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Assessment of otolith function using cervical and ocular vestibular evoked myogenic potentials in individuals with motion sickness a

a

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Niraj Kumar Singh , Preeti Pandey & Soumya Mahesh a

Department of Audiology, All India Institute of Speech and Hearing, Karnataka, India Published online: 15 Sep 2014.

Click for updates To cite this article: Niraj Kumar Singh, Preeti Pandey & Soumya Mahesh (2014) Assessment of otolith function using cervical and ocular vestibular evoked myogenic potentials in individuals with motion sickness, Ergonomics, 57:12, 1907-1918, DOI: 10.1080/00140139.2014.952683 To link to this article: http://dx.doi.org/10.1080/00140139.2014.952683

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Ergonomics, 2014 Vol. 57, No. 12, 1907–1918, http://dx.doi.org/10.1080/00140139.2014.952683

Assessment of otolith function using cervical and ocular vestibular evoked myogenic potentials in individuals with motion sickness Niraj Kumar Singh*, Preeti Pandey and Soumya Mahesh Department of Audiology, All India Institute of Speech and Hearing, Karnataka, India (Received 9 April 2014; accepted 2 August 2014)

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The involvement of otolith organs in motion sickness has long been debated; however, equivocal findings exist in literature. The present study thus aimed at evaluating the otolith functioning in individuals with motion sickness. Cervical and ocular vestibular evoked myogenic potentials were recorded from 30 individuals with motion sickness, 30 professional drivers and 30 healthy individuals. The results revealed no significant difference in latencies and amplitudes between the groups ( p . 0.05). Nonetheless, thresholds were significantly elevated and inter-aural asymmetry ratio significantly higher in motion sickness susceptible group ( p , 0.001) for both the potentials. All the individuals in the motion sickness group had high asymmetry ratio at least on one of the two potentials. Thus, reduced response and/or asymmetric otolithic function seem the likely reasons behind motion sickness susceptibility. Practitioner Summary: Motion sickness is among the most rampant conditions affecting travellers across the globe. Otolith abnormality has been floated as a possible pathologic factor for motion sickness but has not been authenticated as yet. This study explores otolith functionality in individuals with motion sickness in order to evaluate this theory. Keywords: motion sickness; otolith; cervical vestibular evoked myogenic potential; ocular vestibular evoked myogenic potential

Introduction Motion sickness is an expression for a physiological condition that results from movements or whole body vibrations. It is typically defined as a state of discomfort which includes different symptoms (nausea, pallor, cold sweat, etc.) resulting from motion. Also known as ‘kinetosis’, motion sickness typically takes place during atypical motion patterns which bring about incongruity in sensory-motor signals, so that the information about motion in the environment does not match the template of the actual physical reality. Nonetheless, some typical motion patterns which the individuals have had experience with can also result in the symptoms of motion sickness. A host of psychosocial and environmental factors could contribute to the susceptibility of an individual to motion sickness. These risk factor profiles may vary from one individual to another. Motion sickness can originate from a wide variety of motion situations, for example travelling in various modes of transport (Lawther and Griffin 1986, 1988; Turner and Griffin 1999; Turner, Griffin, and Holland 2000), tilting trains (Cohen et al. 2011), funfair rides (Shupak and Gordon 2006), being in space (Bacal, Billica, and Bishop 2003; Nachum et al. 2004) or experiencing virtual reality (So and Lo 1999; Lin et al. 2007). Nearly 90% of the general population has encountered motion-related sickness at some point of time in their entire lifespan (Lovan 1984; Herron 2010), and given an adequately goading motion stimulus, most individual with functioning vestibular systems could be made to experience it (Golding 2006a). Although some appear to experience it more often than others, the true incidence of the pathological motion sickness has been reported in up to 30% of the individuals during various kinds of travels such as sea (Lawther and Griffin 1986, 1988), road (Turner and Griffin 1999) or air (Turner, Griffin, and Holland 2000). In the Indian context, Sharma and Aparna (1997) found slightly higher prevalence of motion sickness among Tibetans and Northeast Indians (28%) than Northwest Indians (26%), with higher overall prevalence among males (27.3%) than females (16.8%). Irrespective of the kind of travel involved, the sign and symptoms of motion sickness include epigastria awareness, pallor, headache, drowsiness, cold sweating, nausea and vomiting (Diamond and Markham 1992a; Sharma and Aparna 1997; Dai, Raphan, and Cohen 2007). The cause of motion sickness is not well understood, but it is believed to be produced by environmental challenges that result in sensory conflicts, postural instability or vertical mismatch. The susceptibility to motion sickness has been hypothesised to be associated with the sensitivity to incongruent or mismatched perceptual information received from the important systems for balance, namely from visual, vestibular and somatosensory systems (Reason 1978). However, a sensory mismatch theory fails to elucidate the motion sickness experienced during certain conditions such as passive

