Biochemical analysis reveals the systematic response of motion sickness mice to ginger (Zingiber officinale) extract's amelioration effect.

ETHNOPHARMACOLOGICAL RELEVANCE: As a common medicinal and edible plant, Zingiber officinale Roscoe (ginger) is often used for the prevention of motion sickness. However, the mechanism of its anti-motion sickness remains to be elucidated. AIM OF THE STUDY: To explore novel treatment for motion sickness with less side effects, anti-motion sickness effect of ginger (Zingiber officinale) extract (GE) and the possible molecular mechanisms were investigated. MATERIALS AND METHODS: The anti-motion sickness effect of ginger was evaluated through mice animal experimental models. Components of ginger that might contribute to the anti-motion sickness effect were analyzed by LC-MS/MS. Subsequently, biochemical analysis integrated with serum metabolomic profiling were performed to reveal the systematic response of motion sickness mice to ginger extract's amelioration effect. RESULTS: Exhaustive swimming time of mice in the GE group reached 8.9 min, which was 52.2% longer than that in the model group. Motion sickness index scores and time taken traversing balance beam of mice in the GE group were decreased by 53.2% and 38.5%, respectively. LC-MS/MS analysis suggested that various active ingredients in GE, such as gingerol, ginger oil and terpenoids, might contribute to its appealing anti-motion sickness activity. Biochemical analysis revealed that GE can relieve motion sickness through reducing histamine and acetylcholine release in vestibular system, regulating fatty acid oxidation, sugar metabolism and bile acid metabolism in mice. CONCLUSION: Gavage of mice with GE can effectively relieve the symptoms of autonomic nervous system dysfunction, improve the balance and coordination ability and ameliorate the ability to complete complex work after rotation stimulation. GE has attractive potential for development and utilization as novel anti-motion sickness food or drugs.

Targeting TRPV1 to relieve motion sickness symptoms in mice by electroacupuncture and gene deletion.

Motion sickness (MS) is an acute disorder that occurs in healthy individuals worldwide regardless of gender, age, or ethnicity. Our study used a mouse model to rule out the effects of any psychological factors related to MS and EA. Subjects were randomly separated into four groups, namely the control group (Con), motion sickness inducing group (MS), mentioning sickness inducing with electroacupuncture treatment group (EA) and motion sickness inducing only in TRPV1 knockout mice group (TRPV1-/-). The consumption of kaolin, a non-nutrient substance, was measured as a behavior observed response of an emetic reflex in a murine model. This behavior is referred to as pica behavior. Our results showed that pica behavior was observed in the MS group. Moreover, kaolin consumption in the EA group decreased to the average baseline of the control group. A similar result was observed in TRPV1 null mice. We also observed an increase of TRPV1 and related molecules in the thalamus, hypothalamic and brain stem after MS stimulation and a significant decrease in the EA and TRPV1 null groups. This is the first study to demonstrate that TRPV1 pathways are possibly associated with mechanisms of MS, and can be attended through EA or TRPV1 genetic manipulation.

Storage of passive motion pattern in hippocampal CA1 region depends on CaMKII/CREB signaling pathway in a motion sickness rodent model.

Sensory mismatch between actual motion information and anticipated sensory patterns (internal model) is the etiology of motion sickness (MS). Some evidence supports that hippocampus might involve the neural storage of the "internal model". This study established an "internal model" acquisition-retention behavioral model using a repeated habituation rotation training protocol. We tried to identify the hippocampal subregion involved in "internal model" retention using chemical lesion methods. Hippocampal kinases (CaMK, CaMKIV, CREB and ERK1/2) phosphorylation in the target subregion was assayed and the effects of kinase inhibitors (KN93 or U0126) on "internal model" retention were investigated. The activities of potential kinases (CaMKII and CREB) were also examined in otoliths deficit het/het mice. In habituated rats, CA1 lesion reproduced MS-related behavioral responses on "internal model" retention day. Habituation training increased CaMKII and CREB activity but had no effect on CaMKIV and ERK1/2 activity in the CA1, while inhibition of CaMKII but not ERK1/2 impaired "internal model" retention. In het/het mice, CaMKII and CREB were not activated in the CA1 on the retention day. These results suggested that CaMKII/CREB pathway might potentially contribute to the storage of the "internal model" in the hippocampal CA1 after motion sickness induced by vestibular stimulation.

