- Email: [email protected]
Vestibular evoked myogenic potentials and motion sickness medications
Clinical Neurophysiology 127 (2016) 2350–2354
Contents lists available at ScienceDirect
Clinical Neurophysiology journal homepage: www.elsevier.com/locate/clinph
Vestibular evoked myogenic potentials and motion sickness medications Dror Tal ⇑, Shir Shemy, Gil Kaminski-Graif, Guy Wiener, Dov Hershkovitz Motion Sickness and Human Performance Laboratory, Israel Naval Medical Institute, Israel Defense Forces Medical Corps, Haifa, Israel
a r t i c l e
i n f o
Article history: Accepted 7 March 2016 Available online 19 March 2016 Keywords: Vestibular evoked myogenic potentials Scopolamine Cinnarizine Dimenhydrinate Seasickness Motion sickness
h i g h l i g h t s We examined cVEMP as a means of evaluating the action of anti-seasickness drugs. Action of scopolamine was demonstrated by changes in cVEMP latencies. cVEMP may be used to evaluate the effect of drugs on the vestibular system.
a b s t r a c t Objective: Seasickness is a widespread problem among naval crew, and has a major impact on their performance at sea. The three pharmacological agents most commonly employed in the treatment of seasickness are dimenhydrinate, cinnarizine, and scopolamine. At present, the effectiveness of antiseasickness drugs is tested by a process of ‘‘trial and error”, while sailing and exposed to sea conditions. A physiological test to evaluate the action of a drug might save crew members long periods of suffering, as well as simplifying the procedure of selecting the appropriate treatment for each individual. The cervical vestibular evoked myogenic potentials (cVEMP) test has come to be recognized as a reliable procedure for the objective evaluation of saccular function. It was the hypothesis of the present study that cVEMP otolith responses may be affected by anti-motion sickness drugs, which might thus make cVEMP a useful clinical neurophysiological tool for the assessment of drug absorption and efficacy. Methods: Thirty male sailors who regularly took medication for the treatment of seasickness participated in the study. Participants underwent the cVEMP test pre- and 1 h post-drug administration. Results: A statistically significant decrease in p13 latency was found after administration of scopolamine compared with baseline (14.46 ms vs. 15.09 ms, p = 0.0049), with significant prolongation of the binaural average inter-latency in this group. No differences were found in the dimenhydrinate and cinnarizine study groups. Conclusions: This study demonstrated that scopolamine absorption can be verified by changes in cVEMP latencies. Significance: The potential of the cVEMP test for predicting action of scopolamine on the vestibular system. Ó 2016 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved.
1. Introduction Seasickness represents a major problem for ships’ crew. Its symptoms are both vegetative and cognitive, with the consequence that the crew’s ability to perform their daily duties is often severely limited. Some crew members undergo habituation to seasickness after 3–6 months experience at sea, although others remain sensitive to sea conditions. Symptoms occur with varying severity in ⇑ Corresponding author at: Motion Sickness and Human Performance Laboratory, The Israel Naval Medical Institute (INMI), Box 22, Rambam Health Care Campus, P.O. Box 9602, 3109601 Haifa, Israel. Tel.: +972 4 8693459; fax: +972 4 8693240. E-mail address: [email protected] (D. Tal).
20–60% of sailors, depending on the sea state and the length of the voyage (Golding and Gresty, 2015). It becomes clear from a review of the literature that the vestibular system plays a significant role in the development of motion sickness. Support for this may be found in the fact that both animals and humans with bilateral vestibular loss are immune to motion sickness (Cheung et al., 1991). Furthermore, motion sickness drugs act via a bilateral vestibular blocking mechanism (Takeda et al., 1993). Riccio and Stoffregen (1991) and Stoffregen (2011) postulated a relationship between the vestibular system and body sway prior to stimulus exposure. The authors pointed out differences in body sway between those persons who developed motion sickness symptoms and those who did not. Simulator studies have
http://dx.doi.org/10.1016/j.clinph.2016.03.010 1388-2457/Ó 2016 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved.
D. Tal et al. / Clinical Neurophysiology 127 (2016) 2350–2354
demonstrated that the vertical linear acceleration component of ship motion (heave) is the most provocative stimulus of seasickness, particularly in the range 0.17–0.23 Hz. The saccule is responsible for monitoring vertical acceleration in the upright position, and therefore it is suggested that the saccule may play an important role in seasickness (Lawther and Griffin, 1987; Tal et al., 2006). In recent years, the cervical vestibular evoked myogenic potentials (cVEMP) test has been used to evaluate saccular function by provoking the inhibitory bipolar myogenic potential of the sternocleidomastoid (SCM) muscle. The response is considered a unilateral reflex, and is measured by surface electrodes located on the SCM ipsilateral to the stimulated ear (Colebatch et al., 1994; Murofushi et al., 2004). It is mediated by a synaptic pathway leading from the vestibular nuclei to the SCM motor nucleus (Phelan et al., 1990). Animal and human studies have documented the presence of muscarinic acetylcholine receptors, as well as histamine receptors, in the peripheral vestibular system and the vestibular nuclei. The activity of the vestibular system is modulated by excitation and inhibition of these receptors. A number of studies have shown the influence of vestibular suppressant drugs on vestibular reflexes (Ishiyama et al., 1997; Phelan et al., 1990; Shupak et al., 1994). Motta et al. (2011) recorded auditory brain response and cVEMP reflexes in anesthetized guinea pigs. Whereas the auditory brain response could be measured normally during anesthesia, the cVEMP response was not recordable. The three main drugs employed in the conventional treatment of motion sickness are dimenhydrinate, a histamine antagonist, cinnarizine, an antihistamine and calcium channel blocker, and scopolamine, which acts via blocking of the muscarinic acetylcholine receptor (Golding and Gresty, 2015). One of the challenges faced by the physician in the motion sickness clinic is to select the appropriate drug for the patient. Difficulties arise due to high variability in the response to the different medications. In the case of seasickness, the current procedure is to examine the drug’s efficacy during real-time exposure to sea conditions. This could involve prolonged suffering on the part of the patient until a suitable treatment is found. However, the major concern is when the patient fails to respond to any of the above mentioned drugs. In such a case, when there is a known history of seasickness, the physician should advise the patient to reconsider his choice of occupation as a crew member aboard a sea-going vessel. The purpose of the present study was therefore to evaluate the effect of seasickness medications on the cVEMP response. 2. Methods 2.1. Subjects
