Substantial efforts have been devoted to exploring the determinants of individual motion sickness (MS) susceptibility. Considering the demographic factors, for example, women are more susceptible to MS than men (1–5), age also has a considerable effect on MS susceptibility; young people are more susceptible to MS than elderly people (1, 2, 4, 5). Considering the psychological factors, there is ample evidence indicating anxiety traits to be associated with MS susceptibility (4–6). Identification of individuals who are prone to MS is important for proactive measures such as recommending less provocative transportation or prescribing MS medicine.

Although it is widely accepted that sensory conflicts of motion information between different modalities cause MS (7–9), vestibular function per se is a predominant physiological determinant of MS susceptibility. The most prominent example is of patients with bilateral vestibular loss, who tend to be less susceptible to MS (4, 10). In addition, it is well documented that astronauts with higher asymmetry in bilateral vestibular function were prone to space MS (8, 11–16). These facts suggest that when placed in an altered acceleration environment, asymmetry of bilateral vestibular function, especially otolith functions, which rarely manifests in daily life can play a role in the development of MS.

However, it remains unclear which functions in the vestibular pathway are associated with MS susceptibility. Vestibular signals from the end organs (otoliths and canals) reach the vestibular nuclei via the vestibular nerve (17–19). The signal is then divided into two functionally distinct pathways, one of which is the reflex pathway, which plays a critical role in stabilizing gaze and posture (20). The other is the cortical pathway via the thalamus (21–23), which is critical for spatial orientation (21, 24, 25). Considering the vestibular reflex pathway, there are few studies suggesting that reflex sensitivity is associated with MS susceptibility (26–28). In contrast, to the best of our knowledge, no data exist on the relationship between vestibular cortical functioning and MS susceptibility in healthy individuals. The best way of filling this gap in the literature is to examine vestibular functions in both the reflex and cortical pathways in the same study population in relation to MS susceptibility.

In the current study, we aimed to investigate whether vestibular functions in the reflex and cortical pathways could predict individual MS susceptibility. Specifically, vestibular functions in the reflex and cortex pathway were assessed using two clinical tests: the ocular counter-rolling (OCR) test for otolith-reflex sensitivity to detect linear acceleration (13, 14, 29, 30) and the head-tilt subjective visual vertical (HT-SVV) test (31, 33). There are a variety of tests that assess the bilateral asymmetry of otolith function. Among these, a widely used clinical test is the vestibular evoked myogenic potentials (VEMP) test in which each unilateral otolith can be separately stimulated by bone/air conduction of sound (34, 35). The VEMP and OCR are complementary tests that evaluate different aspects of otolith function (36). For the aim of this study, we adopted the OCR and HT-SVV tests providing different outcomes to compared the impacts of asymmetry in reflex and cortical pathways on MS susceptibility using the same vestibular stimulation (i.e., lateral head tilt) with the HT-SVV test. Meanwhile, the OCR test produces a different outcome, torsional eye movement around the gaze axis, from the HT-SVV test that measures subjective vertical tests bring different outcomes, that is, torsional eye movement around gaze axis and subjective vertical, respectively. Finally, bilateral asymmetry in each vestibular sensitivity was compared between MS-susceptible and control adults.

Figure 2 is a histogram of the MSSQ scores. Among 402 qualified applicants, MS-susceptible (n = 36) and control (n = 36) groups were selected from both ends of the histogram. All the participants completed the vestibular function tests and were endured to have clinically normal vestibular function. More importantly, there were no between-group differences in the body sway test or the vHIT test (P > 0.1, Supplementary Material for more details). Meanwhile, adequate image quality for the OCR test was not acquired in 21 participants. Thus, the statistical tests of between-group differences in asymmetry indices were conducted in a subpopulation of the participants consisting of 26 MS-susceptible and 25 controls (Figure 1).

Figure 3 shows example results of the HT-SVV test and the OCR test from a MS-susceptible individual (49 year-old female). In this individual, gains and asymmery indices were calculated as follows: S_l = 1.18, S_r = 1.21, I_SVV = 0.013, O_l = −0.25, O_r = −0.35, I_OCR = 0.17.

Figure 4 shows the pairwise correlations between asymmetry indices of vestibular functions. There were no significant correlations between OCR asymmetry and HT-SVV asymmetry (r = −0.03, P = 0.83; (Figure 4), indicating that each index could assess an independent aspect of vestibular functional asymmetry.

