Clinical manifestations

Presentation and course

The most characteristic symptoms of motion sickness are pallor, nausea, and vomiting, with vomiting taking prominence in many studies (especially early drug trials) as an essential feature because it is unambiguous, as is the time from onset of provocative motion to onset of vomiting. More recent studies have relied heavily on surrogate electrophysiological measurements (eg, with the electrogastrogram) or compound questionnaire-based scales.

More generally, motion sickness is associated with prominent vegetative disturbances, particularly involving the gastrointestinal and cardiovascular systems. Gastrointestinal symptoms include anorexia, epigastric discomfort, increased salivation, frequent swallowing, belching, borborygmi, nausea, and eventually vomiting. Cardiovascular manifestations can include facial pallor, clammy extremities, and in severe cases hypotension and a shock-like state. In addition, there may be headache (often frontal), vague dizziness, cold sweating (diaphoresis), tremor or tremulousness, mild hypothermia, and changes in respiratory rhythm (eg, sighing, yawning, and hyperventilation with alkalosis, perioral and acral paresthesias, and occasionally tetany and carpopedal spasms). Yawning has been suggested as a behavioral marker of the onset of soporific effects associated with motion sickness (120). Other symptoms include apathy, fatigue, depression, drowsiness, and exhaustion (126; 64; 14; 100; 120).

The earliest symptom of motion sickness is typically epigastric discomfort (“stomach awareness”), followed by malaise and a feeling of warmth, often coincident with the onset of nausea (14). The development of pallor, diaphoresis, and changes in respiratory rhythm herald the onset of vomiting. Vomiting generally produces some temporary symptomatic improvement (126), but continued exposure produces recurrent waves of nausea and ultimately vomiting or retching (if stomach contents have already been expelled).

In some cases of motion sickness that do not reach the threshold of vomiting, manifestations may be limited to fatigue and drowsiness, a situation that has been termed the “sopite syndrome” (64; 14; 100). Even when motion sickness and soporific symptoms are mild, multitasking cognitive performance declines (121).

Susceptibility to motion sickness varies with age, being rare in infants and toddlers below 2 years of age, rising to a peak prevalence between the ages of 4 and 12 years, and then progressively declining (126; 179; 49; 14; 128; 160; 73; 26; 57). In a cross-sectional study, about 40% of children aged 7 to 12 years report motion sickness when traveling in a car or bus (73).

Susceptibility also varies by gender, with women being more susceptible in most studies (126; 67; 68; 88; 137; 179; 160), particularly during menstruation (67; 68); however, certain motion environments with highly selected samples show different patterns (eg, female astronauts are slightly less susceptible to space sickness than their male colleagues) (88; 137; 14), and women do not show greater tachygastria during exposure to optokinetic stimuli (88; 137).

Other risk factors for motion sickness include a history of motion sickness (79); a history of migraine headaches (102; 08; 06; 68; 160), particularly vestibular migraine (196; 123); menstruation (160); pregnancy (160); family history of motion sickness; and Asian heritage (169). Approximately one half to two thirds of migraineurs report motion sickness susceptibility (102; 08; 06; 161; 128). A quick way to determine motion sickness susceptibility in migraine patients is to ask, “Can you read while travelling in a car without getting motion sick?” (01). Risk factors for motion sickness in zero-g parabolic flights include younger age, and protective factors include prior zero-g flight experience (habituation), and antimotion sickness medication (57). Sleep deprivation may contribute to motion sickness incidence and severity and may also degrade the capacity to compensate for perturbed motion (91). Concussion symptoms significantly increase the risk and severity of visually induced motion sickness (97).

Levels of sickness reported in studies anticipating future increase in transportation using automated vehicles are relatively low in vehicles simulating automated vehicles (154). However, the frequency of motion sickness was significantly higher with rear-facing travel than with forward-facing travel, a difference that was particularly pronounced under urban driving conditions (154).

Prognosis and complications

Individual susceptibility to motion sickness varies greatly, as a function of receptivity, adaptability, and retention of adaptation (144). Receptivity reflects a higher intrinsic susceptibility to motion sickness, presumably as a result of a more intense mismatch signal. Adaptability reflects the speed of adjustment, with those adapting more slowly experiencing presumably a more prolonged mismatch signal and, as a result, a higher likelihood of developing motion sickness than rapid adaptors. Retentivity (retention of adaption) reflects how well protective adaptation from prior exposure is retained and able to be used on re-exposure to a provocative motion stimulus.

If the motion is continued for several days, motion sickness generally diminishes or subsides (126; 195). Active movement in the provocative motion environment may facilitate adaption, as long ago “summed up in the commons-sense axiom that one cannot expect to get one’s sea-legs by lying in bed” (74). Suppression of motion sickness with scopolamine slows the rate of adaptation, indicating that if the nervous system “is not challenged by disruption of normal activation, it does not produce the compensation reactions that result in habituation [adaptation]” (195). Some degree of adaptation to optokinetic rotation is retained for up to a year (81).

The terms “adaptation” and “habituation” have been variously used (126). The word “adaptation” has been used to indicate a decline in response to a provocative motion stimulus, the change in neural processes responsible for the decline in response, the process by which the responsible neural processes are modified, or in a general way to refer to all of these (126). Money has suggested that the term “adaptive change” be used to indicate the change in neural mechanisms responsible for a decline in response to provocative motion, the term “habituation” be used for the acquisition of this adaptive change, and the term “dishabituation” be used for the process of losing an adaptive change (126).

Motion sickness is a risk factor for postoperative vomiting in children (32).

Enhanced motion intolerance is also a characteristic of vestibular migraine, suggesting that in vestibular migraine there is a disruption of normal brain mechanisms that control central vestibular signals to minimize intravestibular sensory conflict (187).

Biological basis

Anatomic localization

Motion sickness results from a mismatch of signals from vestibular, visual, and proprioceptive receptors as integrated in the brainstem and cerebellum (143; 142; 134; 188; 175; 42; 161). Vestibular inputs are felt to be fundamental as deaf-mute individuals with bilateral vestibular hypofunction do not become seasick (87); other individuals with bilateral vestibular hypofunction and experimental animals after bilateral labyrinthectomy are similarly spared (165; 96; 126; 14). Visual influences alone can be provocative in susceptible patients (35; 145; 79; 80; 130; 137; 31; 23; 28; 20), but motion sickness can be elicited in blind individuals (61) or in sighted individuals in darkness or with eyes closed (14).

