REVIEW URRENT C OPINION
Pathophysiology and treatment of motion sickness John F. Golding a and Michael A. Gresty b
Purpose of review Motion sickness remains bothersome in conventional transport and is an emerging hazard in visual information technologies. Treatment remains unsatisfactory but advances in brain imaging, neurophysiology, and neuropharmacology may provide insights into more effective drug and behavioural management. We review these major developments. Recent findings Recent progress has been in identifying brain mechanisms and loci associated with motion sickness and nausea per se. The techniques have included conventional neurophysiology, pathway mapping, and functional MRI, implicating multiple brain regions including cortex, brainstem, and cerebellum. Understanding of the environmental and behavioural conditions provocative of and protective against motion sickness and how vestibular disease may sensitize to motion sickness has increased. The problem of nauseogenic information technology has emerged as a target for research, motivated by its ubiquitous applications. Increased understanding of the neurophysiology and brain regions associated with motion sickness may provide for more effective medication in the future. However, the polysymptomatic nature of motion sickness, high interindividual variability, and the extensive brain regions involved may preclude a single, decisive treatment. Summary Motion sickness is an emerging hazard in information technologies. Adaptation remains the most effective countermeasure together with established medications, notably scopolamine and antihistamines. Neuropharmacological investigations may provide more effective medication in the foreseeable future. Keywords motion sickness, neurophysiology, vestibular, virtual reality
INTRODUCTION
dizziness, and, unsurprisingly, loss of appetite and increased sensitivity to odors [1 ]. The importance and negative impact on performance of sopite is underestimated [2 ], and yawning has been shown to be a behavioural marker [3 ]. The headache provoked can be migrainous and disabling [1 ]. Gastric dysrhythmias may provide a marker of nausea in motion sickness [4], and drop in stomach fundus and sphincter pressure correlates with nausea [5 ]. &&
A resurgence of interest in motion sickness in recent years has been attributable to the use of nauseogenic visual displays and realization of the involvement of the vestibular system, the key mechanism in motion sickness, with clinical disorders including migraine. Nonetheless, characteristic of the history of motion sickness studies, progress has been slow. Some of the central neuronal pathways involved in processing of provocative stimuli have been identified. There is greater understanding of the environmental and behavioural circumstances and medical conditions that modulate motion sickness, but little advance in treatments.
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PROVOCATIVE CIRCUMSTANCES In an extensive survey of a cruise ship, motion sickness was the most common reason for physicians’ a
SYMPTOMATOLOGY Motion sickness is polysymptomatic. Nausea and vomiting may be accompanied by a host of significant symptoms including headache, sopite (drowsiness), sweating, facial pallor, cold sweating, increased salivation, sensations of bodily warmth,
Department of Psychology, University of Westminster and bDivision of Brain Sciences (Neuro-Otology Unit), Imperial College London, Charing Cross Hospital, London, UK Correspondence to Prof John F. Golding, Department of Psychology, University of Westminster, 309 Regent Street, London W1B 2UW, UK. Tel: +44 2079115000; e-mail: [email protected] Curr Opin Neurol 2015, 28:83–88 DOI:10.1097/WCO.0000000000000163
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interpretations and, thus, a frequency region of maximal uncertainty concerning the appropriate frame of reference for orientation. A related ‘ecological’ explanation has been proposed that this frequency tuning is related to mechanical limitations on human body motion. This proposes that a cause of motion sickness may be the difficulty in selecting appropriate tactics to maintain body stability at vehicle motion circa 0.2 Hz, between whole-body GIF alignment, seen at lower frequencies, versus lateropulsion, seen at higher frequencies [1 ].
KEY POINTS Habituation remains the most effective treatment for motion sickness. There have been very few practical advances in antimotion sickness medication over the standard treatments such as scopolamine or antihistamines. Visually induced motion sickness through new technologies such as 3D displays has emerged as a significant new source of motion sickness.
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There has been significant progress in mapping neurophysiological pathways associated with nausea and motion sickness, which may provide a more rational basis for future treatments.
MECHANISMS AND THEORIES
consultations, the incidence of 4.2 per 1000 person/ days being higher than for infections or injuries [6 ]. Up to a quarter of codrivers became motion sick in rally cars if they were reading a book or sitting in the back seat [7]. Although motion perception sensitivity to off-vertical axis rotation increased immediately after return from spaceflight compared to prespaceflight, motion sickness susceptibility decreased [8]. Vection can be induced using auditory cues, although weaker than visually induced vection, and unlike visual motion, auditory cues for motion fail to produce sickness [9]. The addition of body loads while standing can modulate both postural sway and motion sickness induced by visual motion [10]. Watching 3D stereoscopic video films provokes more motion sickness than 2D videos [11 –13 ]. By contrast, another study in both adults and children found only low levels of sickness, with no clear differences between 2D versus 3D, and concluded that use of a stereoscopic 3D system for up to 2 hours was acceptable for most users regardless of age [14 ]. With vehicular movement, nauseogenicity peaks at a mechanical frequency of around 0.2 Hz, and this has also been shown true for exposure to oscillating visual field motion [15 ]. Hypotheses for the frequency dependence of nauseogenicity include a phase error in signalling motion between canal–otolith and somatosensory systems, or a frequency-dependent phase error between the sensed vertical and the subjective or expected vertical. It has also been proposed that a zone of perceptuomotor ambiguity around 0.2 Hz triggers sickness, because at higher frequencies, imposed accelerations are usually interpreted as translation of the self through space, whereas at lower frequencies, imposed accelerations are usually interpreted as a tilt in the gravitoinertial force (GIF) vector [1 ]. The region of 0.2 Hz would be a crossover between these two &&
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The generally accepted explanation of the ‘how’ of motion sickness is based on some form of sensory conflict or sensory mismatch between actual versus expected invariant patterns of vestibular, visual, and kinaesthetic inputs as predicted by an ‘internal model’ [1 ]. Oman and Cullen [16 ] have identified brainstem and cerebellar neurons whose activity corresponds to what might be expected of putative ‘sensory conflict’ neurons. The pathways that integrate vestibular and emetic gastrointestinal signals that produce nausea and vomiting are being elucidated [17 ]. Galvanic vestibular stimulation in the cat produces patterns of neural activation revealed by cfos labelling, some of which correlate with overt signs of motion sickness, others of which show no such relationship but may relate to covert affective aspects such as nausea [18 ]. The onset of visually induced nausea in humans was studied with functional MRI. Increased activity preceding nausea was found in the amygdala, putamen, and dorsal pons/locus coeruleus, whereas, with onset of nausea, activity was observed in a broader network including insular, anterior cingulate, orbitofrontal, somatosensory, and prefrontal cortices. Strong nausea was associated with sustained anterior insula and midcingulate activation, suggesting a close linkage between these specific regions and nausea perception [19 ]. By contrast with the ‘how’ of motion sickness, (i.e., the mechanisms), there is a variety of opinion concerning the ‘why’. The most popular theory is that motion sickness could have evolved from a system designed to protect from potential neurotoxin ingestion by inducing vomiting when unexpected central nervous system inputs are detected that might indicate poisoning (the ‘toxin detector’ hypothesis) [1 ]. This evolutionarily ancient system is inadvertently activated by motion that causes mismatch. Alternative hypotheses propose that motion sickness could be the result of aberrant activation of vestibular–cardiovascular reflexes; it &&
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Pathophysiology and treatment of motion sickness Golding and Gresty
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may be an unfortunate consequence of the physical proximity of the motion detector (vestibular) and vomiting circuitry in the brainstem or originate from a warning system that has evolved to discourage self-exposure to circumstances causing disorientation or motor instability [1 ]. Recent variants of the last idea postulate that motion sickness evolved to discourage risky activity in the ancestral fish that were suffering vestibular malfunction [20] or protohominids would avoid looking for food in swaying trees that might threaten security, thus tending to survive [21].