2351
in the study were dimenhydrinate 100 mg (‘‘Travamin”, Rekah, Holon, Israel), cinnarizine 25 mg (‘‘Stunarone”, Janssen, Latina, Italy), and scopolamine 0.3 mg (‘‘Kwells”, Bayer, Newbury, Berkshire, UK). Adverse effects were documented 1 h after application of the drug. Side effect severity was graded on a four-point scale: 0 – no symptom; 1 – mild; 2 – moderate; 3 – severe. An average score for the three groups was calculated for each symptom. Documented symptoms were far-sighted blurred vision, near-sighted blurred vision, dazzle, eye irritation, drowsiness, headache, fatigue, difficulty concentrating, dryness of the mouth, physical weakness, and mental weakness. 2.2.2. Cervical vestibular evoked myogenic potentials cVEMP was performed bilaterally using the Navigator Pro system (Bio-Logic Systems Corp., Mundelein, IL, USA). Surface electromyographic (EMG) activity was recorded in the supine position, with the subject lying on a firm medical bed, as previously documented (Li et al., 1999; Tal et al., 2006, 2013). Sternocleidomastoid (SCM) muscle voltage was measured using surface Ag/AgCl electrodes fixed to the skin with Ten20 electrode paste. The active electrodes were firmly attached over the main bulk of the muscle, approximately half the distance between the mastoid tip and the sternal notch. A reference electrode was placed over the upper sternum. A ground electrode was placed on the center of the forehead. The cVEMP tests were performed by the same operator for all subjects. The position of each electrode was marked in the pre-medication test in order to reattach it at the same spot in the post-drug test. Stimuli were in the form of bilateral tone bursts, presented to the external ear canal through insert earphones covered with foam plugs. To achieve sufficient activation of the SCM, and thus produce the inhibitory reflex arc, subjects were instructed to lift their head up to an angle of about 30°. EMG activity was recorded bilaterally to avoid asymmetric muscle tension, and also due to the purely unilateral nature of the reflex. Tone bursts were presented at 4.3 Hz, with a central frequency of 500 Hz. The duration of sampling was 53.3 ms from the beginning of each click, and was amplified and filtered to a frequency range of 10– 1500 Hz. Each VEMP signal was derived from an average of 200 responses to click stimuli. Inclusion criteria for VEMP waves were two sequential responses with a correlation above 0.75 and a signal-to-noise ratio (SNR) of at least 2 (Tal et al., 2006, 2013). The cVEMP parameters evaluated for a 90 dB nHL intensity stimulus were p13 wave latency (ms), n23 wave latency (ms), p13–n23 wave inter-latency (ms), p13 wave amplitude (lV), n23 wave amplitude (lV), p13–n23 wave inter-amplitude (lV), and interaural amplitude difference (IAD) ratio. The IAD ratio was defined as the interaural peak-to-peak amplitude difference divided by the sum of the amplitudes in both ears.
Thirty naval crewmembers volunteered to participate in the study. Subjects’ ages ranged from 19 to 41 years (24.59 ± 7.11). A review of their medical history, together with an otoneurologic examination and pure tone and speech audiometry, ruled out any previous inner ear pathology or conductive hearing loss that might affect cVEMP results. Subjects were instructed not to take any medications, drugs or alcohol in the 48 h preceding cVEMP testing. All subjects gave their written informed consent, and the study was approved by the Israel Defense Forces Medical Corps Human Research Committee.
Statistical analysis was carried out using SPSS 12.0 software (SPSS Inc., Chicago, IL, USA). Differences between baseline values and those obtained after administration of the drug were analyzed for the binaural averages of the cVEMP parameters using a paired sample t-test and the Wilcoxon matched-pairs signed-rank test for parametric and non-parametric data, respectively. The adverse effects of the drugs were analyzed by an ANOVA test. A p value of 0.05 was taken as representing statistical significance.
2.2. Experimental protocol
3. Results
2.2.1. Pharmaceutical agents The study population was divided randomly into three drug groups, 10 subjects in each. The pharmaceutical agents employed
cVemp waves were successfully recorded in all subjects. The values obtained for the binaural mean latencies of the parameters evaluated are given in Tables 1–3.
2.3. Statistical analysis
2352
D. Tal et al. / Clinical Neurophysiology 127 (2016) 2350–2354
Table 1 Binaural average values of cVEMP parameters in the scopolamine study group, pre- and post-scopolamine. Pre-scopolamine Latency p13 (ms) Latency n23 (ms) Inter-latency, p13–n23 (ms) Amplitude p13 (lV) Amplitude n23 (lV) Inter-amplitude, p13–n23 (lV) IAD ratio
Post-scopolamine
p value
14.46 ± 1.26 22.97 ± 2.40 8.51 ± 2.12 87.72 ± 50.26 156.05 ± 105.18 243.77 ± 150.01 0.018 ± 0.24
0.0049** NS 0.0126* NS NS NS
Post-dimenhydrinate
p value
15.09 ± 1.32 22.93 ± 2.33 7.83 ± 1.97 91.32 ± 57.96 160.50 ± 133.10 251.83 ± 188.25 0.04 ± 0.23
Data are expressed as mean ± SD. IAD, interaural amplitude difference; NS, not significant. * Significant difference (p < 0.05). ** Significant difference (p < 0.01).
Table 2 Binaural average values of cVEMP parameters in the dimenhydrinate study group, pre- and post-dimenhydrinate. Pre-dimenhydrinate Latency p13 (ms) Latency n23 (ms) Inter-latency, p13–n23 (ms) Amplitude p13 (lV) Amplitude n23 (lV) Inter-amplitude, p13–n23 (lV) IAD ratio
15.44 ± 1.78 25.20 ± 2.44 9.76 ± 1.90 77.09 ± 55.69 138.48 ± 84.54 215.57 ± 139.13 0.083 ± 0.14
15.75 ± 2.15 25.56 ± 2.47 9.80 ± 2.42 68.59 ± 54.97 125.77 ± 96.40 194.36 ± 150.39 0.039 ± 0.18
NS NS NS NS NS NS NS
Post-cinnarizine
p value
Data are expressed as mean ± SD. IAD, interaural amplitude difference; NS, not significant.
Table 3 Binaural average values of cVEMP parameters in the cinnarizine study group, pre- and post-cinnarizine. Pre-cinnarizine Latency p13 (ms) Latency n23 (ms) Inter-latency, p13–n23 (ms) Amplitude p13 (lV) Amplitude n23 (lV) Inter-amplitude, p13–n23 (lV) IAD ratio
15.59 ± 2.41 24.35 ± 2.44 8.75 ± 2.24 81.94 ± 42.78 139.60 ± 71.57 221.54 ± 112.04 0.071 ± 0.23
15.33 ± 2.05 24.55 ± 2.27 9.21 ± 1.60 84.04 ± 45.09 133.20 ± 73.97 217.24 ± 114.93 0.002 ± 0.20
NS NS NS NS NS NS NS
Data are expressed as mean ± SD. IAD, interaural amplitude difference; NS, not significant.