One group has proposed that motion sickness is mediated through the orientation properties of velocity storage in the vestibular system (42; 45; 46) and, specifically, that the nodulus and uvula of the vestibulocerebellum may be the location where sensory mismatch or disparity is assessed, and where habituation occurs (14; 42; 45), but this remains somewhat conjectural (14). Purkinje cells in the cerebellar flocculus have been identified that signal visual-vestibular disparity (115; 14). Furthermore, damage to the vestibulocerebellum impairs or precludes habituation to vestibular stimuli (192) and prevents adaptive modifications to the vestibulo-ocular reflex (150).

Vestibular nuclei have also been proposed as the location of the mismatch comparator (14); however, although second-order neurons in the vestibular nuclei have been identified that respond to visual (optokinetic) and proprioceptive (joint movement) stimuli, no neurons in the vestibular nuclei have been identified to date that signal sensory mismatch (14).

The pathways mediating autonomic nervous system involvement in motion sickness have been incompletely elucidated. Vomiting is mediated by a so-called “vomiting center,” a poorly localized area of the parvicellular reticular formation in the medulla, ventral to the vestibular nuclei and separate from the area postrema (22; 124; 21; 14).

Cerebral influences are not essential for development of the cardinal manifestations of motion sickness, as for example such manifestations can be elicited in experimental decerebrate animals in response to provocative motion stimuli (14); nevertheless the cerebral cortex is involved in the expression of some of the symptoms of motion sickness (eg, nausea, dizziness, somnolence, fatigue) and is involved in conditioned aversive responses to motion or to optokinetic stimuli (14; 55). Other factors can also augment the development of motion sickness, including for example afferent visceral impulses (eg, from movement of viscera distended by gas) and repulsive odors.

Pathophysiology

Sensory conflict. As early as 1881, Irwin suggested a role for sensory conflict in the development of motion sickness, and more specifically a conflict between incoming sensory information from position and motion senses and what is expected from prior experience:

"Sensory rearrangement theory” and “neural mismatch model.” Several authors (127) proposed similar ideas in the century after Irwin’s paper (85) until the synthesis by Reason and Brand in 1975 with their “sensory rearrangement theory” and “neural mismatch model” (143; 142), which utilized some of the concepts of Von Holst and others (185). In their sensory rearrangement theory, Reason and Brant suggested, based on prior information, that the vestibular system must be implicated directly or indirectly (as in visually induced motion sickness), and that provocative stimuli are characterized by “a condition of sensory rearrangement” (ie, learning) in which conflicting motion signals from the labyrinth, eyes, and proprioceptors (ie, new data) are different from “what is expected on the basis of previous transactions with the spatial environment” (existing knowledge). Once learning has occurred, the previously provocative stimulus no longer results in symptoms of motion sickness.

Two types of sensory rearrangement were emphasized: visual-vestibular (ie, a conflict between different sense modalities) and canal-otolith (ie, an intramodality conflict between different vestibular receptor systems). Examples of visual-vestibular conflict or mismatch include reading handheld material in a moving vehicle, making head movements with new glasses (with a changed lens prescription), and watching an IMAX movie. Examples of canal-otolith conflict or mismatch (in a patient with a normal vestibular system) include making head movements in one axis while rotating about another axis (so-called cross-coupled, or Coriolis, stimulation) (90), or making head movements in an atypical acceleration environment (eg, microgravity, or the hypergravity experienced by jet fighter pilots in tight turns). Canal-otolith conflicts are a major contributor to space sickness in astronauts: in weightless the semicircular canals continue to correctly transduce rotational acceleration of the head, but the otoliths provide different afferent information from that provided in a 1-g (terrestrial) environment.

The mechanism proposed by Reason and Brand for adaptation to a provocative stimulus (sensory conflict) was detailed in their neural mismatch model (143; 142) using motor control modeling concepts from Von Holst (185). A “comparator” assesses whether there is a satisfactory match between sensory inputs (“re-afference” from vestibular, visual, proprioceptive signals) and a stored pattern of information in a “neural store” (memory). If not, a “mismatch signal” is generated and fed back to the neural store so the store can be updated using the new information (ie, adaptation, a form of learning). In addition, the mismatch signal can produce illusory and reflex phenomena, as well as motion sickness if the mismatch is greater than some threshold. The neural store and comparator were presumed to be located in the cerebellum.

In this model, the neural store receives information about active movements (via a copy of the command signal called an “efference copy”) and then retrieves and reactivates the patterns of reafferent information that had previously been most closely associated with this specific active movement. The comparator then matches the current sensory information with the reactivated reafferent trace combinations and chooses the optimal trace. When there is a mismatch, the error signal is fed back to the neural store to update the trace, a process of feedback presumed to underlie the process of adaptation.

There has been widespread, though not universal, acceptance of this sensory conflict theory, and available experimental data support the general framework and the specific proposition that sensory conflict causes motion sickness, although symptoms are not necessarily proportional to the magnitude of the conflict or mismatch (188; 128).

Other possible mechanisms. Some have proposed a “leaky integrator” to account for the relatively slow development of motion sickness and its persistence for a period after removal of the provocative stimulus (14) whereas others have suggested that some as-yet-unidentified humoral substance is released and is responsible for the persistence of symptoms.

Just as one must adapt to a novel motion environment, one may also have to readapt to the original terrestrial environment on discontinuation of provocative motion. So, for example, not uncommonly with a cruise aboard ship a sensory mismatch occurs on embarkation, followed by a period of adaptation, and then another sensory mismatch occurs again on disembarkation (from the state adapted to being at sea to being back on land), followed by another period of adaptation. The constellation of symptoms and signs associated with embarkation is appropriately termed motion sickness whereas the syndrome on disembarkation is not (because it is not a provocative motion stimulus, but rather the withdrawal of a provocative motion stimulus) and is more appropriately termed mal de debarquement (ie, sickness of disembarkation). Those who experience mal de debarquement are more likely to have experienced motion sickness (178). Generally, readaptation to the original terrestrial environment proceeds more quickly than adaptation to the novel provocative motion environment.