*Corresponding author. Email: [email protected] q 2014 Taylor & Francis

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low-frequency vertical acceleration (Yates, Millar, and Lucot 1998). This is owing to the fact that there is actual motion which is sensed by both visual and vestibular systems, yet there is motion sickness experienced by some of the individuals in this situation. The most common hypothesis for explaining motion sickness reports the psychological defence mechanism against neurotoxins as the chief culprit behind the symptoms experienced during motion sickness (Treisman 1977). As per this hypothesis, the brain houses an area (area postrema) which is responsible for inducing vomiting when it senses the presence of toxins. Additionally, the area postrema also holds the responsibility for resolving conflicts between the visual and vestibular systems, whenever there is one. In situations where the discrepancy between the information received from these two systems exists, the brain assumes that this discordance is caused by poison ingestion. In reaction, the brain induces vomiting so that the assumed toxins could be flushed out of the system. Although this theory explains the reason behind symptoms experienced during motion sickness, it fails to explain the reason behind motion sickness itself. Later, some of the researchers proposed another theory which claims that uncertainty in the perception of vertical orientation might be the most definitive reason associated with motion sickness (Bles et al. 1998; Bos and Bles 1998; Bles, Bos, and Kruit 2000). According to the subjective vertical conflict theory, the situations that provoke motion sickness characteristically involve a condition in which the then sensed vertical does not match the expected subjective vertical as learnt from a previous similar experience. The sensed vertical is mainly recognised by the otolith organs as they are the organs responsible for maintaining balance during vertical and horizontal linear movements. In addition, if the motion also involves angular acceleration, the semicircular canal inputs become vital for balance maintenance. In accordance with this theory, it has been assumed that motion and space sickness might be attributed to canal-otolith mismatch or otolith asymmetry (Yates, Millar, and Lucot 1998; Tal et al. 2006, 2007). Thus, the mismatched otolith responses might be expected to be the cause behind motion sickness. It has been hypothesised that asymmetries in the otolith function, resulting from differences in the otoconial masses between the two labyrinths, cause motion sickness (von Baumgarten and Thumber 1979). This hypothesis was further boosted by the results of studies which demonstrated the existence of higher susceptibility to motion sickness on passive exposure to variations in gravito-inertial force load in those who exhibited larger asymmetry between the rightward and leftward body tilts on ocular counter-rolling test (Lackner et al. 1987; Diamond and Markham 1992a; Parker 1998). Animal studies on fish also approve this hypothesis (Scherer et al. 2001; Helling et al. 2003). They observed that an unusual situation such as the presence of a coriolis force environment caused uncoordinated or passive swimming behaviour among the fish with significant differences in the otoconia mass as against perseverance of active swimming behaviour exhibited by the fish with nearly symmetrical otoconia mass. Thus, the existing literature tends to suggest towards the role of otolith organs and the asymmetry between them in the phenomenon of motion sickness. The otolith organs, which help in maintaining balance during linear accelerations, remained inaccessible to clinicians until the entity of cervical vestibular evoked myogenic potentials (cVEMPs) were put to clinical use by Colebatch, Halmagyi and Skuse (1994) and that of ocular vestibular evoked myogenic potentials (oVEMPs) by Todd, Rosengren and Colebatch (2003). The cVEMP has been shown to assess the function of saccule via the sacculocolic reflex pathway (Colebatch, Halmagyi, and Skuse 1994; Todd, Cody, and Banks 2000), while the ocular VEMP believed to evaluate the functionality of utricle via the vestibulo-ocular reflex pathway (Rosengren et al. 2009; Curthoys 2010; Curthoys et al. 2012). While the cVEMP can be recorded from the tonically contracted sternocleidomastoid muscle (Colebatch and Halmagyi 1992; Colebatch and Rothwell 1993; Colebatch, Halmagyi, and Skuse 1994), oVEMP is extracted from the inferior oblique muscle and to a lesser extent lateral rectus muscle (Rosengren, Todd, and Colebatch 2005; Rosengren et al. 2009) in response to loud sounds. In one of the earliest studies that examined the otolith functions in individuals with motion sickness, the authors reported significantly smaller amplitudes and elevated (worst) thresholds of cVEMP among individuals with sea sickness susceptibility than the healthy controls (Tal et al. 2006). Later in 2007, another study reported a lack of statistically significant difference in the amplitude and latency parameters of cVEMP between the sea sickness susceptible and nonsusceptible individuals (Tal et al. 2007). However, the incidence of higher asymmetry ratio was observed in motion sickness susceptible individuals when compared to their non-susceptible counterparts, although this also did not fulfil the criteria for statistical significance. The findings of both these studies though could be susceptible to the detrimental effects of small sample size (N # 15 in the sea sickness susceptible group). Due to this, the authors themselves caution against generalisation of the findings to the entire population. In a more recent study, the authors did not find a statistically significant difference in any of the cVEMP parameters between the motion sickness susceptible and non-susceptible groups (Buyuklu, Tarhan, and Ozluoglu 2009). Thus, the above set of studies point towards incongruence regarding the effectiveness of cVEMP in revealing saccular dysfunction, if any, in individuals with motion sickness. More recently, Xie et al. (2012) compared the utricular responses of motion sickness susceptible group against their non-susceptible peers using ocular VEMP. They reported no statistically significant difference between the motion sickness