A statistically significant difference was found for p13 latency pre- and post-drug administration in the scopolamine study group (Student t-test, p = 0.0049). The mean latency was 15.09 ± 1.32 ms and 14.46 ± 1.26 ms for baseline and post-drug administration, respectively (Fig. 1). No significant difference was found in p13 latency duration for the cinnarizine and dimenhydrinate groups (Fig. 2). A statistically significant difference was also found in p13 interlatency pre- and post-drug administration in the scopolamine group (Wilcoxon matched-pairs signed-rank test, p = 0.012). The mean inter-latency was 7.83 ± 1.97 ms and 8.51 ± 2.12 ms for baseline and post-drug administration, respectively. No significant differences were found in the cinnarizine and dimenhydrinate groups. Fatigue as a side effect of the drug was significantly elevated in the scopolamine and dimenhydrinate groups (1.20 ± 1.13 and 1.30 ± 0.82, respectively), compared with the cinnarizine group (0.1 ± 0.31; p = 0.0072, Kruskal–Wallis nonparametric ANOVA). A similar result was obtained for drowsiness. This was severe in the scopolamine and dimenhydrinate groups (1.30 ± 1.06 and 1.50 ± 0. 97, respectively), and minor in the cinnarizine group (0.10 ± 0.31; p = 0.0035, Kruskal–Wallis nonparametric ANOVA). No significant differences were observed in any of the other side effects under the influence of the drugs.
Fig. 1. Representative cVEMP responses pre- and post-scopolamine. The dashed lines refer to p13 latency.
D. Tal et al. / Clinical Neurophysiology 127 (2016) 2350–2354
Fig. 2. Box plot of cVEMP pre- and post-drug treatment. Pre-S, pre-scopolamine; Post-S, post-scopolamine; Pre-D, pre-dimenhydrinate; Post-D, post-dimenhydrinate; Pre-C, pre-cinnarizine; Post-C, post-cinnarizine. Solid lines refer to 25%, 50%, and 75% quantiles, with whiskers at 5% and 95%. ⁄Significant difference.
4. Discussion Some patients treated with anti-seasickness medications do not respond to the first choice drug. The present study examined the reliability of the cVEMP test as a method of evaluating neurophysiological effect of seasickness drugs. The main findings were lengthening of p13–n23 inter-latency and shortening of p13 wave latency after administration of scopolamine. No changes were observed after administration of cinnarizine or dimenhydrinate. The findings of the present study corroborate those of Vanspauwen et al. (2011), who evaluated the effect of anti-motion sickness drugs on the cVEMP reflex. The authors examined a number of motion sickness drugs alone and in combination in a prospective randomized study. They failed to demonstrate changes in cVEMP wave recordings pre- and post-drug administration compared with placebo. Unlike the study of Vanspauwen et al., our investigation also examined scopolamine in its oral form, and significant changes in cVEMP parameters were observed in this study group. Shupak et al. (1994) demonstrated an effect of cinnarizine on the vestibulo-ocular reflex using the sinusoidal harmonic acceleration (SHA) test. No effect of cinnarizine on the vestibular system was observed by Vanspauwen et al. (2011) or in the present investigation. Shupak and his colleagues used the horizontal semicircular canal test, whereas the later studies used a vertical otolith test. These two organs differ in their neuro-anatomic pathways, which may be the reason the drug acted differently. It is well known that the action of motion sickness drugs on the vestibular system is by no means homogeneous. It is believed that scopolamine and lorazepam act mainly on the utricle, whereas promethazine is considered an antihistamine blocker of the semicircular canals (Weerts et al., 2012). Moreover, drugs are not manifested in the same way in different vestibular tests. Dimenhydrinate was found to modulate caloric, SHA and optokinetic parameters compared with placebo, but had no impact on the cVEMP test (Holtmann et al., 1989; Vanspauwen et al., 2011). Pyykkö et al. (1985a) found that transdermal therapeutic system (TTS-) scopolamine and dimenhydrinate significantly reduced
2353
vertigo and nystagmus induced by caloric and rotatory tests. During treatment with lidocaine and tocainide, however, caloric nystagmus was reduced but rotation-induced nystagmus was virtually unchanged. The authors concluded that TTS-scopolamine and dimenhydrinate act on the vestibular nuclei, and that lidocaine and tocainide act on the vestibular end organs. Vestibular test responses may also be dose-dependent. Pyykkö et al. (1985b) showed that one scopolamine patch did not change the caloric or optokinetic response, whereas a double dose of scopolamine reduced both. It therefore becomes clear that evaluating the physiological effect of a drug by objective vestibular assessment depends on the chosen technique, the vestibular end organ, the dose, and the pharmacological properties of the drug. Although the literature has pointed out many diagnostic implications of alterations in cVEMP amplitude, there is almost no information regarding cVEMP latencies (Murofushi et al., 2001). An interesting result of the present study is the changes observed in p13 latency without changes in n23 latency. Placing the electrodes on exactly the same spot in both the pre-medication and post-drug tests ruled out any possibility that the changes in latency were due to electrode positioning. Our finding of a change in latency is corroborated by the study of Murofushi et al. (2001), who demonstrated prolongation of p13 latency and high variability in n23 latency. Their recommendation was to use p13 latency as the better parameter for clinical evaluation, without taking n23 latency into account due to its relatively high standard deviation. Yang et al. (2008) also focused on latencies and not amplitudes. The authors examined the cVEMP reflex in patients suffering from benign paroxysmal positional vertigo and a control group. They found significant prolongation of latencies in the affected ear compared with the unaffected ear and the control group. Differences were not found in the amplitudes, suggesting that cVEMP amplitudes were dramatically sensitive to the evoked reflex technique. The earlier p13 evoked potential might be explained by the antimuscarinic effect of scopolamine and recruitment phenomena. Animal studies demonstrated the presence of nicotinic and muscarinic acetylcholine receptors in the vestibular nucleus, with particularly high density in the medial vestibular nucleus (Burke and Fahn, 1985; Clarke et al., 1985; Rotter et al., 1979; Schwartz, 1986; Wamsley et al., 1981; Zanni et al., 1995). Therefore the saccular information in the medial vestibular nucleus may be partly blocked by scopolamine. Compensation mechanisms such as recruitment could lead to restoration of the signal or the early evoked potential, by elevating the threshold while the vestibular system’s muscarinic receptors are inhibited. In