Deficient postural control or abnormal perceptual-motor responses to disorienting conditions may contribute to motion sickness susceptibility (135; 148; 172). Greater postural instability is positively correlated with motion sickness susceptibility (135), and exposure to provocative moving visual stimuli produces increases in postural sway before onset of motion sickness (172).

Vestibular “overstimulation” as a basis for motion sickness was suggested by studies demonstrating that bilateral vestibular hypofunction prevented development of motion sickness (87). If less vestibular activity (from bilateral vestibular dysfunction) prevented development of motion sickness, it seemed reasonable that motion-induced overstimulation of the vestibular system was responsible for development of motion sickness. However, intriguing this idea may seem, it was overly simplistic and wrong. It was unable to explain why relatively weak vestibular stimulation (eg, cross-coupled stimulation, camel riding) is strongly provocative for development of motion sickness compared to much stronger vestibular stimulation (eg, repeated rapid linear acceleration/deceleration, horseback riding) (126; 14).

Regardless of the mechanism involved, motion sick individuals have genuine deficits in selecting and reweighting multimodal sensory information (48). People have idiosyncratic ways of accomplishing sensory reweighting for postural control, and these various processes are linked to motion sickness susceptibility (48). In addition, vestibular morphological asymmetry can be a source of sensory conflicts in individuals with dysfunctional reciprocal visuovestibular interactions (70).

Migraine-associated vertigo and motion sickness may involve distinct susceptibility genes (138).

Neural structures involved in the production of motion sickness. Neural structures involved in the production of motion sickness include afferent vestibular inputs through the semicircular canals and the otolith organs, and the velocity storage integrator in the vestibular nuclei (43). Separate groups of nodular neurons sense orientation to gravity, roll/tilt, and translation and provide strong inhibitory control of the “vestibular-only” neurons (ie, neurons sensitive only to head movement) of the vestibular complex (43). Velocity storage is produced through the activity of “vestibular-only” neurons under control of neural structures in the nodulus of the vestibulo-cerebellum (43). In addition, the left parietal cortex is involved in motion sickness susceptibility as revealed by multimodal magnetic resonance imaging, which was based on (1) greater network centrality of the left intraparietal sulcus in high, rather than in low, susceptible individuals and (2) linkage of motion sickness susceptibility to white matter integrity in the left inferior fronto-occipital fasciculus (153).

Several kinds of neurotransmitters (eg, acetylcholine, histamine, noradrenaline, GABA) are apparently involved in the processes of motion sickness, based on the pharmacological properties of medications found to be helpful in prevention and controlling motion sickness (Wood and 61; 71; 175; 43). Anticholinergic drugs that don’t cross the blood-brain barrier are ineffective in preventing or treating motion sickness; nevertheless, some authors continue to suggest that anticholinergic drugs may alleviate gastrointestinal symptoms of motion sickness by inhibiting peripheral autonomic nervous system and central vestibulo-autonomic pathways (140). Central cholinergic pathways mediate vection-induced tachygastria with additional modulation by alpha-adrenergic pathways (71). Compounds that selectively antagonize muscarinic M3 receptors, M5 receptors, or both, possess activity against motion sickness (58). Cholinergic and histaminergic pathways are presumably involved in the neural pathways involving the vomiting center (161); scopolamine, the most effective anti-motion sickness medication currently available, is thought to act nonspecifically on all subtypes of muscarinic receptors, and specifically on muscarinic receptors in the vomiting center (161). In addition, acetylcholinergic projections from the nodulus to the stomach, along with other serotonergic inputs from the vestibular nuclei, may induce nausea and vomiting (43). GABA_B receptors modulate and suppress activity in the velocity storage integrator; consequently, baclofen, a GABA_B agonist, causes suppression of motion sickness (43).

Based on studies in rats and dogs, activation of the inner ear arginine vasopressin-vasopressin receptor 2-aquaporin 2 signaling pathway may be involved in the development of motion sickness (197). Furthermore, blocking vasopressin receptor 2 (V2R) with mozavaptan, a V2R antagonist, was effective in reducing motion sickness in both animal species (197).

Many of the physiologic changes in subjects with motion sickness result from altered activity of the autonomic nervous system, and increased secretion of pituitary and adrenal hormones (99; 14).

Gastric and colonic motility decrease, with a concomitant decrease in bowel sounds. Myoelectrical activity of the stomach recorded using surface electrodes affixed to the abdomen (ie, an “electrogastrogram”) shows a reduction in amplitude and an increase in frequency of the background rhythm from three cycles per minute to a faster dysrhythmic four to nine cycles per minute, a phenomenon termed “tachygastria” or “gastric tachyarrhythmia” (170; 71; 129; 130; 99; 88; 14). Tachygastria indicates an increase in frequency of gastric pacemaker potentials and not gastric contraction per se, as tachygastria is associated with decreased gastric motility. Experimental animal data suggest that acute hyperglycemia is related to gastrointestinal symptoms in motion sickness, whereas stable glucose levels can help to prevent or relieve gastrointestinal symptoms in motion sickness (125).

Changes in vascular tone accompanying motion sickness depend on the vascular bed: facial pallor is caused by cutaneous vasoconstriction, but other vessels vasodilate, so for example muscle blood flow increases. The pituitary secretes increased amounts of various hormones, but particularly antidiuretic hormone (vasopressin), which contributes to oliguria (in conjunction with dehydration from decreased intake and vomiting) (99; 14). Levels of the adrenal hormones epinephrine and norepinephrine are elevated as a nonspecific stress response.

Space sickness (space adaptation syndrome)

Space adaptation syndrome or "space sickness" is a kind of motion sickness that occurs during space travel when changes in g-forces compromise one's spatial orientation. For affected individuals, their surroundings visually appear to be in motion but without a corresponding sense of bodily motion. This discrepancy, or visual-vestibular mismatch, leads to motion sickness, which can be severe and disabling.