Low level of swiprosin-1/EFhd2 in vestibular nuclei of spontaneously hypersensitive motion sickness mice.

Susceptibility to motion sickness (MS) varies considerably among humans. However, the cause of such variation is unclear. Here, we used a classical genetic approach to obtain mouse strains highly sensitive and resistant to MS (SMS and RMS). Proteomics analysis revealed substantially lower swiprosin-1 expression in SMS mouse brains. Inducing MS via rotary stimulation decreased swiprosin-1 in the mouse brains. Swiprosin-1 knockout mice were much more sensitive to motion disturbance. Immunohistochemistry revealed strong swiprosin-1 expression in the vestibular nuclei (VN). Over-expressing swiprosin-1 in the VN of SMS mice decreased MS susceptibility. Down-regulating swiprosin-1 in the VN of RMS mice by RNAi increased MS susceptibility. Additional in vivo experiments revealed decreased swiprosin-1 expression by glutamate via the NMDA receptor. Glutamate increased neuronal excitability in SMS or swiprosin-1 knockout mice more prominently than in RMS or wild-type mice. These results indicate that swiprosin-1 in the VN is a critical determinant of the susceptibility to MS.

The role of the parasympathetic nervous system in visually induced motion sickness: systematic review and meta-analysis.

The parasympathetic nervous system (PNS) has been implicated in the development of visually induced motion sickness. The objective of this study was to perform a systematic review and meta-analysis of the effect of visually induced motion sickness on validated parameters of PNS tone. Methods followed PRISMA recommendations. Controlled trials reporting validated measures of PNS tone in visually induced motion sickness in healthy adults were included. One reviewer performed the screening of articles and data extraction, and two reviewers independently performed methodological evaluation. Data were synthesised using standardised mean differences (SMDs) for all relevant outcomes using a random-effects model. Publication bias was assessed via funnel plots and Egger's test. The search strategy identified seven citations comprising 237 healthy individuals. The mean quality score was 4/10 (range 3-7). There was no difference between baseline PNS tone between individuals who developed visually induced motion sickness and those that did not. Visually induced motion sickness (VIMS)-sensitive individuals had a reduction in PNS tone, following exposure to the stimulus (mean weighted SMD = -0.45, 95% confidence interval -0.64 to -0.27, Z = -4.8, p < 0.0001). There was no evidence of heterogeneity or publication bias. These data suggest that baseline PNS parameters do not provide a useful measure of predicting the probability of developing visually induced motion sickness. However, a fall in PNS tone, as indicated by cardiac activity, is characteristic in sensitive individuals. Further work is needed to characterise these responses in clinical populations, in conjunction with improvements and standardisation in study design.

Integration of vestibular and gastrointestinal inputs by cerebellar fastigial nucleus neurons: multisensory influences on motion sickness.

Previous studies demonstrated that ingestion of the emetic compound copper sulfate (CuSO4) alters the responses to vestibular stimulation of a large fraction of neurons in brainstem regions that mediate nausea and vomiting, thereby affecting motion sickness susceptibility. Other studies suggested that the processing of vestibular inputs by cerebellar neurons plays a critical role in generating motion sickness and that neurons in the cerebellar fastigial nucleus receive visceral inputs. These findings raised the hypothesis that stimulation of gastrointestinal receptors by a nauseogenic compound affects the processing of labyrinthine signals by fastigial nucleus neurons. We tested this hypothesis in decerebrate cats by determining the effects of intragastric injection of CuSO4 on the responses of rostral fastigial nucleus to whole-body rotations that activate labyrinthine receptors. Responses to vestibular stimulation of fastigial nucleus neurons were more complex in decerebrate cats than reported previously in conscious felines. In particular, spatiotemporal convergence responses, which reflect the convergence of vestibular inputs with different spatial and temporal properties, were more common in decerebrate than in conscious felines. The firing rate of a small percentage of fastigial nucleus neurons (15%) was altered over 50% by the administration of CuSO4; the firing rate of the majority of these cells decreased. The responses to vestibular stimulation of a majority of these cells were attenuated after the compound was provided. Although these data support our hypothesis, the low fraction of fastigial nucleus neurons whose firing rate and responses to vestibular stimulation were affected by the administration of CuSO4 casts doubt on the notion that nauseogenic visceral inputs modulate motion sickness susceptibility principally through neural pathways that include the cerebellar fastigial nucleus. Instead, it appears that convergence of gastrointestinal and vestibular inputs occurs mainly in the brainstem.