Comparison bs control *P < 0.05 **P < 0.01 ***P < 0.001 (total n = 326)
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MARKERS FOR INDIVIDUAL SUSCEPTIBILITY Monozygotic and dizygotic twin studies indicate human heritability of motion sickness having a concordance of 70% in childhood decreasing to 55% in adulthood, probably because of habituation to differential environmental effects [1 ]. In shrews, selective breeding for high versus low motion sickness susceptibility strains has shown the importance of genetic determinants and that this extends to anaesthesia-induced emesis, indicating some common mechanisms [22 ]. Very young children are relatively immune to motion sickness, susceptibility then increasing and peaking at around 9 years [23 ]. Susceptibility then progressively declines through adolescence, adulthood, and old age although there are great individual differences [24 ]. Females tend to be more susceptible than males although this has a smaller effect size than age. At around menopause, female susceptibility appears to show a transient increase versus their age-equivalent male contemporaries [24 ]. The reason for this is unknown but there may be contribution from changes in migraine headaches to more ‘vertigo-like’ symptoms that peak around menopause in women, an effect that is not seen in men over the same age period (Thomas Lempert, Berlin, Germany, personal communication). Personality traits such as higher anxiety only show very small relationships with motion sickness susceptibility [1 ,24 ]. Some special groups are at lower or higher risk for motion sickness as revealed by studies using both validated self-report motion sickness susceptibility questionnaires and nauseogenic off-vertical axis rotation [24 ,25 ] (Fig. 1). Compared with controls, patients with bilateral vestibular loss (BVL) are either completely resistant to motion sickness or have very low symptom scores. The observation that some patients with BVL can still exhibit some degree of motion sickness is reminiscent of early reports that pseudocoriolis motion could elicit motion sickness in some patients with BVL [1 ] &&
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Vestib BPPV Vestib Clinical neuritis migraine migraine
FIGURE 1. MS susceptibility scores are shown for patient groups together with significances of comparison with ageequivalent healthy controls. The 95% CI is smaller for controls as a consequence of larger numbers. MS susceptibility for Meniere’s disease is not shown because of small numbers but is probably similar to migraine groups. BPPV, benign paroxysmal positional vertigo; BVL, bilateral vestibular loss; CI, confidence interval; MS, motion sickness; UVL, unilateral vestibular loss [24 ,25 ]. &&
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perhaps indicating that other types of sensory conflict without vestibular input are sometimes possible. Unilateral vestibular loss (UVL) also decreases susceptibility but to a lesser extent than BVL; however, it should be noted that these were ‘compensated’ patients with UVL, that is, who have adapted to sensory conflict caused by the loss of vestibular function on one side, since in the acute phase, the usual observation is that patients with UVL may be more sensitive to motion. Patients with vestibular neuritis and benign paroxysmal positional vertigo show no overall difference in susceptibility compared with controls but within this broad picture many individuals have up or downregulated their sensitivity to motion in response to their disease. Vestibular migraine leads to greatly elevated susceptibility and patients attending migraine clinics, but without vestibular migraine, have equivalent elevations of susceptibility. Other recent studies have shown that vestibular symptoms including motion sickness are greater in patients diagnosed with migraine as opposed to tension-type headache [26]. Some patients with vestibular disease may show higher motion sickness susceptibility to optic flow [27]. A telephone survey suggested that patients with Meniere’s disease had elevated motion sickness susceptibility compared with controls but not as elevated as patients with vestibular migraine [28].
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Physiological markers for predicting motion sickness susceptibility have proved elusive. Although motion sickness produces profound autonomic changes, baseline autonomic characteristics are unlikely to provide useful predictors [29]. The evidence that individual differences in postural stability or perceptual style are good predictors of motion sickness susceptibility seems limited and contradictory [1 ,15 ,30 ]. Shorter time constants of the central vestibular velocity store have been suggested to correlate with reduced motion sickness susceptibility [30 ], but there is sufficient contrary evidence to question if this is a reliable predictor; it has been suggested that it is not the duration of the time constant per se, but the ability to modify readily the time constant that may be a candidate marker for success in motion sickness habituation [1 ]. In a similar vein, reduced thresholds for cervical vestibular-evoked myogenic potentials predict future habituation to seasickness, the suggestion being that cervical vestibular-evoked myogenic potentials at lower thresholds indicates that the individual has broader dynamic range in which the reflex can respond and adapt to a wider array of stimulus amplitudes [31]. Individual differences in brain white matter structure revealed by functional MRI may relate to nausea susceptibility [32]. Patients with persistent Mal de debarquement syndrome exhibit impaired postural stability but do not exhibit differences in intracortical excitability compared with controls [33]. &&