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and the healthy group on any of the oVEMP parameters. Nevertheless, they did observe an incidence of higher asymmetry ratio in the motion sickness susceptible group compared to the non-susceptible matches. Barring the above-mentioned sporadic studies, there are no other reports of otolith system assessment in the concurrent literature on motion sickness to the best of our knowledge and even these studies have not evaluated the two sub-systems, utricle (vestibulo-ocular reflex pathway) and saccule (sacculocolic reflex pathways), in the same set of individuals. Hence, there is a need to study the two systems and their functionality in individuals with motion sickness. Thus, the present study aimed at evaluating the utricular and saccular functions in individuals with motion sickness and comparing it with those of non-susceptible healthy individuals and drivers.

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Materials and method Participants Multiple static-group comparison research design was used to compare the groups of individuals with motion sickness who were otherwise healthy (MS), non-susceptible healthy individuals (NS) and healthy professional drivers (PD). The PD was included as professional drivers would be most resistant to effects of motion sickness and therefore would serve as the true control group. This is proven by their track record of driving for long hours without any discomfort. Additionally these subjects (PD) also demonstrated a lack of history for motion sickness even before choosing the profession as drivers, which further enhances their selection as participants of one of the two control groups. The study incorporated 90 participants in the age range of 18 –40 years who were divided into three groups, each consisting of 30 participants. Group I consisted of 30 NS (mean age ¼ 28.52 years), Group II consisted of 30 PD (mean age ¼ 34.83), whereas Group III consisted of 30 MS (mean age ¼ 29.16). All the participants had normal hearing thresholds as ascertained by their pure-tone thresholds of 15 dB HL or less at octave frequencies from 250 Hz through 8000 Hz for air-conduction and 250 Hz through 4000 Hz for bone-conduction stimulation using Carhart and Jerger (1959) modified Hughson and Westlake procedure for threshold estimation. They also had normal middle ear function which was revealed by the existence of ‘A’ type tympanogram and the presence of acoustic reflexes (ipsilateral and contralateral) below 100 dB HL at octave frequencies from 500 Hz through 4000 Hz. In addition, all the participants had uncomfortable level for speech in excess of 100 dB HL in order to ensure tolerance to loud acoustic stimulation during the recording of VEMPs. None of the participants had any history or presence of any other otological, neuromuscular and neurological disorders. The participants also exhibited lack of history of intake of drugs associated with vestibulotoxicity. The existence of retro-cochlear pathology was ruled out by normal click evoked auditory brainstem responses (absolute latencies of waves I, III and V of less than 2, 4 and 6 ms, respectively, inter-peak latency difference # 2.0 ms, inter-aural latency difference # 0.2 ms, wave I/V amplitude ratio # 0.5). The PD had a history of long distance driving ($ 20 hours per week for at least past five years) without any motion sickness related symptoms and passed the screening for motion sickness using Modified Motion Sickness Susceptibility Questionnaire-Short Form (MSSQ-short). This questionnaire is designed to determine the degree of susceptibility of an individual to motion sickness and the types of motion stimuli that most effectively caused motion sickness during childhood as well as over the past 10 years (Golding 2006b). Only the section for adults was used since the study involved adult participants only. A cut-off score of 3.0 was used as indicator of the presence of motion sickness. The same cut-off was used in a study on treatment for motion sickness previously (Simmons et al. 2010) and therefore this cut-off was opted. Almost all the participants in NS and PD had a score of 0 on this questionnaire. The NS reported no episode of symptoms pertaining to motion sickness and also passed the screening using MSSQ-short (score , 3). The MS reported of symptoms such as dizziness, nausea, headache, drowsiness, cold sweating, vomiting and/or blurring of vision while travelling. The selection of participants in the motion sickness group was based on a positive result on MSSQ-short (score . 3). All the participants produced informed written consents before enrolment to the study and the study was approved by the institutional review board for compliance with research ethics concerning human subjects. Procedure The recording of cervical and ocular VEMP was done in a well illuminated air-conditioned acoustically treated room with ambient noise levels well within the permissible limits (ANSIS3.1, 1991). The Biologic Navigator Pro auditory evoked potential system version 7.0.0 (Natus Medical Incorporated, Illinois, USA) with ER-3A insert earphones was used to obtain cVEMP and oVEMP. Recording of cervical vestibular evoked myogenic potential The cVEMP was recorded for all the three groups with the participants seated in an upright position. The electrode placement site was maintained as per our previous studies on cVEMP (Singh et al. 2013a, 2013b; Singh, Kadisonga, and