Brain white matter microstructure is associated with susceptibility to motion-induced nausea.

Nausea is associated with significant morbidity, and there is a wide range in the propensity of individuals to experience nausea. The neural basis of the heterogeneity in nausea susceptibility is poorly understood. Our previous functional magnetic resonance imaging (fMRI) study in healthy adults showed that a visual motion stimulus caused activation in the right MT+/V5 area, and that increased sensation of nausea due to this stimulus was associated with increased activation in the right anterior insula. For the current study, we hypothesized that individual differences in visual motion-induced nausea are due to microstructural differences in the inferior fronto-occipital fasciculus (IFOF), the white matter tract connecting the right visual motion processing area (MT+/V5) and right anterior insula. To test this hypothesis, we acquired diffusion tensor imaging data from 30 healthy adults who were subsequently dichotomized into high and low nausea susceptibility groups based on the Motion Sickness Susceptibility Scale. We quantified diffusion along the IFOF for each subject based on axial diffusivity (AD); radial diffusivity (RD), mean diffusivity (MD) and fractional anisotropy (FA), and evaluated between-group differences in these diffusion metrics. Subjects with high susceptibility to nausea rated significantly (P < 0.001) higher nausea intensity to visual motion stimuli and had significantly (P < 0.05) lower AD and MD along the right IFOF compared to subjects with low susceptibility to nausea. This result suggests that differences in white matter microstructure within tracts connecting visual motion and nausea-processing brain areas may contribute to nausea susceptibility or may have resulted from an increased history of nausea episodes.

Ocular vestibular evoked myogenic potentials and motion sickness susceptibility.

BACKGROUND: A functional vestibular system is a prerequisite for motion sickness (MS) to occur. The otolithic organs (saccule and utricle) are currently considered to be important in the pathogenesis of MS. Recent investigations have demonstrated that the ocular vestibular evoked myogenic potentials (oVEMP) test is an objective evaluation of utricular function. To date, there is no functional guide that can serve as a diagnostic tool for individual susceptibility to MS. Therefore, we investigated the link between oVEMP and MS susceptibility. METHOD: The oVEMP test was performed on 31 MS susceptible and 23 nonsusceptible individuals. MS susceptibility was determined by self-declaration and by using the MS susceptibility questionnaire (MSSQ) and the Hamilton Anxiety Scale (HAS). RESULTS: Bilateral oVEMP responses were obtained in all subjects. HAS and MSSQ scores between the susceptible and nonsusceptible group were 18.27 +/- 5.23 vs. 2.34 +/- 1.21 and 28.12 +/- 6.53 vs. 2.34 +/- 1.45, respectively. Statistically significant differences in MSSQ and HAS scores were found between the MS susceptible and nonsusceptible groups. No differences were found between MS susceptible and nonsusceptible subjects in N10 and P15 wave latencies, N10-P15 interval, or peak-to-peak N10-P15 amplitude. However, there was a trend toward greater asymmetry ratio in the MS susceptible group than in the MS nonsusceptible group (18.55 +/- 10.24% vs. 13.25 +/- 9.47%), although statistical significance was not reached. DISCUSSION: It appears that no relation exists between oVEMP results and MS susceptibility. Nevertheless, the differences in the asymmetry ratios of oVEMP interpeak amplitude between the two groups revealed a trend toward marginal statistical significance.

Implication of substance P neuronal system in the amygdala as a possible mechanism for hypergravity-induced motion sickness.