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motion-induced nausea [39]. Exertion of control reduced motion sickness induced by playing video games on a tablet computer [40]. Lying supine, or aligning the body with changes in the GIF environment, or avoiding head movements can reduce motion sickness [1 ]. Consistent with the latter observation, passive restraint of head, shoulders, hips, and knees reduced motion sickness induced by playing a video game while standing [41]. It has long been known that view of a stable horizon reference can increase resistance to motion sickness [1 ] but provision of an artificial horizon failed to have any effect on Mal de debarquement [42]. Standing with a wider stance width and view of the horizon may reduce postural instability and motion sickness at sea [43 ]. Stroboscopic illumination protected against motion sickness for back seat military helicopter personnel, perhaps by reducing retinal slip [44 ]. Controlled regular breathing has been shown to provide increased motion tolerance, and may involve activation of the known inhibitory reflex between respiration and vomiting [34]. Acupressure bands or electroacupuncture have produced conflicting findings as to their effectiveness against motion sickness [34]. Although galvanic vestibular stimulation (GVS) can cause vertigo and nausea, the opposite effect has been proposed that it may provide a novel, modulatory countermeasure for motion sickness [45]. GVS synchronous with the visual field may normalize electrogastrographic and autonomic responses and reduce motion sickness during flight simulation [46 ]. Repetitive transcranial magnetic stimulation can reduce symptoms for Mal de debarquement syndrome [47]. Providing pleasant (or unpleasant) scents had no effect on motion sickness sensitivity, although motion sickness does enhance sensitivity to odors [48]. Listening to pleasant music can reduce visually induced motion sickness [49]. Positive verbal instructions and placebo can promote reductions in motion sickness [50]. &&
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BEHAVIOURAL TREATMENTS AND OTHER COUNTERMEASURES Habituation offers the surest counter measure to motion sickness being free of side-effects and superior to drug treatments but, by definition, is a long-term approach [34]. Optokinetic training gave improvements in reducing seasickness in 71% of those treated versus 12% of controls [35 ]. Motion sickness decreases with repeated exposures to a high-G flight simulator [36]. More comprehensive motion sickness desensitization programmes are highly effective and long-term success rates of 85% have been achieved [37 ]. Visual-vestibulosomatosensory conflict induced by virtual reality increases postural instability and motion sicknesslike symptoms. Subsequently, the contribution of visual inputs is reduced and such sensory reweighting may reflect adaptation to reduce the impact of such visually provocative environments [38]. Being in control, as driver or pilot rather than being the passenger, affords some protection against motion sickness [1 ]. Similarly, enhanced perceptions of control and predictability appear to reduce &
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PHARMACOLOGICAL COUNTERMEASURES Drugs currently used against motion sickness were identified over 40 years ago [1 ]. They may be divided into the following categories: antimuscarinics (e.g., scopolamine), H1 antihistamines (e.g., dimenhydrinate), and sympathomimetics (e.g., amphetamine). Combinations for example scopolamine and dexamphetamine are highly effective since both drugs combine their different antimotion sickness properties and their respective side-effects of sedation and stimulation cancel each other out. However, &&
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Pathophysiology and treatment of motion sickness Golding and Gresty
such combinations are less used because of the abuse potential of amphetamine. The main practical advances have been in drug delivery, such as the transdermal scopolamine patch to provide extended protection but with slow onset, and the ongoing development of rapid acting intranasal scopolamine. Other classes of potent antiemetics are not effective against motion sickness, including D2 dopamine receptor antagonists and 5HT3 antagonists used for side-effects of chemotherapy. This is probably because their sites of action may be at vagal afferent receptors or the brainstem chemoreceptor trigger zone, whereas antimotion sickness drugs act elsewhere [1 ]. Approaches to developing new antimotion sickness drugs include re-examination of ‘old’ drugs such as phenytoin, as well as the development of newer agents such as neurokinin1 antagonists. Such drugs include phenytoin, betahistine, chlorpheniramine, cetirizine, fexofenadine, benzodiazepines and barbiturates, the antipsychotic droperidol, corticosteroids such as dexamethasone, tamoxifen, opioids such as the m-opiate receptor agonist loperamide, neurokinin NK1 receptor antagonists, vasopressin V1a receptor antagonists, N-methyl-D-aspartate antagonists, 3-hydroxypyridine derivatives, 5HT1a receptor agonists such as the antimigraine triptan rizatriptan, and selective muscarinic M3/M5 receptor antagonists such as zamifenacin and darifenacin [1 ]. So far, none of these drugs have any advantage over those currently available for motion sickness. The reasons vary and include lack of efficacy and complex pharmacokinetics or, in those that are effective, unacceptable side-effects. Research, however, continues on drug treatment. Dexamethasone alleviates motion sickness in rats in part by enhancing the endocannabinoid system [51]. Cannabidiolic acid prevents both motion or toxin-induced vomiting in shrews and nausea-induced behaviour in rats [52]. The relative effects on semicircular canal and otolith functions by various antimotion sickness drugs including meclizine, dimenhydrinate combined with cinnarizine, and promethazine combined with D-amphetamine may provide insights into their mechanism of action [53]. Ginger (active ingredient gingerol) may have antiemetic effects for motion sickness but conflicting reports indicate that such effects are weak [54].
pharmacotherapeutic research has mainly targeted nausea and vomiting, so far, with little advantage over established antimotion sickness drugs. Future development of drugs with highly selective affinities to receptor subtypes relevant to motion sickness may produce an antimotion sickness drug of high efficacy with few side-effects. However, the polysymptomatic nature of motion sickness with its high interindividual variability may preclude a single decisive treatment. In this respect motion sickness is similar to migraine, with which motion sickness is frequently compounded.
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Acknowledgements None. Financial support and sponsorship None. Conflicts of interest There are no conflicts of interest.