Gallaudet Eleven. In the late 1950s, NASA and the U.S. Naval School of Aviation Medicine established a joint research program to study the effects of altered gravity on the human body before sending humans into space. The joint program recruited 11 deaf men from Gallaudet College (now Gallaudet University in Washington, DC): the “Gallaudet Eleven." All but one had become deaf in childhood due to spinal meningitis, which damaged their eighth cranial nerves, affecting both hearing and peripheral vestibular function. Their bilateral vestibulopathy left them "immune" to motion sickness (just as William James had recognized in the late 19th century). The men participated in a decade of experiments that assessed their resistance to motion sickness from physiological and psychological perspectives. In one experiment, four subjects spent 12 days inside a 20-foot slow rotation room, rotating at 10 revolutions per minute. In another experiment, subjects participated in a series of zero-g flights in the “Vomit Comet” aircraft to assess body orientation and gravitational cues. A third experiment, in a ferry off the coast of Nova Scotia, was meant to test their reactions to the choppy seas. However, although the test subjects were unbothered by the irregular motion, the researchers were so overcome with sea sickness that the experiment had to be canceled.

Zero-g and the “Vomit Comet.” The NASA Reduced Gravity Program operated by NASA Lyndon B Johnson Space Center (JSC) in Houston, Texas, provided the "weightless" or zero-g environment of space flight for test and training purposes. This was accomplished using specially equipped jets with parabolic flight trajectories. The maneuver could be modified to provide any level of g-force less than 1 g. Some typical g-levels used on different tests and the approximate corresponding time for each maneuver are as follows: (1) negative-g (-0.1 g), 15 seconds; zero-g, 25 seconds; lunar-g (1/6 g), 40 seconds; Martian-g (1/3 g), 30 seconds. The series of parabolas flown by the KC-135 on a given day represents the only accurate Earth-bound means of fabricating the microgravity environment of space travel.

Early flights using this approach were used with the Mercury astronauts and German-American aerospace engineer Wernher von Braun (1912-1977), who had been appointed technical director of the American lunar program in 1961. Weightless flights were a new form of training for the Mercury astronauts. These flights were nicknamed the "vomit comet" because of the nausea that is often induced (though this term doesn't appear often in official NASA documents, and a search for the term on the NASA website brought no returns).

Later, the KC-135A was used for NASA's microgravity parabolic flights. The primary mission of the KC-135 is the refueling of American strategic long-range bombers. NASA's version, KC-135A, was a specially modified turbojet transport with a cargo bay test area approximately 60 feet long, 10 feet wide, and 7 feet high. Painted on the aircraft nose was a somewhat modified flight trajectory from that used earlier. Although many of the NASA public relations photographs show astronauts and astronaut candidates enjoying the experience, this was not the case for many.

Soviet cosmonaut Gherman Stepanovich Titov and the first experience of space sickness. In August 1961, Soviet cosmonaut Gherman Stepanovich Titov (Russian: Герман Степанович Титов, 1935-2000) became the first human to experience space sickness on Vostok 2 and, consequently, was the first person to vomit in space—a rather dubious honor that was recognized in the Guinness World Records. Titov was recognized on a Russian stamp in 2010 and a Moldovan stamp in 2011, but, oddly, only the Moldovan stamp lists his occupation or provides some context by the image presented.

The Garn scale. Beginning in 1981, U.S. Senator Edwin Jacob "Jake" Garn (b 1932) of Utah pressured NASA to let him fly on a Space Shuttle mission, and in 1985 he was included on the STS-51-D mission of the Space Shuttle Discovery. As a Payload Specialist, Garn's role was as a congressional observer and as a subject for medical experiments on space motion sickness. He did acceptably well in training, including his stint on the KC-135 “Vomit Comet.” Having been a Navy combat pilot, Garn boasted before he boarded the shuttle, “I logged more flying hours than most of the astronauts” (117).

After the launch of STS-51-D from Kennedy Space Center, Florida, on April 12, 1985, Garn spent 6 days, 23 hours, and 55 minutes in space. At the conclusion of the mission, Garn had traveled over 2.5 million miles (4.0 million kilometers) in 108 Earth orbits, logging over 167 hours in space—all that time completely miserable with space sickness! Despite having flown more than 10,000 hours as a Navy combat pilot, the space sickness Garn experienced was so severe that a scale for space sickness was jokingly based on him, where "1 Garn" is the highest possible level of sickness (for a human). Garn suffered from space sickness almost from the very start of the mission and needed help walking after the shuttle landed. Because his only substantive role was to participate as a subject for medical experiments on space motion sickness, the Los Angeles Times mockingly concluded after the mission that Garn had done exactly what was expected of him: "[He] got sick" (50).

The "Garn scale" very quickly came into use by NASA scientists and astronauts. Indeed, it was already in place by the time of the next shuttle mission 2.5 weeks later (Mission STS-51-B of Space Shuttle Challender with launch date April 29, 1985). When Dr. Paul Callahan (1933-2005), the biochemist in charge of the animal experiments for the mission, was asked how sick one of the squirrel monkeys on board was, he replied ''2 Garns" (117). ''I knew exactly how the crew felt,'' the Senator said on Monday after the Challenger blasted off and the first reports came in about the monkey's ‘2-Garn’ sickness." (117).

As the New York Times noted in 1985, "officials [at NASA] do not smile when they hear the term [ie, Garn scale], and some even cringe. For them, space sickness is one of the unresolved problems of space flight. ... More than half of all astronauts have suffered, and no pill, no nostrum and no piece of equipment has been able to reduce their discomfort significantly" (117).

In an oral history interview on May 13, 1999, Dr. Robert E Stevenson (1921-2001), the "Father of Space Oceanography, " recalled Garn's experience with space sickness: “Jake Garn was ... pretty sick. ... Jake Garn, he has made a mark in the Astronaut Corps because he represents the maximum level of space sickness that anyone can ever attain, and so the mark of being totally sick and totally incompetent is one Garn. Most guys will get maybe to a tenth Garn, if that high. And within the Astronaut Corps, he forever will be remembered by that” (Stevenson 1999).

Garn's experience even made it to Time magazine's recounting of the highs and lows of space exploration, before and after Soviet cosmonaut Yuri Gagarin was the first to circle the globe from space (101).