We previously reported that motion sickness was prevented in rats with amygdala lesion and that provocative motion stimuli increased the number of Fos-positive neurons in the amygdala, suggesting that the amygdala is one of the neural substrates involved in the development of motion sickness. NK-1 receptors in the brain stem and amygdala are thought to play an important role in emesis and affective disorders, respectively. In the present study, to elucidate a role of substance P neuronal system and NK-1 receptors in the brain stem and amygdala in the development of motion sickness, we measured changes in gene expression of NK-1 receptors and preprotachykinin, a precursor of substance P, using quantitative real-time PCR methods in solitary tract nucleus and amygdala in rats after provocative motion stimuli induced by 2G hypergravity load. Effects of systemic administration of CP-99,994, an antagonist for NK-1 receptors, on hypergravity-induced motion sickness were also examined using pica behavior, eating non-nutritive substances such as kaolin, as an index of motion sickness in rats. Hypergravity-induced motion sickness was inhibited by CP-99,994 with a dose-dependent and enantioselective manner. Preprotachykinin mRNA expression was increased in basolateral nucleus of amygdala and solitary tract nucleus after hypergravity load for 3h, whereas NK-1 receptor mRNA expression was not changed by hypergravity in amygdala and solitary tract nucleus. Present results suggest that 2G hypergravity load activated the substance P neuronal system in amygdala as well as in the brain stem and this activation would be related to the development of motion sickness.

Role of AQP1 in inner ear in motion sickness.

Inner ear is critical for the development of motion sickness (MS). The present work was designed to test the role of aquaporins (AQPs) in inner ear in MS. After repetitive stimulus of rotation, the MS symptom was steadily alleviated in mice. After repetitive stimulus of rotation, several AQPs mRNA levels including AQP1, AQP2, AQP3, AQP4, AQP6, AQP7, and AQP9 in the inner ears of mice were analyzed. It was found that AQP1 mRNA level was increased remarkably, which was reconfirmed by Western blotting analysis. In addition, the relationship between AQP1 expression and MS sensitivity was studied and it was shown that AQP1 mRNA level was negatively related to MS index in mice. We sought to examine the function of AQP1 in inner ear using an RNAi approach to reduce the AQP1 protein expression in vivo. It was first observed that AQP1 knockdown in inner ear resulted in a significant increase of MS sensitivity in mice. In conclusion, after repetitive stimulus of rotation, the alleviation of MS symptom in mice was, at least in part, due to the upregulation of AQP1 expression in inner ear. In addition, the sensitivity to MS in mice was, at least in part, dependent on the expression of AQP1 in inner ear. AQP1 in inner ear plays an important role in the development of MS, and might be a potential target for the prevention or management of MS.

Prolonged reduction of motion sickness sensitivity by visual-vestibular interaction.

The angular vestibulo-ocular reflex (aVOR) and optokinetic nystagmus (OKN) were elicited simultaneously at low frequencies to study effects of habituation of the velocity storage time constant in the vestibular system on motion sickness. Twenty-nine subjects, eleven of whom were susceptible to motion sickness from common transportation, were habituated by sinusoidal rotation at 0.017 Hz at peak velocities from 5 to 20°/s, while they watched a full-field OKN stimulus. The OKN stripes rotated in the same direction and at the same frequency as the subjects, but at a higher velocity. This produced an OKN opposite in direction to the aVOR response. Motion sickness sensitivity was evaluated with off-vertical axis rotation (OVAR) and by the response to transportation before and after 5 days of visual-vestibular habituation. Habituation did not induce motion sickness or change the aVOR gains, but it shortened the vestibular time constants in all subjects. This greatly reduced motion sickness produced by OVAR and sensitivity to common transport in the motion susceptible subjects, which persisted for up to 18 weeks. Two motion susceptible subjects who only had aVOR/OKN habituation without being tested with OVAR also became asymptomatic. Normal subjects who were not habituated had no reduction in either their aVOR time constants or motion sickness sensitivity. The opposing aVOR/OKN stimulation, which has not been studied before, was well tolerated, and for the first time was an effective technique for rapid and prolonged habituation of motion sickness without exposure to drugs or other nauseating habituation stimuli.

Migraine and motion sickness: what is the link?

The brainstem is a structurally complex region, containing numerous ascending and descending fibres that converge on centres that regulate bodily functions essential to life. Afferent input from the cranial tissues and the special senses is processed, in part, in brainstem nuclei. In addition, brainstem centres modulate the flow of pain messages and other forms of sensory information to higher regions of the brain, and influence the general excitability of these cortical regions. Thus, disruptions in brainstem processing might evoke a complex range of unpleasant symptoms, vegetative changes and neurovascular disturbances and that, together, form attacks of migraine. Migraine is linked with various co-morbid conditions, the most prominent being motion sickness. Symptoms such as nausea, dizziness and headache are common to motion sickness and migraine; moreover, migraine sufferers have a heightened vulnerability to motion sickness. As both maladies involve reflexes that relay in the brainstem, symptoms may share the same neural circuitry. In consequence, subclinical interictal persistence of disturbances in these brainstem pathways could not only increase vulnerability to recurrent attacks of migraine but also increase susceptibility to motion sickness. Mechanisms that mediate symptoms of motion sickness and migraine are explored in this paper. The physiology of motion sickness and migraine is discussed, and neurotransmitters that may be involved in the manifestation of symptoms are reviewed. Recent findings have shed light on the relationship between migraine and motion sickness, and provide insights into the generation of migraine attacks.