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Ashitha 2014). The gold-plated cup-shaped electrodes were placed at forehead (ground electrode), two-thirds the way up the ipsilateral sternocleidomastoid muscle (non-inverting electrode) and sternoclavicular junction (inverting electrode) after scrubbing the skin surface with an abrasive gel in order to obtain absolute and inter-electrode impedance of 2 kV and 5 kV, respectively. During the recording, the participants were instructed to maintain a lateral head turn away from the ear of acoustic stimulation such that the lateral aspect of the chin was aligned with the acromioclavicular joint. This method has been shown to produce similar inter-ear variability to other visual feedback systems for monitoring electromyographic activation and response normalisation systems (McCaslin et al. 2013) and better inter-test reliability than the visual feedback system (Isaradisaikul et al. 2008; Anoop and Singh 2011). The 500 -Hz short-tone bursts with 1 -ms rise/fall time and 2 -ms plateau time were ramped using Blackman window, as found appropriate previously (Cheng and Murofushi 2001a, 2001b; Singh and Apeksha 2014). A total of 200 stimuli were presented at 95 dB nHL (equivalent to 125 dB SPL) using a repetition rate of 5.1 Hz. The responses were band-pass filtered between 10 and 1500 Hz. The lowest level at which replicable waveforms were recorded was considered thresholds of cVEMP. For obtaining the thresholds, the stimulus intensity was reduced in 5 dB nHL steps. A rest period of 2 minutes was given between two recordings in order to avoid response contamination by fatigue. Analysis time was kept at 60 ms with a pre-stimulus baseline recording of 10 ms.

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Recording of ocular vestibular evoked myogenic potential The oVEMP was recorded from the contralateral electrode side as contralateral responses have been found to more prevalent and robust (Iwasaki et al. 2007). For this, the participants were seated in an upright position. The electrode placement sites used for oVEMP recording were same as the ones used previously (Chihara et al. 2007; Singh et al. 2011; Singh and Barman 2013, 2014). As per them, the non-inverting electrode was placed at 1 cm below the centre of the lower eye lid, the inverting on the cheek 2 cm below the non-inverting and ground on the forehead. The absolute and interelectrode impedances were maintained below 5 kV and 2 kV, respectively. The electrodes used were disc type gold-plated electrodes. During the recording, the participants were instructed to fix the gaze up at a point at an elevation of 30 – 358 as was found appropriate for best oVEMP recording (Murnane et al. 2011). The oVEMP was recorded using 500 -Hz short tone-bursts (1 -ms rise/fall time and 2 -ms plateau time, ramped using Blackman window) since 500 Hz has been shown to produce most robust oVEMP responses (Singh and Barman 2013, 2014). Total of 200 stimuli per recording were presented at repetition rate of 5.1 Hz as this rate has been shown to produce best oVEMP responses with highest efficiency (Singh, Kadisonga, and Ashitha 2014). The intensity was reduced using 5 -dB nHL step size, beginning with 95 dB nHL. The lowest level at which replicable waveforms were recorded was considered thresholds of oVEMP. The responses were band-pass filtered between 1 Hz and 1000 Hz. Analysis time was kept at 60 ms with a pre-stimulus baseline acquisition of 10 ms. A rest period of 2 minutes was given between two recordings in order to ensure fatigue free responses. Measures and statistics The cVEMP peaks were marked as P1and N1 whereas the oVEMP peaks were marked as n1and p1 by two experienced audiologists working with VEMPs for more than seven years. After ensuring an excellent inter-judge reliability using Cronbach’s alpha (a $ 0.9) and Pearson’s correlation (r $ 0.9, p , 0.001), the markings of only one of the audiologists was used for further analysis. The parameters measured included absolute latencies, inter-peak latency difference, peak-topeak amplitudes and inter-aural asymmetry ratio. The asymmetry ratio was calculated using the formula used by Li, Houlden and Tomlinson (1999). As per this formula, the percentage inter-aural asymmetry ratio was calculated by dividing the peak-to-peak amplitude difference between the ears by their sum and multiplying the thus obtained value by 100. A commercially available statistical tool Statistical Package for Social Sciences (version 17.0) was used for statistical analysis. The statistical analysis involved one-way repeated measures analysis of variance (one-way repeated measures ANOVA) and one-way analysis of variance (one-way ANOVA) in addition to the descriptive statistics. The Bonferroni adjusted multiple comparisons was administered whenever necessary. Results The present study was conducted in order to compare MS, NS and PD for their otolith functioning. All the participants underwent cVEMP and oVEMP recording from both the ears using the protocol described in the method section. Cervical vestibular evoked myogenic potential All the participants of all the three groups demonstrated the presence of cVEMP bilaterally, therefore showing 100% response rate. Figure 1 shows the representative cVEMP waveforms from one individual of each group.