Table 1 summarizes the results of the OCR and HT-SVV tests. Between-group comparisons revealed a significantly greater asymmetry index of OCR gains in the MS-susceptible rather than the control group Figure 5A) and the comparable asymmetry index of HT-SVV gains between the two groups Figure 5B). In Figure 5A, some outliers were apparent. Thus, we performed Smirnov-Grubbs' outlier test in each group and found three from the MS susceptible and one from the control group as outliers. Having excluded these four outliers, the significant difference remained between the two groups after Welch's t-test (d = 0.66, P = 0.031). Although similar vestibular stimulation (lateral head tilt) was used in both the OCR and the HT-SVV tests, OCR asymmetry was significantly greater than HT-SVV asymmetry (MS-susceptible: d = 0.84, P < 0.001; control: d = 0.65, P = 0.003; paired t-test).

To further confirm the non-significance of HT-SVV asymmetry with a larger sample size, we performed between-group comparisons using all the participants who completed the test (i.e., n = 36 for MS-susceptible group and n = 36 for control group). Consequently, the result was replicated in HT-SVV asymmetry (MS-susceptible: 0.046 ± 0.007; control: 0.044 ± 0.007; g = 0.03, P = 0.90).

Moreover, we compared the MSSQ subscale scores for each vehicle type between individuals with low and high OCR asymmetry in the MS-susceptible group. Using the mean OCR asymmetry index as a threshold, the MS-susceptible group was further divided into low (n = 18) and high (n = 8) asymmetry subgroups. Between-group comparisons in the MSSQ subscale scores revealed, interestingly, that the low OCR asymmetry group was more susceptible to motion stimuli in playground equipment, such as swings and roundabouts, compared to the high OCR asymmetry group. These differences were statistically significant after Bonferroni correction for multiple comparisons (P = 0.001, g = 1.12 for swings; P = 0.002, g = 1.03 for roundabouts; Figure 6).

In the current study, we examined which vestibular functions were associated with MS susceptibility. The results showed a significant association of MS susceptibility with OCR, but not HT-SVV asymmetry. In addition, neither postural control (body sway test) nor semicircular canal function (vHIT) was associated with MS susceptibility. Taken together, these findings suggest that functional asymmetry in bilateral utricles perceiving lateral head acceleration in the vestibular reflex pathway may play a role in individual susceptibility to MS, and this role is not influenced by the asymmetry in cortical function perceiving lateral head acceleration.

Associations between functional asymmetry in the otolith reflex pathway and MS susceptibility have been repeatedly demonstrated. For example, Singh et al. (27) reported that bilateral asymmetry in vestibular-evoked myogenic potentials originating from the otolith organs was significantly higher in individuals susceptible to MS than in controls. In addition, it is well documented that astronauts with higher OCR asymmetry were more prone to space MS (8, 11–16). Such accumulated evidence including ours is consistent with the most accepted theory regarding the etiology of MS, the so-called sensory mismatch theory (7, 8), although it suggests that sensory mismatch not only between different sensory modalities but also within the vestibular sense is capable of causing MS.

The current study was conducted under the assumption that OCR asymmetry represents functional asymmetry in the bilateral otolith organs, particularly the utricle. This assumption stems from the fact that the utricle is more sensitive to outward (ipsilateral) rather than inward (contralateral) head-tilt (43). Although the OCR is always driven by both left and right utricular signals (44), such a directional bias in the utricular sensitivity results in a right utricle dominance for the OCR with a rightward head tilt and vice versa. However, we cannot unequivocally rule out another source of OCR asymmetry. That is, the functional asymmetry in the an efferent, as well as afferent, pathway for the OCR, can also cause OCR asymmetry. For example, imbalanced contraction characteristics of extraocular muscles (i.e., the superior and inferior oblique muscles), if any, result in OCR asymmetry. Although the mechanisms by which functional asymmetries in the efferent pathway are associated with MS susceptibility are unclear, identifying the source of OCR asymmetry is an important research direction to further understand the pathogenesis of MS.