Effects of hypergravity on histamine H1 receptor mRNA expression in hypothalamus and brainstem of rats: implications for development of motion sickness.

CONCLUSION: The study findings suggest that histamine was released from the axon terminals in the hypothalamus and brainstem and the released histamine activated post-synaptic H1 receptors there, resulting in the development of motion sickness. OBJECTIVES: We first examined which subtype of post-synaptic histaminergic receptor was responsible for the development of motion sickness. We then examined whether H1 receptors were up-regulated in various areas of the rat brain after 2 G hypergravity load, because the stimulation of H1 receptor was reported to up-regulate the level of H1 receptor protein expression through augmentation of H1 receptor mRNA expression. MATERIALS AND METHODS: For this purpose, we used an animal model of motion sickness, using pica (eating non-nutritive substances such as kaolin), as a behavioral index in rats. RESULTS: After 2 G hypergravity load, rats ate a significant amount of kaolin, indicating that they suffered from motion sickness. The hypergravity-induced kaolin intake was suppressed by mepyramine, but not by terfinadine or zolantizine. This finding indicates that cerebral post-synaptic H1 but not H2 or peripheral H1 receptors play an important role in the development of motion sickness. The expression of H1 receptor mRNA was up-regulated in the hypothalamus and brainstem, but not in the cerebral cortex after 2 G hypergravity load in rats.

Injury and illness at the Newport-Bermuda race 1998- 2006.

OBJECTIVE: To describe the relative frequency and types of injury and illness in the Newport-Bermuda off-shore yachting race. METHODS: At the end of each race held in even numbered years from 1998-2006, the captain of each boat was asked to complete a survey detailing any injury or illness among his/her crew. RESULTS: There was an overall 87% response rate to the survey. During the study period, 38 injuries and 57 illnesses were reported for an estimated 8105 sailors, yielding rate of injury or illness of 12 per 1000 races per sailor. Most common were injuries to the upper extremity (47%), and lacerations were the most common type of injury (45%). Sea sickness was the most common illness, and the rate of illness and injury increased in races that took place in heavy weather. Radio consultations were used 4 times, and 3 sailors required transport to a hospital. CONCLUSIONS: The rate of injury and illness was relatively low in the Newport-Bermuda race. Injuries to the upper extremities and lacerations were most common, and sea sickness was the most common illness. The majority of illness and injury can be initially managed onboard.

Drop attacks secondary to superior canal dehiscence syndrome.

Two patients with unprovoked drop attacks were found to have dehiscence of the superior semicircular canal on CT of the temporal bone. Both had conductive hearing loss, preservation of stapedius reflex, and abnormal vestibular evoked myogenic potentials. Neither had sound- or pressure-induced nystagmus. Repair of the dehiscence in one case stopped the drop attacks, supporting a causal relationship between the dehiscence and the drop attacks.

Histology of the utricle in kinetotically swimming fish: a parabolic aircraft flight study.

OBJECTIVES: Humans taking part in parabolic aircraft flights (PAFs) may suffer from space motion sickness, which is a form of kinetosis. As it has been repeatedly shown that some fish in a given batch also reveal kinetotic behaviour (especially so-called spinning movements and looping responses) during PAFs, and as a result of the homology of the vestibular apparatus of all vertebrates, fish can be used as model systems to investigate the origin of susceptibility to motion sickness. Therefore. we were prompted to examine the utricular maculae, which are responsible for the internalization of gravity in teleosteans of fish swimming kinetotically in microgravity (microg) in comparison with those of animals from the same batch who swam normally. MATERIAL AND METHODS: Larval cichlid fish (Oreochromis mossambicus) were subjected to PAFs. Post-flight, animals which had behaved normally or kinetotically during the microg phases were examined histologically The sizes of the inner ear utricular maculae as well as the numbers of sensory and supporting cells were determined. RESULTS: The total numbers of both sensory and supporting cells of the utricular maculae did not differ between kinetotic and normally swimming fish. Cell density (number of sensory and supporting cells/100 microm2) was, however, reduced in kinetotic animals (p < 0.0001), which seemed to be due to the presence of malformed epithelial cells of increased size in the kinetotic specimens. CONCLUSION: These results indicate that susceptibility to kinetosis may originate from genetically predisposed malformed sensory epithelia.