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Figure 1. Representative waveforms of cervical vestibular evoked myogenic potential from a driver, a healthy individual and an individual with motion sickness. The upward pointing arrow indicates the time of stimulus presentation. ‘PD’, professional drivers; ‘NS’, non-susceptible healthy individuals; ‘MS’, individuals with motion sickness susceptibility.

The descriptive statistics was done for different parameters of cVEMP. There appeared to be no difference in the latency, amplitude and threshold of cVEMP between the groups. However, the asymmetry ratio appeared to be larger in MS compared to the other two groups. The statistical significance of the above-mentioned observations was evaluated using one-way repeated measures ANOVA for latencies, amplitude and threshold. For the asymmetry ratio one-way ANOVA was used. One-way repeated measures ANOVA for ears with group as between-subject variable revealed no significant main effect of ear as well as group on P1 latency, N1 latency and amplitude ( p . 0.05). There was also no significant interaction between ear and group for any of the above parameters ( p . 0.05). A one-way repeated measures ANOVA for ears with group as between-subject factor revealed a significant main effect of group on the threshold of cVEMP [F(2, 87) ¼ 36.529, p ¼ 0.000]. However, there was no main effect of ear [F (1,87) ¼ 0.085, p ¼ 0.772] or interaction between ear and group [F(2,87) ¼ 0.419, p ¼ 0.659] for threshold. The Bonferroni adjusted multiple comparisons was done for pair-wise analysis between groups. There was no difference between PD and NS ( p ¼ 1.000). The MS demonstrated significantly larger (elevated) threshold compared to the other two groups ( p ¼ 0.000). One-way ANOVA was also administered to compare the three groups for asymmetry ratio. The results revealed a significant main effect of group on asymmetry ratio of cVEMP [F(2,87) ¼ 21.255, p ¼ 0.000]. The comparison between the groups was achieved using Bonferroni adjusted multiple comparisons. The MS demonstrated significantly higher asymmetry ratio compared to the other two groups ( p ¼ 0.000). However, there was no significant difference between the asymmetry ratio of PD and NS ( p ¼ 1.000). Thus, MS was different from PD and NS only in terms of asymmetry ratio of cVEMP but not on latency, amplitude or threshold. Figure 2 shows the comparison between the groups on various parameters of cVEMP.

Ocular vestibular evoked myogenic potentials Ocular VEMP were recorded from both ears of all the individuals irrespective of the groups. The responses were present in all the individuals of all the three groups thereby resulting in 100% response prevalence in all the three groups. Figure 3 shows the representative waveforms recorded from one individual from each of the groups.

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Figure 2. Mean and 95% confidence intervals of latencies (top left panel), peak-to-peak amplitude (top right panel), threshold (bottom left panel) and asymmetry ratio (bottom right panel) of cervical vestibular evoked myogenic potential. The star marked comparisons are statistically significant ( p , 0.001). ‘PD’, professional drivers; ‘NS’, non-susceptible healthy individuals; ‘MS’, individuals with motion sickness susceptibility.