REFERENCES AND RECOMMENDED READING Papers of particular interest, published within the annual period of review, have been highlighted as: & of special interest && of outstanding interest
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CONCLUSION Main advances in recent years have been in identifying brain mechanisms and loci that are associated with motion sickness and/or nausea. Similarly, although motion sickness is polysymptomatic,
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Neuro-ophthalmology and neuro-otology 12. Solimini AG. Are there side effects to watching 3D movies? A prospective crossover observational study on visually induced MS. PLoS One 2013; 8:e56160. Highlights the implication of new visual technologies for motion sickness. 13. Bos JE, Ledegang WD, Lubeck AJ, Stins JF. Cinerama sickness and postural & instability. Ergonomics 2013; 56:1430–1436. Highlights the implication of new visual technologies for motion sickness. 14. Po¨lo¨nen M, Ja¨rvenpa¨a¨ T, Bilcu B. Stereoscopic 3D entertainment and its & effect on viewing comfort: comparison of children and adults. Appl Ergon 2013; 44:151–160. Gives a different appraisal of the impact new visual technologies for motion sickness. 15. Diels C, Howarth PA. Frequency characteristics of visually induced MS. Hum && Factors 2013; 55:595–604. Builds on previous work showing the frequency tuning of motion sickness. 16. Oman CM, Cullen KE. Brainstem processing of vestibular sensory exaffer&& ence: implications for MS etiology. Exp Brain Res 2014; 232:2483–2492. Synthesis of theory, neurophysiology, and possible identification of the existence of the long predicted ‘sensory conflict’ neuron, the ‘Higgs Boson’ of motion sickness research. 17. Yates BJ, Catanzaro MF, Miller DJ, McCall AA. Integration of vestibular and & emetic gastrointestinal signals that produce nausea and vomiting: potential contributions to motion sickness. Exp Brain Res 2014; 232:2455–2469. Further elucidation of neurophysiological pathways subserving motion sickness in an animal model. 18. Balaban CD, Ogburn SW, Warshafsky SG, et al. Identification of neural networks & that contribute to MS through principal components analysis of fos labelling induced by galvanic vestibular stimulation. PLoS One 2014; 9:e86730. Further elucidation of neurophysiological pathways subserving motion sickness in an animal model. 19. Napadow V, Sheehan JD, Kim J, et al. The brain circuitry underlying the && temporal evolution of nausea in humans. Cereb Cortex 2013; 23:806–813. Elucidation of brain loci associated with nausea in humans. 20. Thornton WE, Bonato F. Space MS and MS: symptoms and etiology. Aviat Space Environ Med 2013; 84:716–721. 21. Knox GW. MS: an evolutionary and genetic basis for the negative reinforcement model. Aviat Space Environ Med 2014; 85:46–49. 22. Horn CC, Meyers K, Oberlies N. Musk shrews selectively bred for MS display && increased anesthesia-induced vomiting. Physiol Behav 2014; 124:129–137. Animal model showing common genetic underpinning of motion sickness and other types of sicknesses. 23. Henriques IF, Douglas de Oliveira DW, Oliveira-Ferreira F, Andrade PM. MS & prevalence in school children. Eur J Pediatr 2014; 173:1473–1482. Pinpoints the age of peak MS susceptibility. 24. Paillard AC, Quarck G, Paolino F, et al. MS susceptibility in healthy subjects && and vestibular patients: effects of gender, age and trait-anxiety. J Vest Res 2013; 23:203–210. Comprehensive survey of motion sickness susceptibility and its modulation by factors including demographic, personality, and vestibular disease. 25. Murdin L, Chamberlain F, Cheema S, et al. Motion sickness in migraine and && vestibular disorders. J Neurol Neurosurg Psychiatry 2014; doi: 10.1136/jnnp2014-308331. [Epub ahead of print] Comprehensive study of motion sickness and its modulation by vestibular disease and migraine using both self-report and response to provocative laboratory stimuli. 26. Akdal G, Ozge A, Ergo¨r G. The prevalence of vestibular symptoms in migraine or tension-type headache. J Vestib Res 2013; 23:101–106. 27. Whitney SL, Sparto PJ, Cook JR, et al. Symptoms elicited in persons with vestibular dysfunction while performing gaze movements in optic flow environments. J Vestib Res 2013; 23:51–60. 28. Sharon JD, Hullar TE. Motion sensitivity and caloric responsiveness in vestibular migraine and Meniere’s disease. Laryngoscope 2014; 124:969–973. 29. Farmer AD, Al Omran Y, Aziz Q, Andrews PL. The role of the parasympathetic nervous system in visually induced MS: systematic review and meta-analysis. Exp Brain Res 2014; 232:2665–2673. 30. Lackner JR. MS: more than nausea and vomiting. Exp Brain Res 2014; & 232:2493–2510. Useful review and highlights the importance of velocity store in motion sickness. 31. Tal D, Hershkovitz D, Kaminski-Graif G, et al. Vestibular evoked myogenic potentials and habituation to seasickness. Clin Neurophysiol 2013; 124:2445–2449. &
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32. Napadow V, Sheehan J, Kim J, et al. Brain white matter microstructure is associated with susceptibility to motion-induced nausea. Neurogastroenterol Motil 2013; 25:448–450. 33. Clark BC, LePorte A, Clark S, et al. Effects of persistent Mal de debarquement syndrome on balance, psychological traits, and motor cortex excitability. J Clin Neurosci 2013; 20:446–450. 34. Bronstein AM, Golding JF, Gresty MA. Vertigo and dizziness from environmental motion: MS and Drivers’ disorientation. Semin Neurol 2013; 33:219–230. 35. Ressiot E, Dolz M, Bonne L, Marianowski R. Prospective study on the efficacy & of optokinetic training in the treatment of seasickness. Eur Ann Otorhinolaryngol Head Neck Dis 2013; 130:263–268. Details an effective behavioural therapy with a controlled trial. 36. Newman MC, McCarthy GW, Glaser ST, et al. MS adaptation to Coriolisinducing head movements in a sustained G flight simulator. Aviat Space Environ Med 2013; 84:104–109. 37. Lucertini M, Verde P, Trivelloni P. Rehabilitation from airsickness in military && pilots: long-term treatment effectiveness. Aviat Space Environ Med 2013; 84:1196–1200. Shows effectiveness of motion sickness desensitization with a long-term follow-up of success rates. 38. Nishiike S, Okazaki S, Watanabe H, et al. The effect of visual-vestibulosomatosensory conflict induced by virtual reality on postural stability in humans. J Med Invest 2013; 60:236–239. 39. Levine ME, Stern RM, Koch KL. Enhanced perceptions of control and predictability reduce motion-induced nausea and gastric dysrhythmia. Exp Brain Res 2014; 232:2675–2684. 40. Stoffregen TA, Chen YC, Koslucher FC. Motion control, MS, and the postural dynamics of mobile devices. Exp Brain Res 2014; 232:1389–1397. 41. Chang CH, Pan WW, Chen FC, Stoffregen TA. Console video games, postural activity, and MS during passive restraint. Exp Brain Res 2013; 229:235–242. 42. Tal D, Wiener G, Shupak A. Mal de debarquement, motion sickness and the effect of an artificial horizon. J Vestib Res 2014; 24:17–23. 43. Stoffregen TA, Chen FC, Varlet M, et al. Getting your sea legs. PLoS One && 2013; 8:e66949. An extensive set of experiments in the real-world environment at sea. 44. Webb CM, Estrada A, Athy JR. MS prevention by an 8-Hz stroboscopic && environment during air transport. Aviat Space Environ Med 2013; 84:177 – 183. Shows how strobe can reduce motion sickness in the real-world environment of passengers in military helicopters. 45. Rizzo-Sierra CV, Gonzalez-Castan˜o A, Leon-Sarmiento FE. Galvanic vestibular stimulation: a novel modulatory countermeasure for vestibular-associated movement disorders. Arq Neuropsiquiatr 2014; 72:72–77. 46. Cevette MJ, Pradhan GN, Cocco D, et al. Electrogastrographic and auto&& nomic responses during oculovestibular recoupling in flight simulation. Aviat Space Environ Med 2014; 85:15–24. The latest of two papers showing GVS as a novel motion sickness countermeasure. 47. Cha YH, Cui Y, Baloh RW. Repetitive transcranial magnetic stimulation for Mal de debarquement syndrome. Otol Neurotol 2013; 34:175–179. 48. Paillard AC, Lamoˆre´ M, Etard O, et al. Is there a relationship between odours and MS? Neurosci Lett 2014; 566:326–330. 49. Keshavarz B, Hecht H. Pleasant music as a countermeasure against visually induced MS. Appl Ergon 2014; 45:521–527. 50. Horing B, Weimer K, Schrade D, et al. Reduction of MS with an enhanced placebo instruction: an experimental study with healthy participants. Psychosom Med 2013; 75:497–504. 51. Zheng Y, Wang XL, Mo FF, Li M. Dexamethasone alleviates MS in rats in part by enhancing the endocannabinoid system. Eur J Pharmacol 2014; 727:99–105. 52. Bolognini D, Rock EM, Cluny NL, et al. Cannabidiolic acid prevents vomiting in Suncus murinus and nausea-induced behaviour in rats by enhancing 5-HT1A receptor activation. Br J Pharmacol 2013; 168:1456–1470. 53. Weerts AP, Vanspauwen R, Fransen E, et al. Space MS countermeasures: a pharmacological double-blind, placebo-controlled study. Aviat Space Environ Med 2014; 85:638–644. 54. Palatty PL, Haniadka R, Valder B, et al. Ginger in the prevention of nausea and vomiting: a review. Crit Rev Food Sci Nutr 2013; 53:659–669.