Size and cell number of the utricle in kinetotically swimming fish: a parabolic aircraft flight study.

Humans taking part in parabolic aircraft flights (PAFs) may suffer from space motion sickness (SMS, a kinetosis). Since it has been repeatedly shown earlier that some fish of a given batch also reveal a kinetotic behavior during PAFs (especially so-called spinning movements and looping responses) and due to the homology of the vestibular apparatus among all vertebrates, fish can be used as model systems to investigate the origin of susceptibility to motion sickness. Therefore, we examined the utricular maculae (they are responsible for the internalization of gravity in teleosteans) of fish swimming kinetotically at microgravity in comparison with animals from the same batch who swam normally. On the histological level, it was found that the total number of both sensory and supporting cells of the utricular maculae did not differ between kinetotic animals as compared to normally swimming fish. Cell density (sensory and supporting cells/100 micrometers2), however, was reduced in kinetotic animals (p<0.0001), which seemed to be due to malformed epithelial cells (increase in cell size) of the kinetotic specimens. Susceptibility to kinetoses may therefore originate in malformed sensory epithelia.

Vestibular modulation of plasma vasopressin levels in rats.

Recent studies, which have shown an increase of plasma vasopressin (VP) in experimental motion sickness and the efficacy of VP antagonists for motion sickness, suggest an important role of VP in the development of vestibulo-autonomic responses. We have recently found evidence of the co-existence of vasopressinergic neurons with the stress-sensitive chemokinergic neuronal system in the hypothalamo-pituitary pathway in rats, which uses cytokine-induced neutrophil chemoattractant (CINC) as an effector molecule. In this study, to elucidate possible roles of VP and CINC in the vestibulo-autonomic responses, we simultaneously measured plasma VP and CINC concentrations after electrical or caloric vestibular stimulation in urethane-anesthetized rats. Electrical vestibular stimulation with more than 200 microA increased the plasma levels of VP in a current intensity-dependent manner, and stimulation with 500 microA increased the plasma VP levels to 350% of the normal control group, which received no stimulation. Caloric vestibular stimulation with cold water increased the plasma VP levels to 262% of the control group, which received caloric stimulation with water at 37 degrees C, and stimulation with warm water tended to increase the plasma VP levels. Plasma CINC levels were neither affected by electrical nor caloric vestibular stimulation. These findings indicate that vestibular stimulation increased plasma levels of VP but not CINC, and this vestibular-induced activation of VP neurons may be involved in a mechanism of vestibulo-autonomic responses.

Autonomic nervous system activity associated with postural disturbances in patients with perilymphatic fistula: sympathetic or vagal origin?

The study focused on patients suffering from perilymphatic fistula (PLF), whether they had undergone surgery or not. Vestibular disturbances can be harmless but are associated with varying symptoms, demonstrating disorders within the autonomic nervous system (ANS). The aim was to test whether the orthosympathetic is involved as the vagal part is often suspected of eliciting a feeling of sickness. Non-invasive and uninterrupted recording of ANS activity represents an objectivation technique to evidence such disturbances. Electrodermal activity, thermovascular variables, instantaneous cardiac rate and blood pressure were recorded. Discomfort was triggered experimentally by applying various stimulations successively to the intact ear then to the PLF (or operated) side. Twelve subjects took part in the experiment. Two types of ANS activity were distinguished: (1) phasic responses during stimulation and (2) tonic evolution thereafter. Results show strong activation in orthosympathetic variables when the PLF side was stimulated. No further significant difference between the two sides was to be observed following surgery. After stimulation, a sudden increase in skin resistance was observed, associated with slight bradycardia. No vagal signs having been evidenced, actual nausea may result from brief inhibition of sympathetic activation resulting, in turn from primary over-activation of this system.