The Gary Trudeau Doonesbury cartoon was published on February 13, 1985, with the final panel showing toilet paper floating in weightlessness: "'Barfin' Jake" Garn. A man and his mission."

Curiously, even though it was expected that animals would have even more difficulty with space adaptation than humans, this was not correct as was evident even from the Shuttle Challenger flight at the end of May 1985: "Dr. William E. Thornton, one of two physician-astronauts serving on the Spacelab where the animals are caged, said the Boston monkey was ill briefly after liftoff, but that he himself would have liked to have adapted to the rigors of space as quickly as the monkeys had" (116).

Sensory conflict between semicircular duct and utricular signals. The utricle senses the sum of inertial force due to head translation and head tilt relative to gravitational vertical. Changing from 1-g (Earth) to 0-g (space) environments, an astronaut experiences difficulties in orientation and instability, resembling those of a patient with an acute vestibulopathy (54; 25). Adaptation to the weightless state and readaptation after space flight to the 1-g environment on the ground are both accompanied by various transitory symptoms of vestibular instability, motion sickness (kinetosis), and illusory sensations (184). Utricular adaptive responses to changes in gravity are needed to resolve the underlying conflict, allowing the disorientation to subside. It often takes days for astronauts to recover to tolerable conditions in weightlessness. Similarly, following even relatively short exposures to weightlessness, the astronaut must readapt to the “new” gravity on Earth.

In microgravity, the absence of gravitational stimulation of the otolith organs and the occasional stimulation of the semicircular canals by head and body movements is a form of sensory mismatch, or sensory conflict, between the canal and otolith signals that can elicit motion sickness (54; 44). Experiments in parabolic flights and in spacecraft showed that the otolith organs do respond to changes of acceleration in zero-g environments (54). During the transition from 1-g to zero-g, the frequency of nerve impulses from the otolith organs is initially transiently increased but then becomes drastically decreased before finally dropping to a steady discharge rate that is somewhat lower than normal level (54).

Oculogravic, audiogravic, and somatogravic illusions. Graybiel and colleagues noted in the early 1950s that human subjects experience visual illusions during centrifugation; in particular, a real target and a visual afterimage seemed to rise in the visual field when the subjects were looking toward the axis of rotation ("oculogravic illusion") (60; 60). This and related phenomena have been investigated in a series of experiments spanning more than 60 years (60; 60; 27; 36; 37; 38; 65; 63; 44). The oculogravic illusion is caused by linear acceleration or deceleration, which gives a feeling of a false climb or descent, respectively. Individuals exposed to both a change in magnitude and a rotation of the gravitoinertial acceleration vector experience changes in visual and auditory localization and apparent body orientation—the oculogravic, audiogravic, and somatogravic illusions, respectively (103). The occurrence of these multimodal effects, acting in parallel, suggests that the internal spatial reference system is shifted or remapped in response to the changes in gravitoinertial acceleration ("gravitoinertial acceleration-induced remapping of a peripersonal spatial referent") (103). Part of this illusion is caused by eye movements that are triggered by the changing input from the otolith system, and another part is based on a change of the subjective horizontal (184).

Caloric reactions in weightlessness. The standard thermal convection mechanism of the caloric nystagmus is from Robert Bárány’s publications from 1906 and 1907, work for which he was awarded the Nobel Prize in Medicine or Physiology in 1914 (although there were subsequent allegations that he usurped the work of others) (10; 09; 07). With the patient supine with head up 30 degrees, so that the lateral (horizontal) semicircular canal is oriented vertically, instillation of cold or hot water or air will induce a thermal change in the density of the endolymph of the nearby horizontal canal (which is the semicircular canal located closest to the tympanic membrane) and a resulting thermal convection in the endolymph. This convection current then causes cupular deflection (ampullopetal with cold stimuli, and ampullofugal with warm stimuli).

Stahle summarized it as follows:

Bárány's thermoconvective theory would predict that the intensity of the caloric nystagmus would be equal in intensity in the supine and prone positions (though oppositely directed) and that the head positions in which the nystagmus reverses direction should be 180 degrees apart in the pitch plane. However, it has been known since the 1940s that caloric responses are stronger in a supine than a prone position and that the reversal points are not 180 degrees apart (12; 13; 122; 41; 107).

Coats and Smith studied the relationship between the caloric response and body position through 360 degrees in the pitch plane (41). The maximum response was in the supine position with the head elevated 30 degrees; a rotation of 180 degrees in the pitch plane reversed the direction of nystagmus, but the nystagmus was then of lesser intensity. The supine-prone asymmetry and the other findings suggested that the caloric response was comprised of two components: (1) the standard gravity-dependent convective mechanism and (2) a nonconvective component that does not vary with gravity or, hence, head position and that results in excitation with warm stimuli and inhibition with cool stimuli. With the head 30 degrees up from supine, these different mechanisms are additive, whereas in the prone position with the head down 30 degrees, the two mechanisms operate against each other, with the typical thermoconvective component still dominating (but in any case, with less intense caloric nystagmus in this position because of the oppositely directed effects). Coats and Smith suggested a direct thermal effect on the hair cells or vestibular nerve.

Several human and animal experiments have also been done in subjects with plugging of the horizontal canal (duct). For example, Young and Lowry studied a patient with a unilateral plug of granulation tissue in the horizontal duct (200). Caloric stimuli on the nonplugged side produced nystagmus that reversed directions in the supine and prone positions, whereas caloric stimuli on the plugged side did not vary in the supine and prone positions (slow-phase deviations were ipsilateral with cold stimuli). As the authors concluded, “The findings imply that a caloric mechanism exists which is independent of the conventionally accepted one involving convection currents within the canal.”

During the European Spacelab mission (SL1) in 1983, caloric testing in long-term weightlessness demonstrated that unequivocal caloric nystagmus as present after 2 days of orbital flight (157; 159). When I was a resident in Neurology at University Hospitals in Cleveland, the Spacelab experiments were actively discussed, as were issues of space motion sickness and caloric reactions in microgravity, primarily by Robert Daroff and R John Leigh (109). I was fortunate to have been included in one of their discussions concerning the effect of testing caloric reactions prone versus supine and the implications of the Spacelab experiments. In 2014, after an Oral History Interview of Robert Daroff for the American Academy of Neurology (104), I asked John Leigh to elaborate on his recollections of that time (Leigh RJ 2014, personal communication).