such a case, when the threshold is reached neighbor neurons will be recruited, resulting in rapid nerve conduction and activation of motor units. Similar examples of recruitment may be observed in parallel fields such as loudness recruitment, acoustic neuroma, and small PCA tumors (Lajtman et al., 2000; Thomsen and Tos, 1990). A further explanation for early excitation of the p13 potential may be drawn from the study of Willott and Lu (1982), who analyzed the response of auditory neurons in the inferior colliculi of mice pre- and post-exposure to intense noise. As expected, intense noise caused loss of auditory sensitivity. However, in 31% of the neurons unexpected alterations of temporal pattern were observed in the action potentials. Suprathreshold stimuli that had evoked a transient response or inhibition of spontaneous discharge prior to noise exposure came to elicit sustained excitation after exposure. The authors hypothesized that noise-induced hearing loss may be associated with an increase in neural responsiveness and changes in the normal neural coding processes. On the basis of the present study and previous investigations, earlier p13 latency may be supported by models of recruitment and neural coding modulation. The effect of scopolamine on the
2354
D. Tal et al. / Clinical Neurophysiology 127 (2016) 2350–2354
cVEMP reflex arc may serve as a clinical neurophysiological indicator of the drug’s absorption. Acknowledgments This work was supported by a grant from the Israel Defense Forces Medical Corps. The authors are grateful to Mr. Richard Lincoln for his assistance in the preparation of the manuscript. Conflict of interest: None. References Burke RE, Fahn S. Choline acetyltransferase activity of the principal vestibular nuclei of rat, studied by micropunch technique. Brain Res 1985;328:196–9. Cheung BSK, Howard IP, Money KE. Visually-induced sickness in normal and bilaterally labyrinthine-defective subjects. Aviat Space Environ Med 1991;62:527–31. Clarke PBS, Schwartz RD, Paul SM, Pert CB, Pert A. Nicotinic binding in rat brain: autoradiographic comparison of [3H]acetylcholine, [3H]nicotine, and [125I]-abungarotoxin. J Neurosci 1985;5:1307–15. Colebatch JG, Halmagyi GM, Skuse NF. Myogenic potentials generated by a clickevoked vestibulocollic reflex. J Neurol Neurosurg Psychiatry 1994;57:190–7. Golding JF, Gresty MA. Pathophysiology and treatment of motion sickness. Curr Opin Neurol 2015;28:83–8. Holtmann S, Clarke AH, Scherer H, Höhn M. The anti-motion sickness mechanism of ginger. A comparative study with placebo and dimenhydrinate. Acta Otolaryngol 1989;108:168–74. Ishiyama A, López I, Wackym PA. Molecular characterization of muscarinic receptors in the human vestibular periphery. Implications for pharmacotherapy. Am J Otol 1997;18:648–54. Lajtman Z, Manestar D, Borcic´ V, Znaor T. Recruitment in the diagnosis of small PCA tumors. Acta Med Croatica 2000;54:85–9. Lawther A, Griffin MJ. Prediction of the incidence of motion sickness from the magnitude, frequency, and duration of vertical oscillation. J Acoust Soc Am 1987;82:957–66. Li MW, Houlden D, Tomlinson RD. Click evoked EMG responses in sternocleidomastoid muscles: characteristics in normal subjects. J Vestib Res 1999;9:327–34. Motta G, Sequino G, Menafro A, Vesce G, Marcuccio G, Brancaccio A, et al. Effect of anesthetic drugs on vestibular evoked myogenic potential recording. Open Otorhinolaryngol J 2011;5:35–9. Murofushi T, Shimizu K, Takegoshi H, Cheng P-W. Diagnostic value of prolonged latencies in the vestibular evoked myogenic potential. Arch Otolaryngol Head Neck Surg 2001;127:1069–72. Murofushi T, Ochiai A, Ozeki H, Iwasaki S. Laterality of vestibular evoked myogenic potentials. Int J Audiol 2004;43:66–8.
Phelan KD, Nakamura J, Gallagher JP. Histamine depolarizes rat medial vestibular nucleus neurons recorded intracellularly in vitro. Neurosci Lett 1990;109: 287–92. Pyykkö I, Padoan S, Schalén L, Lyttkens L, Magnusson M, Henriksson NG. The effects of TTS-scopolamine, dimenhydrinate, lidocaine, and tocainide on motion sickness, vertigo, and nystagmus. Aviat Space Environ Med 1985a;56:777–82. Pyykkö I, Schalén L, Matsuoka I. Transdermally administered scopolamine vs. dimenhydrinate. II. Effect on different types of nystagmus. Acta Otolaryngol 1985b;99:597–604. Riccio GE, Stoffregen TA. An ecological theory of motion sickness and postural instability. Ecol Psychol 1991;3:195–240. Rotter A, Birdsall NJM, Field PM, Raisman G. Muscarinic receptors in the central nervous system of the rat. II. Distribution of binding of [3H] propylbenzilycholine mustard in the midbrain and hindbrain. Brain Res 1979;180:167–83. Schwartz RD. Autoradiographic distribution of high affinity muscarinic and nicotinic cholinergic receptors labeled with [3H]acetylcholine in rat brain. Life Sci 1986;38:2111–9. Shupak A, Doweck I, Gordon CR, Spitzer O. Cinnarizine in the prophylaxis of seasickness: laboratory vestibular evaluation and sea study. Clin Pharmacol Ther 1994;55:670–80. Stoffregen TA. Motion sickness considered as a movement disorder. Mov Sport Sci/ Sci Mot 2011;74:19–30. Takeda N, Morita M, Hasegawa S, Horii A, Kubo T, Matsunaga T. Neuropharmacology of motion sickness and emesis. A review. Acta Otolaryngol 1993(Suppl. 501): 10–5. Tal D, Hershkovitz D, Kaminski G, Bar R. Vestibular evoked myogenic potential threshold and seasickness susceptibility. J Vestib Res 2006;16:273–8. Tal D, Hershkovitz D, Kaminski-Graif G, Wiener G, Samuel O, Shupak A. Vestibular evoked myogenic potentials and habituation to seasickness. Clin Neurophysiol 2013;124:2445–9. Thomsen J, Tos M. Acoustic neuroma: clinical aspects, audiovestibular assessment, diagnostic delay, and growth rate. Am J Otol 1990;11:12–9. Vanspauwen R, Weerts A, Hendrickx M, Buytaert KI, Blaivie C, Jorens PG, et al. No effects of anti-motion sickness drugs on vestibular evoked myogenic potentials outcome parameters. Otol Neurotol 2011;32:497–503. Wamsley JK, Lewis MS, Young 3rd WS, Kuhar MJ. Autoradiographic localization of muscarinic cholinergic receptors in rat brainstem. J Neurosci 1981;1:176–91. Weerts AP, De Meyer G, Pauwels G, Vanspauwen R, Dornhoffer JL, Van de Heyning PH, et al. Pharmaceutical countermeasures have opposite effects on the utricles and semicircular canals in man. Audiol Neurootol 2012;17:235–42. Willott JF, Lu S-M. Noise-induced hearing loss can alter neural coding and increase excitability in the central nervous system. Science 1982;216:1331–2. Yang WS, Kim SH, Lee JD, Lee W-S. Clinical significance of vestibular evoked myogenic potentials in benign paroxysmal positional vertigo. Otol Neurotol 2008;29:1162–6. Zanni M, Giardino L, Toschi L, Galetti G, Calzà L. Distribution of neurotransmitters, neuropeptides, and receptors in the vestibular nuclei complex of the rat: an immunocytochemical, in situ hybridization and quantitative receptor autoradiographic study. Brain Res Bull 1995;36:443–52.