The recorded responses were analysed for individual peak latencies, peak-to-peak amplitude, and threshold and asymmetry ratio. The obtained values were subjected to descriptive statistics in order to get mean and standard deviation values of each of the above-mentioned parameters of oVEMP. While there was no difference between the groups for latencies and amplitude, threshold and asymmetry ratio seemed to be larger in MS compared to the PD and NS. PD and MS appeared comparable across all the parameters of oVEMP. A one-way repeated measure ANOVA was administered in order to compare the ears and groups across the parameters of oVEMP. The results revealed no significant main effect of ear or group on latencies and amplitude. There was also no interaction between ear and group for any of these parameters. The one-way repeated measures ANOVA for ears with group as between-subject factor revealed no significant main effect of ear [F(1,87) ¼ 0.120, p ¼ 0.730] or interaction between ear and group [F(2,87) ¼ 0.637, p ¼ 0.531] for threshold. However, there was a significant main effect of group on threshold of oVEMP [F(2, 87) ¼ 29.378, p ¼ 0.000]. The Bonferroni adjusted multiple comparisons for between group pair-wise analysis revealed no difference in threshold between PD and NS ( p ¼ 1.000). However, the threshold of oVEMP in MS was significantly higher (elevated) compared to the other two groups ( p ¼ 0.000). The inter-aural asymmetry ratio was calculated by dividing the difference between the two ears’ peak-to-peak amplitudes by their sum and multiplying the thus obtained value by 100 to obtain the percentage value. The obtained interaural asymmetry ratios were subjected to statistical analysis using one-way ANOVA which revealed a significant main effect of group on asymmetry ratio of cVEMP [F(2,87) ¼ 21.706, p ¼ 0.000]. The Bonferroni adjusted multiple comparisons was done in order to get a pair-wise comparison. MS was shown to demonstrate significantly larger asymmetry ratio than PD and NS ( p ¼ 0.000). However, there was no significant difference between PD and NS ( p ¼ 0.322). MS

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Figure 3. Representative ocular vestibular evoked myogenic potential waveforms from a driver, a healthy individual and an individual with motion sickness. The upward pointing arrow depicts the time of stimulus onset. ‘PD’, professional drivers; ‘NS’, non-susceptible healthy individuals; ‘MS’, individuals with motion sickness susceptibility.

differed from PD and NS only on asymmetry ratio. On all the other parameters of oVEMP, the groups were comparable. Figure 4 shows the comparison between the groups on various oVEMP parameters. When the asymmetry ratio is in excess of 30%, it is generally considered an abnormal response and this is true for cVEMP [58, 59] as well as oVEMP [41]. This criterion was fulfilled by only 17 (56.7%) subjects for cVEMP and 5 (16.7%) subjects for oVEMP in MS. In the present study, a ‘high asymmetry ratio’ was defined as the asymmetry ratio that fell 2 standard deviations beyond the mean of asymmetry ratio for healthy individuals and drivers taken together. Although significant differences existed between the groups for asymmetry ratio of oVEMP and cVEMP, both the potentials did not always show large asymmetry in the same individual. A ‘high asymmetry ratio’ of cVEMP was seen in 21 (70%) whereas the ‘high asymmetry ratio’ of oVEMP existed in 18 (60%) of the subjects in MS. The abnormality of both cVEMP and oVEMP was seen in 10 (33.3%) participants of MS only. However, when the abnormality existed on both the potentials, they coexisted in the same ear. Additionally there was no individual in this group who did not demonstrate ‘high asymmetry ratio’ on at least on one of the two potentials. Discussion The latencies of cVEMP (both P1 and N1) did not reveal any significant difference between MS, NS and PD. The findings of present study are in agreement with those reported previously (Tal et al. 2006, 2007; Buyuklu, Tarhan, and Ozluoglu 2009). Although they did not use PD as a separate group, they reported a lack of significant difference in the latencies of cVEMP between MS and NS. In case of oVEMP, like cVEMP, MS revealed similar latencies of n1 and p1 to PD and NS. These findings are in congruence with those reported by Xie et al. (2012) for oVEMP latencies. Since the latency abnormalities of cVEMP and oVEMP have been reported to most often exist in neural pathologies rather than the labyrinthine pathologies (Xue and Yang 2008; Gabelic et al. 2013), the findings of the present study indicate towards a lack of neural involvement at least in the vestibulo-spinal and vestibulo-ocular reflex pathways in individuals with motion sickness. The results also indicate insensitivity of latency parameters of cVEMP and oVEMP in discriminating the motion sickness susceptible individuals from non-susceptible individuals. MS were compared with NS and PD using the amplitude parameters of cVEMP and oVEMP. The results revealed no difference between the groups for cVEMP and oVEMP amplitudes. The findings of the present study are in agreement with those by Tal et al. (2007) and Buyuklu, Tarhan and Ozluoglu (2009) for cVEMP and Xie et al. (2012) for oVEMP. However, these findings are in dissonance with those reported by Tal et al. (2006). They reported significantly smaller amplitudes of cVEMP in individuals with sea sickness compared to the controls. The difference in findings between the present study and those reported by Tal et al. (2006) might be attributed to the differences in sample size between the

