motion sickness in railroads. Ind Med Surg 1964; 33:648–51.
  13. Kennedy RS, Berbaum KS, Lilienthal MG. Disorientation and postural ataxia following fl ight simulation. Aviat Space Environ Med 1997; 68:13–7.
  14. Klosterhalfen S, Kellerman S, Pan F. Effects of ethnicity and gender on motion sickness susceptibility. Aviat Space Environ Med 2005; 76:1051–7.
  15. Klosterhalfen S, Pan F, Kellerman S. Gender and race as determinants of nausea induced by circular vection. Gend Med 2006; 3:236–42.
  16. Lawther A, Griffi n MJ. Motions of a ship at sea and the consequent motion sickness amongst passengers. Ergonomics 1986; 29:535–52.
  17. Lawther A, Griffi n MJ. Survey of the occurrence of motion sickness amongst passengers at sea. Aviat Space Environ Med 1988; 59:399–406.
  18. Lederer LG, Kidera GJ. Passenger comfort in commercial air travel with reference to motion sickness. Int Rec Med Gen Pract Clin 1954; 167:661.
  19. Lentz JM, Collins WE. Motion sickness susceptibility and related behavioral characteristics in men and women. Aviat Space Environ Med 1977; 48:316–22.
  20. Levy GD, Rapaport MH. Transderm scopolamine effi cacy related to time of application prior to the onset of motion. Aviat Space Environ Med 1985; 56:591–3.
  21. Liu L, Yuan L, Wang HB. The human alpha(2A) – AR gene and the genotype of site-1296 and the susceptibility to motion sickness. Sheng Wu Hua Xue Yu Sheng Wu Wu Li Xue Bao (Shanghai) (Chinese Journal of Biochemistry and Biophysics) 2002; 34:291–7.
  22. Lockette W, Shepard N, Boismer T. Motion sickness is associated with a genetic polymorphism of the alpha-2 adrenergic receptor. [Abstract] Aviat Space Environ Med 1992; 63:391.
  23. Money K, Cheung B Another function of the inner ear: facilitation of the emetic response to poisons. Aviat Space Environ Med 1983; 54:208–11.
  24. Oman C Motion sickness: a synthesis and evaluation of the sensory conflict theory. Can J Physiol Pharmacol 1990; 68:294–303.
  25. Ossenkopp KP, Rabi YJ, Eckel LA, Hargreaves EL. Reductions in body temperature and spontaneous activity in rats exposed to horizontal rotation: abolition following chemical labyrinthectomy. Physiol Behav 1994; 56:319–24.
  26. Park AH, Hu S. Gender differences in motion sickness history and susceptibility to optokinetic rotation-induced motion sickness. Aviat Space Environ Med 1999; 70:1077–80.
  27. Reason JT. Relations between motion sickness susceptibility, the spiral after-effect and loudness estimation. Br J Psychol 1968; 59:385–93.
  28. Reavley CM, Golding JF, Cherkas LF. Genetic infl uences on motion sickness susceptibility in adult women: a classical twin study. Aviat Space Environ Med 2006; 77:1148–52.
  29. Rowlands E. Is motion sickness in your genes? Research Penn State 2005; Retrived 1 August 2012 from http://www.rps.psu.edu/probing/motionsickness.html
  30. Sharma K, Sharma P, Sharma A. Phenylthiocarbamide taste perception and susceptibility to motion sickness: linking higher susceptibility with higher phenylthiocarbamide taste acuity. J Laryngol Otol 2008; 122:1064–73.
  31. Stern RM, Hu S, LeBlanc R. Chinese hyper-susceptibility to vection-induced motion sickness. Aviat Space Environ Med 1993; 64:827–30.
  32. Stern RM, Hu S, Uijtdehaage SH. Asian hypersusceptibility to motion sickness. Hum Hered 1996; 46:7–14.
  33. Treisman M. Motion sickness: an evolutionary hypothesis. Science 1977; 197:493–5.
  34. Turner M. A survey of motion sickness in road coaches. In: Proceedings of the United Kingdom Informal Group Meeting on Human Response to Vibration, 18-19 September 1975, Farnborough, The Army Personnel Research Establishment, Ministry of Defence. Southampton, UK: University of Southampton, Institute of Sound and Vibration Research; 1975.
  35. Turner M, Griffin MJ, Holland I. Airsickness and aircraft motion during short-haul fl ights . Aviat Space Environ Med 2000; 71:1181–9.
  36. Watt DG, Bouyer LJ, Nevo IT, Smith AV, Tiande Y. What is motion sickness? Ann N Y Acad Sci 1992; 656:660–7.
  37. Yanus TM, Malmstrom FV. Is motion sickness hereditary? Proc Hum Fact Ergon Sci Ann Meeting 1994; 38:796-800.
  38. Yates BJ, Kerman IA. Post-spacefl ight orthostatic intolerance: possible relationship to microgravity-induced plasticity in the vestibular system . Brain Res Brain Res Rev 1998; 28:73–82.

From the University of Florida Health – Jacksonville, Department of Surgery, Division of Otolaryngology, Jacksonville, FL. This manuscript was received for review in August 2012. It was accepted for publication in September 2013.

Address reprint requests and correspondence to: Glenn W. Knox, M.D., J.D., Associate Professor, UF Health-Jacksonville, 653 West Eighth St., Jacksonville, FL 32209; gwknox@bellsouth.net.

Reprint & Copyright © by the Aerospace Medical Association, Alexandria, VA. DOI: 10.3357/ASEM.3519.2013