Contents lists available at ScienceDirect
Clinical Neurophysiology journal homepage: www.elsevier.com/locate/clinph
Vestibular evoked myogenic potentials and motion sickness medications Dror Tal ⇑, Shir Shemy, Gil Kaminski-Graif, Guy Wiener, Dov Hershkovitz Motion Sickness and Human Performance Laboratory, Israel Naval Medical Institute, Israel Defense Forces Medical Corps, Haifa, Israel
a r t i c l e
i n f o
Article history: Accepted 7 March 2016 Available online 19 March 2016 Keywords: Vestibular evoked myogenic potentials Scopolamine Cinnarizine Dimenhydrinate Seasickness Motion sickness
h i g h l i g h t s We examined cVEMP as a means of evaluating the action of anti-seasickness drugs. Action of scopolamine was demonstrated by changes in cVEMP latencies. cVEMP may be used to evaluate the effect of drugs on the vestibular system.
a b s t r a c t Objective: Seasickness is a widespread problem among naval crew, and has a major impact on their performance at sea. The three pharmacological agents most commonly employed in the treatment of seasickness are dimenhydrinate, cinnarizine, and scopolamine. At present, the effectiveness of antiseasickness drugs is tested by a process of ‘‘trial and error”, while sailing and exposed to sea conditions. A physiological test to evaluate the action of a drug might save crew members long periods of suffering, as well as simplifying the procedure of selecting the appropriate treatment for each individual. The cervical vestibular evoked myogenic potentials (cVEMP) test has come to be recognized as a reliable procedure for the objective evaluation of saccular function. It was the hypothesis of the present study that cVEMP otolith responses may be affected by anti-motion sickness drugs, which might thus make cVEMP a useful clinical neurophysiological tool for the assessment of drug absorption and efficacy. Methods: Thirty male sailors who regularly took medication for the treatment of seasickness participated in the study. Participants underwent the cVEMP test pre- and 1 h post-drug administration. Results: A statistically significant decrease in p13 latency was found after administration of scopolamine compared with baseline (14.46 ms vs. 15.09 ms, p = 0.0049), with significant prolongation of the binaural average inter-latency in this group. No differences were found in the dimenhydrinate and cinnarizine study groups. Conclusions: This study demonstrated that scopolamine absorption can be verified by changes in cVEMP latencies. Significance: The potential of the cVEMP test for predicting action of scopolamine on the vestibular system. Ó 2016 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved.
1. Introduction Seasickness represents a major problem for ships’ crew. Its symptoms are both vegetative and cognitive, with the consequence that the crew’s ability to perform their daily duties is often severely limited. Some crew members undergo habituation to seasickness after 3–6 months experience at sea, although others remain sensitive to sea conditions. Symptoms occur with varying severity in ⇑ Corresponding author at: Motion Sickness and Human Performance Laboratory, The Israel Naval Medical Institute (INMI), Box 22, Rambam Health Care Campus, P.O. Box 9602, 3109601 Haifa, Israel. Tel.: +972 4 8693459; fax: +972 4 8693240. E-mail address: [email protected] (D. Tal).
20–60% of sailors, depending on the sea state and the length of the voyage (Golding and Gresty, 2015). It becomes clear from a review of the literature that the vestibular system plays a significant role in the development of motion sickness. Support for this may be found in the fact that both animals and humans with bilateral vestibular loss are immune to motion sickness (Cheung et al., 1991). Furthermore, motion sickness drugs act via a bilateral vestibular blocking mechanism (Takeda et al., 1993). Riccio and Stoffregen (1991) and Stoffregen (2011) postulated a relationship between the vestibular system and body sway prior to stimulus exposure. The authors pointed out differences in body sway between those persons who developed motion sickness symptoms and those who did not. Simulator studies have
http://dx.doi.org/10.1016/j.clinph.2016.03.010 1388-2457/Ó 2016 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved.
D. Tal et al. / Clinical Neurophysiology 127 (2016) 2350–2354
demonstrated that the vertical linear acceleration component of ship motion (heave) is the most provocative stimulus of seasickness, particularly in the range 0.17–0.23 Hz. The saccule is responsible for monitoring vertical acceleration in the upright position, and therefore it is suggested that the saccule may play an important role in seasickness (Lawther and Griffin, 1987; Tal et al., 2006). In recent years, the cervical vestibular evoked myogenic potentials (cVEMP) test has been used to evaluate saccular function by provoking the inhibitory bipolar myogenic potential of the sternocleidomastoid (SCM) muscle. The response is considered a unilateral reflex, and is measured by surface electrodes located on the SCM ipsilateral to the stimulated ear (Colebatch et al., 1994; Murofushi et al., 2004). It is mediated by a synaptic pathway leading from the vestibular nuclei to the SCM motor nucleus (Phelan et al., 1990). Animal and human studies have documented the presence of muscarinic acetylcholine receptors, as well as histamine receptors, in the peripheral vestibular system and the vestibular nuclei. The activity of the vestibular system is modulated by excitation and inhibition of these receptors. A number of studies have shown the influence of vestibular suppressant drugs on vestibular reflexes (Ishiyama et al., 1997; Phelan et al., 1990; Shupak et al., 1994). Motta et al. (2011) recorded auditory brain response and cVEMP reflexes in anesthetized guinea pigs. Whereas the auditory brain response could be measured normally during anesthesia, the cVEMP response was not recordable. The three main drugs employed in the conventional treatment of motion sickness are dimenhydrinate, a histamine antagonist, cinnarizine, an antihistamine and calcium channel blocker, and scopolamine, which acts via blocking of the muscarinic acetylcholine receptor (Golding and Gresty, 2015). One of the challenges faced by the physician in the motion sickness clinic is to select the appropriate drug for the patient. Difficulties arise due to high variability in the response to the different medications. In the case of seasickness, the current procedure is to examine the drug’s efficacy during real-time exposure to sea conditions. This could involve prolonged suffering on the part of the patient until a suitable treatment is found. However, the major concern is when the patient fails to respond to any of the above mentioned drugs. In such a case, when there is a known history of seasickness, the physician should advise the patient to reconsider his choice of occupation as a crew member aboard a sea-going vessel. The purpose of the present study was therefore to evaluate the effect of seasickness medications on the cVEMP response. 2. Methods 2.1. Subjects