The current understanding of the caloric reaction is that both a gravity-dependent, thermal-convective mechanism and a simultaneous gravity-independent, non-convective thermal mechanism act together in the caloric response (155; 156; 158; 66). In regular clinical testing, the thermal convective mechanism is dominant. However, the other mechanism explains the problems leveled against Bárány's theory as the sole explanation of the caloric reaction. Various explanations of the gravity-independent mechanism have been suggested, including changes in endolymphatic pressure within the semicircular duct, a direct thermal effect on vestibular hair cells, etc. Animal experiments suggest that a direct thermal effect on hair cells is the most likely explanation (201; 174), but it is possible that multiple contributing mechanisms are involved in the generation of the caloric reaction in weightlessness.

There are additional issues that complicate interpretation of the available studies, including the discrepant findings of a disappearance of caloric nystagmus during short episodes of weightlessness and the presence of caloric nystagmus during periods of extended weightlessness (39; 40). Even the issue of convection is now controversial based on experiments in animals (181).

The history of vestibular experiments in space. Vestibular experiments have been one of the top priorities of Skylab, Spacelab, and the International Space Station (146).

Skylab vestibular experiments. Skylab was the first United States space station, which was occupied for about 24 weeks between May 1973 and February 1974. It was operated by three separate 3-astronaut crews: Skylab 2, Skylab 3, and Skylab 4. Skylab's orbit eventually decayed, and it disintegrated in the atmosphere on July 11, 1979, scattering debris across the Indian Ocean and Western Australia.

The Skylab program studied the human body's reaction to long-duration flight in a microgravity (weightless) environment. Skylab astronauts used a rotating "litter chair" to test their balance, coordination, and susceptibility to motion sickness in space. Data were collected about changes in human gravity receptors and about the sensitivity of the semicircular canals of the inner ear where motion is perceived. The motion tests were conducted on each of the long-duration flights of 28, 59, and 84 days in 1973 and 1974.

Spacelab vestibular experiments. Spacelab was a reusable laboratory developed by the European Space Agency (ESA) and was used on spaceflights flown by the U.S. Space Shuttle. Spacelab allowed scientists to perform experiments in microgravity in geocentric orbit. There were at least 22 major Spacelab missions between 1983 and 1998.

Vestibular experiments performed during the flight of Spacelab-1 included caloric stimulation with and without linear accelerations, threshold measurements of response to linear acceleration, assessment of response to motion sickness provocative stimuli, optokinetic stimulation, tests of vestibulo-ocular reflexes during linear and angular stimulation, estimation of the subjective vertical, and assessment of static ocular counterrotation at various tilt angles, using a tilt table (93; 94; 183; 15; 16; 17; 157; 182). The caloric experiment proved that caloric nystagmus may occur in space by a mechanism other than thermoconvection (93; 157; 183). Other tests indicated a greater dependence on visual and somatosensory cues, rather than otolith cues, in the microgravity environment. The raised threshold to perception of linear acceleration in flight and the temporary reduction of ocular counterrotation at lateral tilts postflight suggest a decreased gain of the otolith system as a possible effect of space vestibular adaptation.

International Space Station (ISS) vestibular experiments. The International Space Station (ISS) is the largest artificial object in space and is regularly visible to the naked eye from Earth's surface. It maintains an orbit with an average altitude of 400 kilometers (250 miles) by means of reboost maneuvers using the engines of the Zvezda Service Module or visiting spacecraft. The ISS circles the Earth in about 93 minutes, completing 15.5 orbits per day.

The ISS is a multinational collaborative project involving five participating space agencies: NASA, the Russian State Space Corporation "Roscosmos," the Japan Aerospace Exploration Agency (JAXA), the European Space Agency (ESA), and the Canadian Space Agency (CSA). Construction effectively began with the launch of the first component in 1998, although the first long-term residents did not arrive until November 2, 2000. The station has since been continuously occupied, serving as a microgravity and space environment research laboratory that continues to be used for neurovestibular experiments.

After the U.S. Space Shuttle program ended in 2011, NASA relied on Russia to ferry U.S. astronauts to and from the ISS. U.S. astronauts launched on Soyuz rockets from the Baikonur Cosmodrome (a spaceport in an area of southern Kazakhstan leased to Russia) from 2011 to 2020. American and European astronauts participated with Russian cosmonauts in joint preflight training and vestibular experiments and cooperated during missions as well.

With the launch of Crew Dragon Demo-2 in 2020 (also called Crew Demo-2, SpaceX Demo-2, or Demonstration Mission-2), the U.S. regained the ability to shuttle its own astronauts, the significance of which has gained further salience following the 2022 Russian invasion of Ukraine and subsequent international sanctions on Russia. Russia has reported that it intends to quit the ISS and is working to develop its own orbital station but has presented conflicting information on when the transition will take place.

Epidemiology

Motion sickness susceptibility from infancy to adolescence follows an inverse U-shaped curve with three phases that may be related to the visual-vestibular mismatch theory (84). Motion sickness susceptibility is low in the first year of life; infants do not yet use visual cues for self-motion perception and consequently may be less subject to visual-vestibular mismatch. Motion sickness susceptibility increases to a prepubertal peak, possibly due to sensorimotor maturation. Motion sickness susceptibility declines after puberty, possibly due to habituation through repetitive motion stimulation during vehicle transportations.

For sailors traversing the Southern Ocean, predictive factors identified for motion sickness were greater intrinsic susceptibility (determined from scores on the Motion Sickness Susceptibility Questionnaire), younger age, and greater cabin distance from the center of gravity (19).

Differential diagnosis

Confusing conditions

The diagnosis of motion sickness is usually straightforward and is largely based on the history and a normal examination except for expected autonomic changes (eg, pallor, mild hypothermia, etc.). Motion sickness is distinct from mal de debarquement because subjects with motion sickness experience symptoms during the period of motion and briefly afterwards, whereas mal de debarquement subjects experience symptoms following termination of motion. Furthermore, subjects with mal de debarquement do not commonly have associated nausea, vomiting, diaphoresis, or headache, all of which are common with motion sickness (118; 69).