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Figure 4. Mean and 95% confidence intervals of latencies (top left panel), peak-to-peak amplitude (top right panel), threshold (bottom left panel) and asymmetry ratio (bottom right panel) of ocular vestibular evoked myogenic potential. The star marked comparisons are statistically significant ( p , 0.001). ‘PD’, professional drivers; ‘NS’, non-susceptible healthy individuals; ‘MS’, individuals with motion sickness susceptibility.

studies. The sample size in Tal et al. (2006) was relatively smaller (N ¼ 15 in sea sickness group) than that in the present study (N ¼ 30 in each group). The lack of statistical difference in amplitudes of cVEMP and oVEMP between the groups might be attributed to the presence of large variability in amplitudes, as indicated by large standard deviations despite a relatively large sample size in the present study. The findings of the present study thus suggest that absolute amplitudes of cVEMP and oVEMP are not sensitive to identifying the differences that exist between the motion sickness susceptible and non-susceptible individuals. The threshold of cVEMP/oVEMP was defined as the lowest sound intensity at which replicable peaks could be obtained for the respective potential. The thresholds of cVEMP and oVEMP in MS were compared to NS and PD. The results revealed significantly elevated (worst) thresholds of both the VEMP types in MS compared to the other two groups of the study. This is in agreement with those reported previously by Tal et al. (2006) who also reported elevated cVEMP thresholds in individuals with motion sickness susceptibility compared to the non-susceptible individuals. Although Tal et al. (2007) obtained cVEMP responses from sea sickness susceptible and non-susceptible groups, they did not obtain thresholds. The only study using oVEMP (Xie et al. 2012) for comparing the motion sickness susceptible and nonsusceptible groups of individuals did not explore the threshold aspect oVEMP. The findings of the present study are the first in this regard. This suggests towards lesser efficiency in functioning of the otolith organs in individuals with higher susceptibility for motion sickness than those who are non-susceptible, as revealed by the presence of worst thresholds in MS than the two control groups. This further indicates that threshold of cVEMP and oVEMP rather than the absolute amplitudes is better suited to evaluation of otolith function in individuals with motion sickness. The inter-aural asymmetry ratio for cVEMP and oVEMP was calculated by dividing the difference between two side responses by their sum and multiplying the so obtained value by 100 which produced the percentage value. This is the most well-accepted way of assessing the existence of asymmetry between the functioning of two side otolith organs (Li, Houlden,