2351
in the study were dimenhydrinate 100 mg (‘‘Travamin”, Rekah, Holon, Israel), cinnarizine 25 mg (‘‘Stunarone”, Janssen, Latina, Italy), and scopolamine 0.3 mg (‘‘Kwells”, Bayer, Newbury, Berkshire, UK). Adverse effects were documented 1 h after application of the drug. Side effect severity was graded on a four-point scale: 0 – no symptom; 1 – mild; 2 – moderate; 3 – severe. An average score for the three groups was calculated for each symptom. Documented symptoms were far-sighted blurred vision, near-sighted blurred vision, dazzle, eye irritation, drowsiness, headache, fatigue, difficulty concentrating, dryness of the mouth, physical weakness, and mental weakness. 2.2.2. Cervical vestibular evoked myogenic potentials cVEMP was performed bilaterally using the Navigator Pro system (Bio-Logic Systems Corp., Mundelein, IL, USA). Surface electromyographic (EMG) activity was recorded in the supine position, with the subject lying on a firm medical bed, as previously documented (Li et al., 1999; Tal et al., 2006, 2013). Sternocleidomastoid (SCM) muscle voltage was measured using surface Ag/AgCl electrodes fixed to the skin with Ten20 electrode paste. The active electrodes were firmly attached over the main bulk of the muscle, approximately half the distance between the mastoid tip and the sternal notch. A reference electrode was placed over the upper sternum. A ground electrode was placed on the center of the forehead. The cVEMP tests were performed by the same operator for all subjects. The position of each electrode was marked in the pre-medication test in order to reattach it at the same spot in the post-drug test. Stimuli were in the form of bilateral tone bursts, presented to the external ear canal through insert earphones covered with foam plugs. To achieve sufficient activation of the SCM, and thus produce the inhibitory reflex arc, subjects were instructed to lift their head up to an angle of about 30°. EMG activity was recorded bilaterally to avoid asymmetric muscle tension, and also due to the purely unilateral nature of the reflex. Tone bursts were presented at 4.3 Hz, with a central frequency of 500 Hz. The duration of sampling was 53.3 ms from the beginning of each click, and was amplified and filtered to a frequency range of 10– 1500 Hz. Each VEMP signal was derived from an average of 200 responses to click stimuli. Inclusion criteria for VEMP waves were two sequential responses with a correlation above 0.75 and a signal-to-noise ratio (SNR) of at least 2 (Tal et al., 2006, 2013). The cVEMP parameters evaluated for a 90 dB nHL intensity stimulus were p13 wave latency (ms), n23 wave latency (ms), p13–n23 wave inter-latency (ms), p13 wave amplitude (lV), n23 wave amplitude (lV), p13–n23 wave inter-amplitude (lV), and interaural amplitude difference (IAD) ratio. The IAD ratio was defined as the interaural peak-to-peak amplitude difference divided by the sum of the amplitudes in both ears.
Thirty naval crewmembers volunteered to participate in the study. Subjects’ ages ranged from 19 to 41 years (24.59 ± 7.11). A review of their medical history, together with an otoneurologic examination and pure tone and speech audiometry, ruled out any previous inner ear pathology or conductive hearing loss that might affect cVEMP results. Subjects were instructed not to take any medications, drugs or alcohol in the 48 h preceding cVEMP testing. All subjects gave their written informed consent, and the study was approved by the Israel Defense Forces Medical Corps Human Research Committee.
Statistical analysis was carried out using SPSS 12.0 software (SPSS Inc., Chicago, IL, USA). Differences between baseline values and those obtained after administration of the drug were analyzed for the binaural averages of the cVEMP parameters using a paired sample t-test and the Wilcoxon matched-pairs signed-rank test for parametric and non-parametric data, respectively. The adverse effects of the drugs were analyzed by an ANOVA test. A p value of 0.05 was taken as representing statistical significance.
2.2. Experimental protocol
3. Results
2.2.1. Pharmaceutical agents The study population was divided randomly into three drug groups, 10 subjects in each. The pharmaceutical agents employed
cVemp waves were successfully recorded in all subjects. The values obtained for the binaural mean latencies of the parameters evaluated are given in Tables 1–3.
2.3. Statistical analysis
2352
D. Tal et al. / Clinical Neurophysiology 127 (2016) 2350–2354
Table 1 Binaural average values of cVEMP parameters in the scopolamine study group, pre- and post-scopolamine. Pre-scopolamine Latency p13 (ms) Latency n23 (ms) Inter-latency, p13–n23 (ms) Amplitude p13 (lV) Amplitude n23 (lV) Inter-amplitude, p13–n23 (lV) IAD ratio
Post-scopolamine
p value
14.46 ± 1.26 22.97 ± 2.40 8.51 ± 2.12 87.72 ± 50.26 156.05 ± 105.18 243.77 ± 150.01 0.018 ± 0.24
0.0049** NS 0.0126* NS NS NS
Post-dimenhydrinate
p value
15.09 ± 1.32 22.93 ± 2.33 7.83 ± 1.97 91.32 ± 57.96 160.50 ± 133.10 251.83 ± 188.25 0.04 ± 0.23
Data are expressed as mean ± SD. IAD, interaural amplitude difference; NS, not significant. * Significant difference (p < 0.05). ** Significant difference (p < 0.01).
Table 2 Binaural average values of cVEMP parameters in the dimenhydrinate study group, pre- and post-dimenhydrinate. Pre-dimenhydrinate Latency p13 (ms) Latency n23 (ms) Inter-latency, p13–n23 (ms) Amplitude p13 (lV) Amplitude n23 (lV) Inter-amplitude, p13–n23 (lV) IAD ratio
15.44 ± 1.78 25.20 ± 2.44 9.76 ± 1.90 77.09 ± 55.69 138.48 ± 84.54 215.57 ± 139.13 0.083 ± 0.14
15.75 ± 2.15 25.56 ± 2.47 9.80 ± 2.42 68.59 ± 54.97 125.77 ± 96.40 194.36 ± 150.39 0.039 ± 0.18
NS NS NS NS NS NS NS
Post-cinnarizine
p value
Data are expressed as mean ± SD. IAD, interaural amplitude difference; NS, not significant.
Table 3 Binaural average values of cVEMP parameters in the cinnarizine study group, pre- and post-cinnarizine. Pre-cinnarizine Latency p13 (ms) Latency n23 (ms) Inter-latency, p13–n23 (ms) Amplitude p13 (lV) Amplitude n23 (lV) Inter-amplitude, p13–n23 (lV) IAD ratio
15.59 ± 2.41 24.35 ± 2.44 8.75 ± 2.24 81.94 ± 42.78 139.60 ± 71.57 221.54 ± 112.04 0.071 ± 0.23
15.33 ± 2.05 24.55 ± 2.27 9.21 ± 1.60 84.04 ± 45.09 133.20 ± 73.97 217.24 ± 114.93 0.002 ± 0.20
NS NS NS NS NS NS NS
Data are expressed as mean ± SD. IAD, interaural amplitude difference; NS, not significant.