Volume 28 Number 1 February 2015
Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
Pathophysiology and treatment of motion sickness John F. Golding a and Michael A. Gresty b
Purpose of review Motion sickness remains bothersome in conventional transport and is an emerging hazard in visual information technologies. Treatment remains unsatisfactory but advances in brain imaging, neurophysiology, and neuropharmacology may provide insights into more effective drug and behavioural management. We review these major developments. Recent findings Recent progress has been in identifying brain mechanisms and loci associated with motion sickness and nausea per se. The techniques have included conventional neurophysiology, pathway mapping, and functional MRI, implicating multiple brain regions including cortex, brainstem, and cerebellum. Understanding of the environmental and behavioural conditions provocative of and protective against motion sickness and how vestibular disease may sensitize to motion sickness has increased. The problem of nauseogenic information technology has emerged as a target for research, motivated by its ubiquitous applications. Increased understanding of the neurophysiology and brain regions associated with motion sickness may provide for more effective medication in the future. However, the polysymptomatic nature of motion sickness, high interindividual variability, and the extensive brain regions involved may preclude a single, decisive treatment. Summary Motion sickness is an emerging hazard in information technologies. Adaptation remains the most effective countermeasure together with established medications, notably scopolamine and antihistamines. Neuropharmacological investigations may provide more effective medication in the foreseeable future. Keywords motion sickness, neurophysiology, vestibular, virtual reality
INTRODUCTION
dizziness, and, unsurprisingly, loss of appetite and increased sensitivity to odors [1 ]. The importance and negative impact on performance of sopite is underestimated [2 ], and yawning has been shown to be a behavioural marker [3 ]. The headache provoked can be migrainous and disabling [1 ]. Gastric dysrhythmias may provide a marker of nausea in motion sickness [4], and drop in stomach fundus and sphincter pressure correlates with nausea [5 ]. &&
A resurgence of interest in motion sickness in recent years has been attributable to the use of nauseogenic visual displays and realization of the involvement of the vestibular system, the key mechanism in motion sickness, with clinical disorders including migraine. Nonetheless, characteristic of the history of motion sickness studies, progress has been slow. Some of the central neuronal pathways involved in processing of provocative stimuli have been identified. There is greater understanding of the environmental and behavioural circumstances and medical conditions that modulate motion sickness, but little advance in treatments.
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PROVOCATIVE CIRCUMSTANCES In an extensive survey of a cruise ship, motion sickness was the most common reason for physicians’ a
SYMPTOMATOLOGY Motion sickness is polysymptomatic. Nausea and vomiting may be accompanied by a host of significant symptoms including headache, sopite (drowsiness), sweating, facial pallor, cold sweating, increased salivation, sensations of bodily warmth,
Department of Psychology, University of Westminster and bDivision of Brain Sciences (Neuro-Otology Unit), Imperial College London, Charing Cross Hospital, London, UK Correspondence to Prof John F. Golding, Department of Psychology, University of Westminster, 309 Regent Street, London W1B 2UW, UK. Tel: +44 2079115000; e-mail: [email protected] Curr Opin Neurol 2015, 28:83–88 DOI:10.1097/WCO.0000000000000163
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interpretations and, thus, a frequency region of maximal uncertainty concerning the appropriate frame of reference for orientation. A related ‘ecological’ explanation has been proposed that this frequency tuning is related to mechanical limitations on human body motion. This proposes that a cause of motion sickness may be the difficulty in selecting appropriate tactics to maintain body stability at vehicle motion circa 0.2 Hz, between whole-body GIF alignment, seen at lower frequencies, versus lateropulsion, seen at higher frequencies [1 ].
KEY POINTS Habituation remains the most effective treatment for motion sickness. There have been very few practical advances in antimotion sickness medication over the standard treatments such as scopolamine or antihistamines. Visually induced motion sickness through new technologies such as 3D displays has emerged as a significant new source of motion sickness.
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There has been significant progress in mapping neurophysiological pathways associated with nausea and motion sickness, which may provide a more rational basis for future treatments.