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and Tominson 1999). In the present study, MS showed significantly higher asymmetry ratio than PD and NS. The findings of the present study are in dissonance with those reported previously for cVEMP (Tal et al. 2006, 2007; Buyuklu, Tarhan, and Ozluoglu 2009) and oVEMP (Xie et al. 2012), who reported no significant difference in asymmetry ratio between motion sickness susceptible and non-susceptible individuals. However, these previous studies did reveal a tendency for higher asymmetry ratio in the motion sickness susceptible group than the non-susceptible group, although statistical significance was not attained. Even though asymmetry ratio is amplitude-related parameter, MS revealed significantly larger asymmetry ratio than the other two groups despite there being no ear effect for amplitude. While some individuals demonstrated smaller amplitudes in right ears, others did so in the left ears in MS. This probably nullified any difference between the ears for peak-to-peak amplitude. However, asymmetry ratio is obtained by comparing between the amplitudes of the two ears of an individual, as defined earlier. Hence, this comparison for each individual retained the amplitude difference between the ears. The findings of the present study indicate towards the presence of large asymmetry in the otolith responses between the two sides of the same individual. Although some asymmetry between the two side otolith organs exists in almost all the human beings, the difference (usually less than 20%) is not large enough to produce discrepant information reaching the cortical areas. Nonetheless, if the difference between the two side otolith responses is large, one side is likely to send much higher levels of neural impulses to the central balance structures than the other side. This is likely to confuse the central structures as one side suggests large degree of acceleration whereas the other suggests smaller degree of acceleration, even though the whole body is undergoing same amount of acceleration. This discrepancy in the information might prompt the autonomic nervous system activation which would produce the symptoms of motion sickness such as dizziness, nausea, vomiting, headache, drowsiness and cold sweating. The findings of the present study revealed elevated threshold and higher asymmetry ratio of cVEMP and oVEMP in MS than NS and PD. This might be explained on the basis of the theories proposed to explain the phenomenon of motion sickness. In explaining the event of motion sickness, a role for the vertical sensation conflict theory has been proposed (Bles et al. 1998). According to this, each individual has a subjective vertical which is decided by the congregation and assimilation of information from the systems important for withholding balance namely visual, vestibular and somatosensory systems. Motion sickness occurs when there is a discrepancy between the information available from the subjective vertical and the sensed vertical (Bos and Bles 1998). Since the sensation of vertical is provided by the otolith organs, a reduced otolith response may lead to a disturbed vestibular sense of the vertical. This will increase the discrepancy between the less accurate vestibular signal and the information received from the other sensory neural systems, resulting in the sharp neural conflict. The reduced otolith responses in the present study may be indicative of impaired signals from the otolith organs, which would increase the discrepancy between the information from the various sensory neural systems and result in higher motion sickness susceptibility. The presence of significantly higher asymmetry ratio for oVEMP and cVEMP in the motion sickness susceptible group than the other two groups in the present study could be delineated on the basis of previously proposed otolith asymmetry theory as a potential cause of sensory conflict that might lead to motion sickness (Lackner et al. 1987; Scherer et al. 2001). According to this theory, regular motion conditions are guarded against autonomic activation despite the existence of otolith asymmetry due to compensation which is a well-explained phenomenon in vestibular sciences. However, the exposure to an unfamiliar or less often encountered motion patterns will bring about a sensory mismatch for which compensation does not occur owing to lack of previous exposure or infrequent exposures. The support for this comes from a study on astronauts who experienced space sickness. The astronauts were found to exhibit significantly more disconjugate eye torsions, which is believed to be a symptom resulting out of otolith asymmetry, during parabolic flight than those who were free of symptoms in space (Diamond and Markham 1992a). This finding is consistent with the asymmetry hypothesis of otolith function (Diamond and Markham 1992b). A number of animal studies also lend support to this hypothesis. A large inter-aural difference in the otoconial mass of utricule among the fish that exhibited abnormal swimming behaviour during the exposure to a coriolis force environment compared with normal swimming patterns in those that had symmetrical mass has been reported (Scherer et al. 2001; Helling et al. 2003). Thus, the findings of the present study, which revealed otolithic response asymmetry between the two labyrinths, are in congruence with the existing knowledge in literature. The results of the present study further revealed existence of ‘high asymmetry ratio’ in at least one of the two otolithic potentials in all individuals with motion sickness. However, a coexistence of ‘high asymmetry ratio’ was found in only 33.3% of the individuals with motion sickness. This throws light on the importance of utricle and saccule for non-perception of motion sickness in non-susceptible individuals. It also provides evidence that unilateral reduction in the function of either of the otolith organs could result in the symptoms of motion sickness. The results of the present study therefore confirm the presence of otolith asymmetry in individuals with motion sickness. This prompts us to propose the otolith asymmetry as a probable cause behind motion sickness in these individuals.

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Conclusions A group of motion sickness susceptible individuals was compared against a group of non-susceptible healthy individuals and professional drivers on parameters of cVEMP and oVEMP in order to establish the role of otolith organs in the percept of motion sickness. Among the several parameters of cVEMP and oVEMP that were evaluated, only the threshold and asymmetry ratio could separate the motion sickness susceptible group from the non-susceptible groups. The group of individuals with motion sickness demonstrated higher (worst) thresholds and larger asymmetry ratio than healthy individuals and drivers on both these potentials. While some individuals revealed high cVEMP asymmetry alone and some of the others demonstrated high oVEMP abnormality alone, nearly one-third showed high asymmetry on both. The presence of a high asymmetry ratio on at least one of the two potentials in all the subjects with motion sickness tends to suggest towards a possible role of otolith asymmetry in producing symptoms of motion sickness. It also suggests that a hypofunction of both or either of the two otolith organs could produce these symptoms. Thus, reduced response and/or asymmetric otolithic function seem the likely reasons behind symptoms of motion sickness. Acknowledgements

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We would like to extend our sincere thanks to the director of our institute and head of the Department of Audiology for granting permission to carry out the study. We would also like to thank all the participants for participation and kind cooperation during the course of the study.

Conflict of interest Authors declare no conflicts of interest.

Funding This research work was not funded by any government or non-government agency.

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