A statistically significant difference was found for p13 latency pre- and post-drug administration in the scopolamine study group (Student t-test, p = 0.0049). The mean latency was 15.09 ± 1.32 ms and 14.46 ± 1.26 ms for baseline and post-drug administration, respectively (Fig. 1). No significant difference was found in p13 latency duration for the cinnarizine and dimenhydrinate groups (Fig. 2). A statistically significant difference was also found in p13 interlatency pre- and post-drug administration in the scopolamine group (Wilcoxon matched-pairs signed-rank test, p = 0.012). The mean inter-latency was 7.83 ± 1.97 ms and 8.51 ± 2.12 ms for baseline and post-drug administration, respectively. No significant differences were found in the cinnarizine and dimenhydrinate groups. Fatigue as a side effect of the drug was significantly elevated in the scopolamine and dimenhydrinate groups (1.20 ± 1.13 and 1.30 ± 0.82, respectively), compared with the cinnarizine group (0.1 ± 0.31; p = 0.0072, Kruskal–Wallis nonparametric ANOVA). A similar result was obtained for drowsiness. This was severe in the scopolamine and dimenhydrinate groups (1.30 ± 1.06 and 1.50 ± 0. 97, respectively), and minor in the cinnarizine group (0.10 ± 0.31; p = 0.0035, Kruskal–Wallis nonparametric ANOVA). No significant differences were observed in any of the other side effects under the influence of the drugs.
Fig. 1. Representative cVEMP responses pre- and post-scopolamine. The dashed lines refer to p13 latency.
D. Tal et al. / Clinical Neurophysiology 127 (2016) 2350–2354
Fig. 2. Box plot of cVEMP pre- and post-drug treatment. Pre-S, pre-scopolamine; Post-S, post-scopolamine; Pre-D, pre-dimenhydrinate; Post-D, post-dimenhydrinate; Pre-C, pre-cinnarizine; Post-C, post-cinnarizine. Solid lines refer to 25%, 50%, and 75% quantiles, with whiskers at 5% and 95%. ⁄Significant difference.
4. Discussion Some patients treated with anti-seasickness medications do not respond to the first choice drug. The present study examined the reliability of the cVEMP test as a method of evaluating neurophysiological effect of seasickness drugs. The main findings were lengthening of p13–n23 inter-latency and shortening of p13 wave latency after administration of scopolamine. No changes were observed after administration of cinnarizine or dimenhydrinate. The findings of the present study corroborate those of Vanspauwen et al. (2011), who evaluated the effect of anti-motion sickness drugs on the cVEMP reflex. The authors examined a number of motion sickness drugs alone and in combination in a prospective randomized study. They failed to demonstrate changes in cVEMP wave recordings pre- and post-drug administration compared with placebo. Unlike the study of Vanspauwen et al., our investigation also examined scopolamine in its oral form, and significant changes in cVEMP parameters were observed in this study group. Shupak et al. (1994) demonstrated an effect of cinnarizine on the vestibulo-ocular reflex using the sinusoidal harmonic acceleration (SHA) test. No effect of cinnarizine on the vestibular system was observed by Vanspauwen et al. (2011) or in the present investigation. Shupak and his colleagues used the horizontal semicircular canal test, whereas the later studies used a vertical otolith test. These two organs differ in their neuro-anatomic pathways, which may be the reason the drug acted differently. It is well known that the action of motion sickness drugs on the vestibular system is by no means homogeneous. It is believed that scopolamine and lorazepam act mainly on the utricle, whereas promethazine is considered an antihistamine blocker of the semicircular canals (Weerts et al., 2012). Moreover, drugs are not manifested in the same way in different vestibular tests. Dimenhydrinate was found to modulate caloric, SHA and optokinetic parameters compared with placebo, but had no impact on the cVEMP test (Holtmann et al., 1989; Vanspauwen et al., 2011). Pyykkö et al. (1985a) found that transdermal therapeutic system (TTS-) scopolamine and dimenhydrinate significantly reduced
2353
vertigo and nystagmus induced by caloric and rotatory tests. During treatment with lidocaine and tocainide, however, caloric nystagmus was reduced but rotation-induced nystagmus was virtually unchanged. The authors concluded that TTS-scopolamine and dimenhydrinate act on the vestibular nuclei, and that lidocaine and tocainide act on the vestibular end organs. Vestibular test responses may also be dose-dependent. Pyykkö et al. (1985b) showed that one scopolamine patch did not change the caloric or optokinetic response, whereas a double dose of scopolamine reduced both. It therefore becomes clear that evaluating the physiological effect of a drug by objective vestibular assessment depends on the chosen technique, the vestibular end organ, the dose, and the pharmacological properties of the drug. Although the literature has pointed out many diagnostic implications of alterations in cVEMP amplitude, there is almost no information regarding cVEMP latencies (Murofushi et al., 2001). An interesting result of the present study is the changes observed in p13 latency without changes in n23 latency. Placing the electrodes on exactly the same spot in both the pre-medication and post-drug tests ruled out any possibility that the changes in latency were due to electrode positioning. Our finding of a change in latency is corroborated by the study of Murofushi et al. (2001), who demonstrated prolongation of p13 latency and high variability in n23 latency. Their recommendation was to use p13 latency as the better parameter for clinical evaluation, without taking n23 latency into account due to its relatively high standard deviation. Yang et al. (2008) also focused on latencies and not amplitudes. The authors examined the cVEMP reflex in patients suffering from benign paroxysmal positional vertigo and a control group. They found significant prolongation of latencies in the affected ear compared with the unaffected ear and the control group. Differences were not found in the amplitudes, suggesting that cVEMP amplitudes were dramatically sensitive to the evoked reflex technique. The earlier p13 evoked potential might be explained by the antimuscarinic effect of scopolamine and recruitment phenomena. Animal studies demonstrated the presence of nicotinic and muscarinic acetylcholine receptors in the vestibular nucleus, with particularly high density in the medial vestibular nucleus (Burke and Fahn, 1985; Clarke et al., 1985; Rotter et al., 1979; Schwartz, 1986; Wamsley et al., 1981; Zanni et al., 1995). Therefore the saccular information in the medial vestibular nucleus may be partly blocked by scopolamine. Compensation mechanisms such as recruitment could lead to restoration of the signal or the early evoked potential, by elevating the threshold while the vestibular system’s muscarinic receptors are inhibited. In