MECHANISMS AND THEORIES
consultations, the incidence of 4.2 per 1000 person/ days being higher than for infections or injuries [6 ]. Up to a quarter of codrivers became motion sick in rally cars if they were reading a book or sitting in the back seat [7]. Although motion perception sensitivity to off-vertical axis rotation increased immediately after return from spaceflight compared to prespaceflight, motion sickness susceptibility decreased [8]. Vection can be induced using auditory cues, although weaker than visually induced vection, and unlike visual motion, auditory cues for motion fail to produce sickness [9]. The addition of body loads while standing can modulate both postural sway and motion sickness induced by visual motion [10]. Watching 3D stereoscopic video films provokes more motion sickness than 2D videos [11 –13 ]. By contrast, another study in both adults and children found only low levels of sickness, with no clear differences between 2D versus 3D, and concluded that use of a stereoscopic 3D system for up to 2 hours was acceptable for most users regardless of age [14 ]. With vehicular movement, nauseogenicity peaks at a mechanical frequency of around 0.2 Hz, and this has also been shown true for exposure to oscillating visual field motion [15 ]. Hypotheses for the frequency dependence of nauseogenicity include a phase error in signalling motion between canal–otolith and somatosensory systems, or a frequency-dependent phase error between the sensed vertical and the subjective or expected vertical. It has also been proposed that a zone of perceptuomotor ambiguity around 0.2 Hz triggers sickness, because at higher frequencies, imposed accelerations are usually interpreted as translation of the self through space, whereas at lower frequencies, imposed accelerations are usually interpreted as a tilt in the gravitoinertial force (GIF) vector [1 ]. The region of 0.2 Hz would be a crossover between these two &&
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The generally accepted explanation of the ‘how’ of motion sickness is based on some form of sensory conflict or sensory mismatch between actual versus expected invariant patterns of vestibular, visual, and kinaesthetic inputs as predicted by an ‘internal model’ [1 ]. Oman and Cullen [16 ] have identified brainstem and cerebellar neurons whose activity corresponds to what might be expected of putative ‘sensory conflict’ neurons. The pathways that integrate vestibular and emetic gastrointestinal signals that produce nausea and vomiting are being elucidated [17 ]. Galvanic vestibular stimulation in the cat produces patterns of neural activation revealed by cfos labelling, some of which correlate with overt signs of motion sickness, others of which show no such relationship but may relate to covert affective aspects such as nausea [18 ]. The onset of visually induced nausea in humans was studied with functional MRI. Increased activity preceding nausea was found in the amygdala, putamen, and dorsal pons/locus coeruleus, whereas, with onset of nausea, activity was observed in a broader network including insular, anterior cingulate, orbitofrontal, somatosensory, and prefrontal cortices. Strong nausea was associated with sustained anterior insula and midcingulate activation, suggesting a close linkage between these specific regions and nausea perception [19 ]. By contrast with the ‘how’ of motion sickness, (i.e., the mechanisms), there is a variety of opinion concerning the ‘why’. The most popular theory is that motion sickness could have evolved from a system designed to protect from potential neurotoxin ingestion by inducing vomiting when unexpected central nervous system inputs are detected that might indicate poisoning (the ‘toxin detector’ hypothesis) [1 ]. This evolutionarily ancient system is inadvertently activated by motion that causes mismatch. Alternative hypotheses propose that motion sickness could be the result of aberrant activation of vestibular–cardiovascular reflexes; it &&
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MS susceptibility 95% CI
may be an unfortunate consequence of the physical proximity of the motion detector (vestibular) and vomiting circuitry in the brainstem or originate from a warning system that has evolved to discourage self-exposure to circumstances causing disorientation or motor instability [1 ]. Recent variants of the last idea postulate that motion sickness evolved to discourage risky activity in the ancestral fish that were suffering vestibular malfunction [20] or protohominids would avoid looking for food in swaying trees that might threaten security, thus tending to survive [21].
Comparison bs control *P < 0.05 **P < 0.01 ***P < 0.001 (total n = 326)
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MARKERS FOR INDIVIDUAL SUSCEPTIBILITY Monozygotic and dizygotic twin studies indicate human heritability of motion sickness having a concordance of 70% in childhood decreasing to 55% in adulthood, probably because of habituation to differential environmental effects [1 ]. In shrews, selective breeding for high versus low motion sickness susceptibility strains has shown the importance of genetic determinants and that this extends to anaesthesia-induced emesis, indicating some common mechanisms [22 ]. Very young children are relatively immune to motion sickness, susceptibility then increasing and peaking at around 9 years [23 ]. Susceptibility then progressively declines through adolescence, adulthood, and old age although there are great individual differences [24 ]. Females tend to be more susceptible than males although this has a smaller effect size than age. At around menopause, female susceptibility appears to show a transient increase versus their age-equivalent male contemporaries [24 ]. The reason for this is unknown but there may be contribution from changes in migraine headaches to more ‘vertigo-like’ symptoms that peak around menopause in women, an effect that is not seen in men over the same age period (Thomas Lempert, Berlin, Germany, personal communication). Personality traits such as higher anxiety only show very small relationships with motion sickness susceptibility [1 ,24 ]. Some special groups are at lower or higher risk for motion sickness as revealed by studies using both validated self-report motion sickness susceptibility questionnaires and nauseogenic off-vertical axis rotation [24 ,25 ] (Fig. 1). Compared with controls, patients with bilateral vestibular loss (BVL) are either completely resistant to motion sickness or have very low symptom scores. The observation that some patients with BVL can still exhibit some degree of motion sickness is reminiscent of early reports that pseudocoriolis motion could elicit motion sickness in some patients with BVL [1 ] &&
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Vestib BPPV Vestib Clinical neuritis migraine migraine
FIGURE 1. MS susceptibility scores are shown for patient groups together with significances of comparison with ageequivalent healthy controls. The 95% CI is smaller for controls as a consequence of larger numbers. MS susceptibility for Meniere’s disease is not shown because of small numbers but is probably similar to migraine groups. BPPV, benign paroxysmal positional vertigo; BVL, bilateral vestibular loss; CI, confidence interval; MS, motion sickness; UVL, unilateral vestibular loss [24 ,25 ]. &&
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perhaps indicating that other types of sensory conflict without vestibular input are sometimes possible. Unilateral vestibular loss (UVL) also decreases susceptibility but to a lesser extent than BVL; however, it should be noted that these were ‘compensated’ patients with UVL, that is, who have adapted to sensory conflict caused by the loss of vestibular function on one side, since in the acute phase, the usual observation is that patients with UVL may be more sensitive to motion. Patients with vestibular neuritis and benign paroxysmal positional vertigo show no overall difference in susceptibility compared with controls but within this broad picture many individuals have up or downregulated their sensitivity to motion in response to their disease. Vestibular migraine leads to greatly elevated susceptibility and patients attending migraine clinics, but without vestibular migraine, have equivalent elevations of susceptibility. Other recent studies have shown that vestibular symptoms including motion sickness are greater in patients diagnosed with migraine as opposed to tension-type headache [26]. Some patients with vestibular disease may show higher motion sickness susceptibility to optic flow [27]. A telephone survey suggested that patients with Meniere’s disease had elevated motion sickness susceptibility compared with controls but not as elevated as patients with vestibular migraine [28].