Diagnostic workup

History and physical examination are usually sufficient to diagnose motion sickness and no diagnostic tests are generally required. However, it should, of course, be remembered that individuals in provocative motion environments may develop other medical illnesses such as gastroenteritis (eg, norovirus exposure on cruise ships) that may present with pallor, nausea, and vomiting.

For research purposes various studies have sought to identify vestibular testing abnormalities in patients with motion sickness susceptibility, with somewhat variable results (59; 141; 119; 131; 75). To date, no clear relationship with predictive power has been established for a measure of vestibular function and motion sickness susceptibility (14). Gordon and colleagues reported that subjects susceptible to motion sickness had significantly higher vestibular-ocular reflex gain, and lower phase lead than nonsusceptible subjects using sinusoidal harmonic acceleration testing with a rotary chair (59). Quarck and colleagues reported no correlation between horizontal canal-ocular reflex gain and motion sickness susceptibility, but a positive correlation with the time constant and a negative correlation with otolith-ocular reflex magnitude (141). Mallinson and Longridge found no relationship between the response to caloric testing and development of motion sickness (119). Hoffer and colleagues reported abnormal vestibulospinal reflex function in 70% of those with motion sickness susceptibility on dynamic platform posturography, and abnormal time constants in 60% on rotary chair step-velocity testing (75).

Management

Behavioral and environmental modifications. Prevention or reduction in the severity of motion sickness can be achieved by avoiding provocative motion environments, or, when such environments cannot be avoided, by either decreasing the intensity of provocative stimuli or increasing individual tolerance to provocative motion (ie, avoidance, minimization, and habituation to motion stimuli) (110). When riding in a car, for example, factors that increase risk of developing motion sickness include reading a book, sitting in the rear seat, stress, on-board smells, and higher on-board temperature (139).

Several behavioral countermeasures are helpful to decrease provocative stimuli. To minimize visual-vestibular mismatch, it helps to be able to have correct visual cues for orientation. Active head tilt towards the centripetal direction and keeping the eyes open greatly reduces the severity of motion sickness (186). It also helps to direct attention to a stable orientational reference (eg, looking at the horizon while aboard ship, or looking out through the windshield at a distant point ahead while a passenger in the front seat of a car, as opposed to looking out a side window from the back seat, or worse trying to read), to avoid enclosed cabins, and to avoid focusing on nearby objects (eg, waves, other vehicles) and especially tasks involving visual search of nearby objects (eg, reading or map reading) (179; 180; 161; 128). Sailors long ago recognized the helpfulness of fixating on the horizon to minimize the likelihood of developing sea sickness, as expressed by Hill:

Anticipation of true motion is helpful, which is maximized by controlling the trajectory, acceleration, and deceleration of a vehicle: of those aboard, the driver, skipper, or pilot is the least likely to suffer motion sickness (165; 14; 33; 82). Compared to the driver, passengers experience more conflicts among multimodal sensory systems and a greater demand for neurophysiological regulation (82).

Some even find it helpful to close the eyes to minimize conflicting visual cues, although this is often not feasible, and some find this more anxiety provoking. To minimize the intensity of the provocative motion stimuli, it is helpful for susceptible individuals to position themselves within a vehicle where low frequency heave acceleration (linear vertical motion) is least, so low-down and near the center of a ship, or near the wing roots of a plane (“over the wing” in airline parlance) (53; 14). With simulator motion sickness, optical correction of the mismatch between the actual distance to the screen and the depicted distances in the simulator’s graphics can significantly reduce (but not eliminate) simulator sickness; airflow also helps (28; 47). Other actions that can sometimes help include lying down in a supine (not prone) position (85; 126; 53; 14; 128); taking off outer layers of clothing, maintaining a lower ambient temperature; providing a fresh breeze on the face (eg, by rolling down the window in a car); regular, deep, slow breathing (89; 198; 199; 128); and listening to music (128).

Consistent with the sensory conflict theory of motion sickness, eliminating visual input may reduce visual/nonvisual sensory conflict by decreasing the influence of the visual channel (86). For example, visual occlusion can decrease motion sickness in a simulator by delaying onset and decreasing severity of symptoms (86). Allocating less attention to central vision during vection also correlates with less motion sickness (191).

Motion sickness may not be governed entirely by an inter-sensory conflict per se, but by beliefs concerning the actual self-motion. In an experiment, illusory self-motion and motion sickness were elicited in healthy human subjects who were seated on a stationary rotary chair inside a rotating optokinetic drum; motion sickness was positively correlated with the discrepancy between subjects' perceived self-motion and their beliefs about the actual motion (132).

Controlled diaphragmatic breathing may be helpful for managing motion sickness in a virtual realty environment (151; 173).

The role of diet is less clear, as some have reported that protein-predominant foods are helpful (111), whereas others have reported the opposite (114). Also, fatty meals (51), high-calorie meals (114), high sodium foods (114), and foods high in thiamin (114) have been associated with motion sickness susceptibility, but it is not clear that any of these reported associations reflect a direct causal relationship.

Increasing individual tolerance can be facilitated by gradual exposure to progressively more intense provocative motion (128). Once habituation has been achieved, regular exposure to the provocative motion stimulus is necessary to maintain it. This can work effectively for sailors and aviators but is not feasible for most individuals who are only occasionally exposed to provocative motion stimuli. More formal desensitization therapy approaches, or variants that include other adapting stimuli (eg, vertical linear oscillation or optokinetic stimuli), sometimes combined with biofeedback and “autogenic therapy” (to help develop an individual’s ability to control autonomic responses) have been used with military personnel (eg, pilots and flight personnel) and occasionally with civilians (14). In addition, verbal suggestions combined with a conditioning procedure can be effective in reducing symptoms of motion sickness (76). Sleep deprivation can accentuate motion sickness severity and decrease the rate of adaptation to motion sickness (91).