Contrasting with the OCR asymmetry, functional asymmetry in a vestibular cortical pathway, assessed by the HT-SVV test, was not associated with MS susceptibility. This may be explained by the central compensation for vestibular sensation (45). Head motion information detected in the bilateral vestibular organs is integrated into the cortical vestibular system (19). When the information from either left or right otolith is unreliable due to unilateral dysfunction of the inner ear, the cortical vestibular system compensates the unreliable otolith afferent signals using head motion information from visual (46) and/or somatosensory (47) systems. This compensatory mechanism could minimize the impact of bilateral asymmetry in the otolith afferent signals in the vestibular cortical pathway. HT-SVV asymmetry was significantly smaller than OCR asymmetry. Also in the reflex pathway, a lot of studies of unilateral vestibular lesions show that asymmetry in the bilateral vestibulo-ocular reflex is known to be diminished over the long term (45, 48, 49). However, in some studies, such compensation in the otolith reflex pathway is incomplete as compared to that in the cortical pathway (45, 50). Our findings are consistent with this evidence. The difference between the patients with unilateral vestibular disorders and the participants in this study is that the participants did not show any difficulties in their daily life or any atypical vestibular functions according to self-reports and screening tests. The reason why the MS-susceptible participants had no difficulties in their daily activities may be because asymmetry in their vestibular function had been corrected, probably by a mechanism similar to the compensatory function in patients. Nevertheless, the MS-susceptible participants had problems specifically in vehicles. This fact may suggest that acceleration during vehicle rides differs from that in other daily activities, such that influences in bilateral vestibular asymmetry appears during vehicle rides, but not during low-motion daily activities.

It should be noted, however, that OCR asymmetry is not the only factor that determines MS susceptibility. Our data showed that a certain portion of participants susceptible to MS was comparable with the control group in terms of OCR asymmetry. This fact enables us to infer the existence of other dominant factors for MS susceptibility, independent of OCR asymmetry. According to our additional analysis for the MSSQ subscale scores, individuals susceptible to MS with lower OCR asymmetry tended to be more prone to MS in swings and roundabouts. Although the peculiarities of motion stimuli in swings and roundabouts compared to other vehicles are unknown, acceleration environments in such playground equipment could reveal other vestibular functions that cannot be accessed using the OCR test. A potential candidate could be the saccular function since the OCR is considered to reflect mainly utricular responses to interaural acceleration accompanied with lateral head tilt (51, 52). In fact, Singh et al. (27) reported that individual MS susceptibility was associated not only with utricular functional asymmetry but also with saccular functional asymmetry, using vestibular evoked potentials. To identify individuals who are prone to MS more accurately, discovering complementary factors for OCR asymmetry is an important future research direction.

This study has certain limitations. A major limitation is the small sample size. This resulted from the high exclusion rate of participants during the OCR measurement. Follow-up studies with a larger sample size are warranted to confirm our findings. To achieve that, a more robust measurement system and algorithm for the OCR are desired. Another limitation is the use of OCR to assess otolith function; in general, the OCR is measured in the photopic condition. In this study, we, thus, followed general methods; however, the OCR in the photopic condition could be compromised by the torsional optokinetic reflex because rotational retinal slips occur accompanying lateral head tilts. In addition, the OCR is primarily associated with utricular function. It is an important future research direction to assess vestibular functions that associate with MS susceptibility using VEMP because VEMP and OCR are complemental for vestibular assessment (36). In addition, as several studies suggested, the role of individual differences in other cortical functions, such as multisensory integration and psychological processes, in the development of MS should also be considered.

The datasets presented in this article are not readily available because of privacy restrictions in the written informed consent provided by the participants that prevent them from being shared with third parties. Requests to access the datasets should be directed to Tomoko Sugawara, sugawara@mosk.tytlabs.co.jp.

The studies involving human participants were reviewed and approved by the Institutional Review Board of Toyota Central Research & Development Laboratories, Inc. and the Ethics Committee of Nara Medical University. The patients/participants provided their written informed consent to participate in this study.

TS, HS, and YW designed the study. TS built the processing program for torsional estimation and analyzed data. TS and HS wrote the manuscript. All the authors were involved in the execution of the experiment and approved the manuscript.

This study received funding from Toyota Central Research & Development Laboratories, Inc. The funder had no role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript.

TS and HS were employed by Toyota Central Research & Development Laboratories, Inc. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.