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Physiological markers for predicting motion sickness susceptibility have proved elusive. Although motion sickness produces profound autonomic changes, baseline autonomic characteristics are unlikely to provide useful predictors [29]. The evidence that individual differences in postural stability or perceptual style are good predictors of motion sickness susceptibility seems limited and contradictory [1 ,15 ,30 ]. Shorter time constants of the central vestibular velocity store have been suggested to correlate with reduced motion sickness susceptibility [30 ], but there is sufficient contrary evidence to question if this is a reliable predictor; it has been suggested that it is not the duration of the time constant per se, but the ability to modify readily the time constant that may be a candidate marker for success in motion sickness habituation [1 ]. In a similar vein, reduced thresholds for cervical vestibular-evoked myogenic potentials predict future habituation to seasickness, the suggestion being that cervical vestibular-evoked myogenic potentials at lower thresholds indicates that the individual has broader dynamic range in which the reflex can respond and adapt to a wider array of stimulus amplitudes [31]. Individual differences in brain white matter structure revealed by functional MRI may relate to nausea susceptibility [32]. Patients with persistent Mal de debarquement syndrome exhibit impaired postural stability but do not exhibit differences in intracortical excitability compared with controls [33]. &&
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motion-induced nausea [39]. Exertion of control reduced motion sickness induced by playing video games on a tablet computer [40]. Lying supine, or aligning the body with changes in the GIF environment, or avoiding head movements can reduce motion sickness [1 ]. Consistent with the latter observation, passive restraint of head, shoulders, hips, and knees reduced motion sickness induced by playing a video game while standing [41]. It has long been known that view of a stable horizon reference can increase resistance to motion sickness [1 ] but provision of an artificial horizon failed to have any effect on Mal de debarquement [42]. Standing with a wider stance width and view of the horizon may reduce postural instability and motion sickness at sea [43 ]. Stroboscopic illumination protected against motion sickness for back seat military helicopter personnel, perhaps by reducing retinal slip [44 ]. Controlled regular breathing has been shown to provide increased motion tolerance, and may involve activation of the known inhibitory reflex between respiration and vomiting [34]. Acupressure bands or electroacupuncture have produced conflicting findings as to their effectiveness against motion sickness [34]. Although galvanic vestibular stimulation (GVS) can cause vertigo and nausea, the opposite effect has been proposed that it may provide a novel, modulatory countermeasure for motion sickness [45]. GVS synchronous with the visual field may normalize electrogastrographic and autonomic responses and reduce motion sickness during flight simulation [46 ]. Repetitive transcranial magnetic stimulation can reduce symptoms for Mal de debarquement syndrome [47]. Providing pleasant (or unpleasant) scents had no effect on motion sickness sensitivity, although motion sickness does enhance sensitivity to odors [48]. Listening to pleasant music can reduce visually induced motion sickness [49]. Positive verbal instructions and placebo can promote reductions in motion sickness [50]. &&
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BEHAVIOURAL TREATMENTS AND OTHER COUNTERMEASURES Habituation offers the surest counter measure to motion sickness being free of side-effects and superior to drug treatments but, by definition, is a long-term approach [34]. Optokinetic training gave improvements in reducing seasickness in 71% of those treated versus 12% of controls [35 ]. Motion sickness decreases with repeated exposures to a high-G flight simulator [36]. More comprehensive motion sickness desensitization programmes are highly effective and long-term success rates of 85% have been achieved [37 ]. Visual-vestibulosomatosensory conflict induced by virtual reality increases postural instability and motion sicknesslike symptoms. Subsequently, the contribution of visual inputs is reduced and such sensory reweighting may reflect adaptation to reduce the impact of such visually provocative environments [38]. Being in control, as driver or pilot rather than being the passenger, affords some protection against motion sickness [1 ]. Similarly, enhanced perceptions of control and predictability appear to reduce &
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PHARMACOLOGICAL COUNTERMEASURES Drugs currently used against motion sickness were identified over 40 years ago [1 ]. They may be divided into the following categories: antimuscarinics (e.g., scopolamine), H1 antihistamines (e.g., dimenhydrinate), and sympathomimetics (e.g., amphetamine). Combinations for example scopolamine and dexamphetamine are highly effective since both drugs combine their different antimotion sickness properties and their respective side-effects of sedation and stimulation cancel each other out. However, &&
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Pathophysiology and treatment of motion sickness Golding and Gresty
such combinations are less used because of the abuse potential of amphetamine. The main practical advances have been in drug delivery, such as the transdermal scopolamine patch to provide extended protection but with slow onset, and the ongoing development of rapid acting intranasal scopolamine. Other classes of potent antiemetics are not effective against motion sickness, including D2 dopamine receptor antagonists and 5HT3 antagonists used for side-effects of chemotherapy. This is probably because their sites of action may be at vagal afferent receptors or the brainstem chemoreceptor trigger zone, whereas antimotion sickness drugs act elsewhere [1 ]. Approaches to developing new antimotion sickness drugs include re-examination of ‘old’ drugs such as phenytoin, as well as the development of newer agents such as neurokinin1 antagonists. Such drugs include phenytoin, betahistine, chlorpheniramine, cetirizine, fexofenadine, benzodiazepines and barbiturates, the antipsychotic droperidol, corticosteroids such as dexamethasone, tamoxifen, opioids such as the m-opiate receptor agonist loperamide, neurokinin NK1 receptor antagonists, vasopressin V1a receptor antagonists, N-methyl-D-aspartate antagonists, 3-hydroxypyridine derivatives, 5HT1a receptor agonists such as the antimigraine triptan rizatriptan, and selective muscarinic M3/M5 receptor antagonists such as zamifenacin and darifenacin [1 ]. So far, none of these drugs have any advantage over those currently available for motion sickness. The reasons vary and include lack of efficacy and complex pharmacokinetics or, in those that are effective, unacceptable side-effects. Research, however, continues on drug treatment. Dexamethasone alleviates motion sickness in rats in part by enhancing the endocannabinoid system [51]. Cannabidiolic acid prevents both motion or toxin-induced vomiting in shrews and nausea-induced behaviour in rats [52]. The relative effects on semicircular canal and otolith functions by various antimotion sickness drugs including meclizine, dimenhydrinate combined with cinnarizine, and promethazine combined with D-amphetamine may provide insights into their mechanism of action [53]. Ginger (active ingredient gingerol) may have antiemetic effects for motion sickness but conflicting reports indicate that such effects are weak [54].
pharmacotherapeutic research has mainly targeted nausea and vomiting, so far, with little advantage over established antimotion sickness drugs. Future development of drugs with highly selective affinities to receptor subtypes relevant to motion sickness may produce an antimotion sickness drug of high efficacy with few side-effects. However, the polysymptomatic nature of motion sickness with its high interindividual variability may preclude a single decisive treatment. In this respect motion sickness is similar to migraine, with which motion sickness is frequently compounded.
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Acknowledgements None. Financial support and sponsorship None. Conflicts of interest There are no conflicts of interest.