Even something as simple as chewing gum may be useful as an affordable, acceptable, and easy-to-access way to mitigate motion sickness (95).

Pharmacotherapy. Pharmacotherapy should be considered in the prevention or treatment of severe motion sickness, particularly for patients who do not respond to conservative measures. Unfortunately, few medications have been proven in laboratory or field trials to be more effective than placebo, and none of the available beneficial medications provide complete protection and none is without side effects (see Table 1) (129; 14; 56). Most of the studies have been conducted on young healthy men (128).

Antimuscarinics (especially scopolamine) and antihistamines are the most effective drugs to control the vegetative symptoms associated with motion sickness (160; 56; 110; 92; 98). These anti-motion sickness medications are most effective when combined with behavioral and environmental modifications (110).

Table 1. Anti-Motion Sickness Drugs Available in the United States

Transdermal scopolamine (l-hyoscine) is probably the most effective available medication for prevention of motion sickness (14; 166). Scopolamine is a centrally active, muscarinic cholinergic antagonist. Scopolamine is not well tolerated by children or the elderly and can aggravate glaucoma or bladder outlet obstruction as in benign prostatic hypertrophy (113). The transdermal patch provides a loading dose of 200 µg, followed by controlled release of 20 µg/hour for up to 3 days. The patch should be applied to the hairless area behind the ear at least 4 to 6 hours before needed. Common side effects include dry mouth (approximately two thirds of patients), drowsiness (less than one sixth of patients), and impaired accommodation with blurred vision and pupillary dilation. Other reported side effects include precipitation of acute angle-closure glaucoma; dry, flushed skin; difficulty urinating; confusion or delirium; memory disturbances; acute psychosis; and hallucinations. Scopolamine may also delay or dampen habituation (128).

Although scopolamine is an effective prophylactic medication, both oral and transdermal formulations are slowly absorbed. Intranasal scopolamine is a promising and well-tolerated alternative for use in dynamic operational environments without significant cognitive or other side effects (163; 168). Unfortunately, more work is still needed to identify optimal intranasal formulation and dispensing methods (168).

Several medications that were developed primarily for their antihistaminic properties are also effective for motion sickness prophylaxis, including promethazine, dimenhydrinate, and meclizine (14; 190). All of these medications are histamine H1-receptor antagonists, but all have central anticholinergic activity as well (14). All of them can cause drowsiness, particularly promethazine and dimenhydrinate. Other side effects include dry mouth, blurred vision, and dizziness.

According to a Cochrane review, first-generation antihistamines probably reduce the risk of developing motion sickness symptoms under naturally occurring conditions of motion in motion sickness-susceptible adults but, compared to placebo, are more likely to cause sedation (92). No studies have evaluated the treatment of existing motion sickness, and few data concern the effect of antihistamines in children. Existing comparisons with scopolamine, antiemetics, and acupuncture are of low or very low certainty (92).

In migraineurs, prophylactic medication for migraine improves the headaches but also improves associated dizziness and motion sickness (108).

Ginger may also be helpful but randomized, blinded, controlled clinical trials are needed (133). Pretreatment with ginger (1 to 2 gm) reduced nausea, tachygastria, and vasopressin release induced by circular vection (112).

Phenytoin at plasma concentrations of 10 to 20 µg/mL is also effective at increasing tolerance to provocative motion, but its use for motion sickness prophylaxis is not recommended because of its narrow therapeutic index, the nonlinear relationship between dose and plasma concentration, and the potential for significant side effects and drug interactions (14; 02).

Amphetamines combined with scopolamine were used empirically for motion sickness in World War II, and later, in the 1960s amphetamines were demonstrated to increase tolerance to provocative motion and to have an additive preventive effect when combined with scopolamine while minimizing some of the drowsiness often associated with scopolamine (14). Subsequently, this combination was used extensively in the space program to minimize space sickness (“space adaptation syndrome”), and it has been studied more recently in combination with promethazine (190). However, because of its addictive potential, amphetamine has not found general utility among civilians (161; 128). Another central nervous system stimulant, modafinil, has not been found effective, but a combination of modafinil and scopolamine allowed experimental subjects to tolerate significantly more head tilts than placebo (78). The combination of modafinil and scopolamine can counteract some of the side effects experienced from scopolamine, including anxiety (202).

Parenteral or rectal administration of antiemetic medications may be necessary for the treatment of severe vomiting due to motion sickness. Once vomiting is controlled, fluid losses can usually be replaced by mouth, but in severe cases or when vomiting has not been controlled, intravenous replacement of fluids and electrolytes may be necessary.

The serotonin agonist, rizatriptan, can reduce vestibular-induced motion sickness in migraineurs, apparently by influencing serotonergic vestibular-autonomic projections (52).

Deceptive placebos, but not nondeceptive open-label placebos, reduce nausea associated with virtual reality, raising questions regarding the utility of open-label interventions for nausea related to motion sickness (11).

Other treatments. In a prospective randomized crossover study, transcutaneous electrical acustimulation ameliorated motion sickness induced by a rotary chair in healthy subjects (203). Transcutaneous electrical acustimulation involves applying a low-intensity electrical current to acupuncture points without puncturing the skin. Compared with sham transcutaneous electrical acustimulation, transcutaneous electrical acustimulation significantly prolonged the total tolerable rotation time of motion sickness stimuli, lowered motion sickness symptom scores, improved the percentage of normal gastric slow waves, and significantly enhanced vagal activity compared with sham transcutaneous electrical acustimulation. In addition, the increased serum levels of arginine vasopressin and norepinephrine on motion sickness stimulation were markedly suppressed by transcutaneous electrical acustimulation treatment compared with sham transcutaneous electrical acustimulation.

In a preliminary study, transcranial direct current stimulation (ie, unipolar cathodal stimulation) over the left parietal cortex can reportedly suppress the vestibular system, increase the time to develop moderate nausea during off-vertical axis rotation, and facilitate recovery from motion sickness symptoms (05). In contrast, anodal stimulation produced no significant effects, excluding both adaptation and nonspecific effects due to transcranial direct current stimulation.

Noisy vestibular stimulation can reduce simulator sickness, but its utility across a broader range of motion sickness conditions has not yet been evaluated (189).