such a case, when the threshold is reached neighbor neurons will be recruited, resulting in rapid nerve conduction and activation of motor units. Similar examples of recruitment may be observed in parallel fields such as loudness recruitment, acoustic neuroma, and small PCA tumors (Lajtman et al., 2000; Thomsen and Tos, 1990). A further explanation for early excitation of the p13 potential may be drawn from the study of Willott and Lu (1982), who analyzed the response of auditory neurons in the inferior colliculi of mice pre- and post-exposure to intense noise. As expected, intense noise caused loss of auditory sensitivity. However, in 31% of the neurons unexpected alterations of temporal pattern were observed in the action potentials. Suprathreshold stimuli that had evoked a transient response or inhibition of spontaneous discharge prior to noise exposure came to elicit sustained excitation after exposure. The authors hypothesized that noise-induced hearing loss may be associated with an increase in neural responsiveness and changes in the normal neural coding processes. On the basis of the present study and previous investigations, earlier p13 latency may be supported by models of recruitment and neural coding modulation. The effect of scopolamine on the
2354
D. Tal et al. / Clinical Neurophysiology 127 (2016) 2350–2354
cVEMP reflex arc may serve as a clinical neurophysiological indicator of the drug’s absorption. Acknowledgments This work was supported by a grant from the Israel Defense Forces Medical Corps. The authors are grateful to Mr. Richard Lincoln for his assistance in the preparation of the manuscript. Conflict of interest: None. References Burke RE, Fahn S. Choline acetyltransferase activity of the principal vestibular nuclei of rat, studied by micropunch technique. Brain Res 1985;328:196–9. Cheung BSK, Howard IP, Money KE. Visually-induced sickness in normal and bilaterally labyrinthine-defective subjects. Aviat Space Environ Med 1991;62:527–31. Clarke PBS, Schwartz RD, Paul SM, Pert CB, Pert A. Nicotinic binding in rat brain: autoradiographic comparison of [3H]acetylcholine, [3H]nicotine, and [125I]-abungarotoxin. J Neurosci 1985;5:1307–15. Colebatch JG, Halmagyi GM, Skuse NF. Myogenic potentials generated by a clickevoked vestibulocollic reflex. J Neurol Neurosurg Psychiatry 1994;57:190–7. Golding JF, Gresty MA. Pathophysiology and treatment of motion sickness. Curr Opin Neurol 2015;28:83–8. Holtmann S, Clarke AH, Scherer H, Höhn M. The anti-motion sickness mechanism of ginger. A comparative study with placebo and dimenhydrinate. Acta Otolaryngol 1989;108:168–74. Ishiyama A, López I, Wackym PA. Molecular characterization of muscarinic receptors in the human vestibular periphery. Implications for pharmacotherapy. Am J Otol 1997;18:648–54. Lajtman Z, Manestar D, Borcic´ V, Znaor T. Recruitment in the diagnosis of small PCA tumors. Acta Med Croatica 2000;54:85–9. Lawther A, Griffin MJ. Prediction of the incidence of motion sickness from the magnitude, frequency, and duration of vertical oscillation. J Acoust Soc Am 1987;82:957–66. Li MW, Houlden D, Tomlinson RD. Click evoked EMG responses in sternocleidomastoid muscles: characteristics in normal subjects. J Vestib Res 1999;9:327–34. Motta G, Sequino G, Menafro A, Vesce G, Marcuccio G, Brancaccio A, et al. Effect of anesthetic drugs on vestibular evoked myogenic potential recording. Open Otorhinolaryngol J 2011;5:35–9. Murofushi T, Shimizu K, Takegoshi H, Cheng P-W. Diagnostic value of prolonged latencies in the vestibular evoked myogenic potential. Arch Otolaryngol Head Neck Surg 2001;127:1069–72. Murofushi T, Ochiai A, Ozeki H, Iwasaki S. Laterality of vestibular evoked myogenic potentials. Int J Audiol 2004;43:66–8.
Phelan KD, Nakamura J, Gallagher JP. Histamine depolarizes rat medial vestibular nucleus neurons recorded intracellularly in vitro. Neurosci Lett 1990;109: 287–92. Pyykkö I, Padoan S, Schalén L, Lyttkens L, Magnusson M, Henriksson NG. The effects of TTS-scopolamine, dimenhydrinate, lidocaine, and tocainide on motion sickness, vertigo, and nystagmus. Aviat Space Environ Med 1985a;56:777–82. Pyykkö I, Schalén L, Matsuoka I. Transdermally administered scopolamine vs. dimenhydrinate. II. Effect on different types of nystagmus. Acta Otolaryngol 1985b;99:597–604. Riccio GE, Stoffregen TA. An ecological theory of motion sickness and postural instability. Ecol Psychol 1991;3:195–240. Rotter A, Birdsall NJM, Field PM, Raisman G. Muscarinic receptors in the central nervous system of the rat. II. Distribution of binding of [3H] propylbenzilycholine mustard in the midbrain and hindbrain. Brain Res 1979;180:167–83. Schwartz RD. Autoradiographic distribution of high affinity muscarinic and nicotinic cholinergic receptors labeled with [3H]acetylcholine in rat brain. Life Sci 1986;38:2111–9. Shupak A, Doweck I, Gordon CR, Spitzer O. Cinnarizine in the prophylaxis of seasickness: laboratory vestibular evaluation and sea study. Clin Pharmacol Ther 1994;55:670–80. Stoffregen TA. Motion sickness considered as a movement disorder. Mov Sport Sci/ Sci Mot 2011;74:19–30. Takeda N, Morita M, Hasegawa S, Horii A, Kubo T, Matsunaga T. Neuropharmacology of motion sickness and emesis. A review. Acta Otolaryngol 1993(Suppl. 501): 10–5. Tal D, Hershkovitz D, Kaminski G, Bar R. Vestibular evoked myogenic potential threshold and seasickness susceptibility. J Vestib Res 2006;16:273–8. Tal D, Hershkovitz D, Kaminski-Graif G, Wiener G, Samuel O, Shupak A. Vestibular evoked myogenic potentials and habituation to seasickness. Clin Neurophysiol 2013;124:2445–9. Thomsen J, Tos M. Acoustic neuroma: clinical aspects, audiovestibular assessment, diagnostic delay, and growth rate. Am J Otol 1990;11:12–9. Vanspauwen R, Weerts A, Hendrickx M, Buytaert KI, Blaivie C, Jorens PG, et al. No effects of anti-motion sickness drugs on vestibular evoked myogenic potentials outcome parameters. Otol Neurotol 2011;32:497–503. Wamsley JK, Lewis MS, Young 3rd WS, Kuhar MJ. Autoradiographic localization of muscarinic cholinergic receptors in rat brainstem. J Neurosci 1981;1:176–91. Weerts AP, De Meyer G, Pauwels G, Vanspauwen R, Dornhoffer JL, Van de Heyning PH, et al. Pharmaceutical countermeasures have opposite effects on the utricles and semicircular canals in man. Audiol Neurootol 2012;17:235–42. Willott JF, Lu S-M. Noise-induced hearing loss can alter neural coding and increase excitability in the central nervous system. Science 1982;216:1331–2. Yang WS, Kim SH, Lee JD, Lee W-S. Clinical significance of vestibular evoked myogenic potentials in benign paroxysmal positional vertigo. Otol Neurotol 2008;29:1162–6. Zanni M, Giardino L, Toschi L, Galetti G, Calzà L. Distribution of neurotransmitters, neuropeptides, and receptors in the vestibular nuclei complex of the rat: an immunocytochemical, in situ hybridization and quantitative receptor autoradiographic study. Brain Res Bull 1995;36:443–52.