REFERENCES AND RECOMMENDED READING Papers of particular interest, published within the annual period of review, have been highlighted as: & of special interest && of outstanding interest
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CONCLUSION Main advances in recent years have been in identifying brain mechanisms and loci that are associated with motion sickness and/or nausea. Similarly, although motion sickness is polysymptomatic,
1. Golding JF, Gresty MA. Motion sickness and disorientation in vehicles. In: Adolfo M, editor. Bronstein Oxford textbook of vertigo and imbalance. Oxford, UK: Oxford University Press; 2013. pp. 293–305. A comprehensive and partially historical review extending to more general disorientation. 2. Lawson BD. MS symptomatology and origins. In: Handbook of virtual en& vironments: design, implementation, and applications. 2nd ed. New York, NY: CRC Press; 2014; pp. 531–599. Highlights significant soporific effect of motion sickness. 3. Matsangas P, McCauley ME. Yawning as a behavioral marker of mild MS and & sopite syndrome. Aviat Space Environ Med 2014; 85:658–661. Highlights significant soporific effect of motion sickness and possible objective markers. 4. Koch KL. Gastric dysrhythmias: a potential objective measure of nausea. Exp Brain Res 2014; 232:2553–2561. 5. Schaub N, Ng K, Kuo P, et al. Gastric and lower esophageal sphincter & pressures during nausea: a study using visual motion-induced nausea and high-resolution manometry. Am J Physiol Gastrointest Liver Physiol 2014; 306:G741–G747. Demonstrates the value of modern internal monitoring technique. 6. Schutz L, Zak D, Holmes JF. Pattern of passenger injury and illness && on expedition cruise ships to Antarctica. J Travel Med 2014; 21:228– 234. A large study that also quantified the relative importance of motion sickness compared to other common disorders. 7. Perrin P, Lion A, Bosser G, et al. MS in rally car co-drivers. Aviat Space Environ Med 2013; 84:473–477. 8. Cle´ment G, Wood SJ. Eye movements and motion perception during offvertical axis rotation after spaceflight. J Vestib Res 2013; 23:13–22. 9. Keshavarz B, Hettinger LJ, Vena D, Campos JL. Combined effects of auditory and visual cues on the perception of vection. Exp Brain Res 2014; 232:827–836. 10. Koslucher FC, Haaland EJ, Stoffregen TA. Body load and the postural precursors of MS. Gait Posture 2014; 39:606–610. 11. Naqvi SA, Badruddin N, Malik AS, et al. Does 3D produce more symptoms & of visually induced MS? Conf Proc IEEE Eng Med Biol Soc 2013; 2013:6405–6408. Highlights the implication of new visual technologies for motion sickness. &&
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32. Napadow V, Sheehan J, Kim J, et al. Brain white matter microstructure is associated with susceptibility to motion-induced nausea. Neurogastroenterol Motil 2013; 25:448–450. 33. Clark BC, LePorte A, Clark S, et al. Effects of persistent Mal de debarquement syndrome on balance, psychological traits, and motor cortex excitability. J Clin Neurosci 2013; 20:446–450. 34. Bronstein AM, Golding JF, Gresty MA. Vertigo and dizziness from environmental motion: MS and Drivers’ disorientation. Semin Neurol 2013; 33:219–230. 35. Ressiot E, Dolz M, Bonne L, Marianowski R. Prospective study on the efficacy & of optokinetic training in the treatment of seasickness. Eur Ann Otorhinolaryngol Head Neck Dis 2013; 130:263–268. Details an effective behavioural therapy with a controlled trial. 36. Newman MC, McCarthy GW, Glaser ST, et al. MS adaptation to Coriolisinducing head movements in a sustained G flight simulator. Aviat Space Environ Med 2013; 84:104–109. 37. Lucertini M, Verde P, Trivelloni P. Rehabilitation from airsickness in military && pilots: long-term treatment effectiveness. Aviat Space Environ Med 2013; 84:1196–1200. Shows effectiveness of motion sickness desensitization with a long-term follow-up of success rates. 38. Nishiike S, Okazaki S, Watanabe H, et al. The effect of visual-vestibulosomatosensory conflict induced by virtual reality on postural stability in humans. J Med Invest 2013; 60:236–239. 39. Levine ME, Stern RM, Koch KL. Enhanced perceptions of control and predictability reduce motion-induced nausea and gastric dysrhythmia. Exp Brain Res 2014; 232:2675–2684. 40. Stoffregen TA, Chen YC, Koslucher FC. Motion control, MS, and the postural dynamics of mobile devices. Exp Brain Res 2014; 232:1389–1397. 41. Chang CH, Pan WW, Chen FC, Stoffregen TA. Console video games, postural activity, and MS during passive restraint. Exp Brain Res 2013; 229:235–242. 42. Tal D, Wiener G, Shupak A. Mal de debarquement, motion sickness and the effect of an artificial horizon. J Vestib Res 2014; 24:17–23. 43. Stoffregen TA, Chen FC, Varlet M, et al. Getting your sea legs. PLoS One && 2013; 8:e66949. An extensive set of experiments in the real-world environment at sea. 44. Webb CM, Estrada A, Athy JR. MS prevention by an 8-Hz stroboscopic && environment during air transport. Aviat Space Environ Med 2013; 84:177 – 183. Shows how strobe can reduce motion sickness in the real-world environment of passengers in military helicopters. 45. Rizzo-Sierra CV, Gonzalez-Castan˜o A, Leon-Sarmiento FE. Galvanic vestibular stimulation: a novel modulatory countermeasure for vestibular-associated movement disorders. Arq Neuropsiquiatr 2014; 72:72–77. 46. Cevette MJ, Pradhan GN, Cocco D, et al. Electrogastrographic and auto&& nomic responses during oculovestibular recoupling in flight simulation. Aviat Space Environ Med 2014; 85:15–24. The latest of two papers showing GVS as a novel motion sickness countermeasure. 47. Cha YH, Cui Y, Baloh RW. Repetitive transcranial magnetic stimulation for Mal de debarquement syndrome. Otol Neurotol 2013; 34:175–179. 48. Paillard AC, Lamoˆre´ M, Etard O, et al. Is there a relationship between odours and MS? Neurosci Lett 2014; 566:326–330. 49. Keshavarz B, Hecht H. Pleasant music as a countermeasure against visually induced MS. Appl Ergon 2014; 45:521–527. 50. Horing B, Weimer K, Schrade D, et al. Reduction of MS with an enhanced placebo instruction: an experimental study with healthy participants. Psychosom Med 2013; 75:497–504. 51. Zheng Y, Wang XL, Mo FF, Li M. Dexamethasone alleviates MS in rats in part by enhancing the endocannabinoid system. Eur J Pharmacol 2014; 727:99–105. 52. Bolognini D, Rock EM, Cluny NL, et al. Cannabidiolic acid prevents vomiting in Suncus murinus and nausea-induced behaviour in rats by enhancing 5-HT1A receptor activation. Br J Pharmacol 2013; 168:1456–1470. 53. Weerts AP, Vanspauwen R, Fransen E, et al. Space MS countermeasures: a pharmacological double-blind, placebo-controlled study. Aviat Space Environ Med 2014; 85:638–644. 54. Palatty PL, Haniadka R, Valder B, et al. Ginger in the prevention of nausea and vomiting: a review. Crit Rev Food Sci Nutr 2013; 53:659–669.
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