- Email: [email protected]
Acoustic, mechanical and galvanic stimulation modes elicit ocular vestibular-evoked myogenic potentials
Clinical Neurophysiology 120 (2009) 1841–1844
Contents lists available at ScienceDirect
Clinical Neurophysiology journal homepage: www.elsevier.com/locate/clinph
Acoustic, mechanical and galvanic stimulation modes elicit ocular vestibular-evoked myogenic potentials Po-Wen Cheng a, Chien-Cheng Chen a, Shou-Jen Wang b, Yi-Ho Young c,* a
Department of Otolaryngology, Far Eastern Memorial Hospital, Taipei, Taiwan Institute of Biomedical Engineering, College of Medicine and College of Engineering, National Taiwan University, Taipei, Taiwan c Department of Otolaryngology, National Taiwan University Hospital, Taipei, Taiwan b
a r t i c l e
i n f o
Article history: Accepted 3 August 2009 Available online 29 August 2009 Keywords: Air-conducted sound Bone-conducted vibration Galvanic vestibular stimulation Vestibular-evoked myogenic potential Ocular
a b s t r a c t Objective: This study compared the characteristic parameters of ocular vestibular-evoked myogenic potentials (oVEMPs) elicited by the air-conducted sound (ACS) and bone-conducted vibration (BCV) stimulation modes as well as the galvanic vestibular stimulation (GVS) mode. Design: Fifteen healthy subjects underwent oVEMP tests using ACS (127 dBSPL), BCV (142 dB force level), and GVS (5 mA) modes. The response rate, latencies of nI and pI, nI–pI interval and amplitude were measured for each mode and compared among modes. Results: All 15 healthy subjects (30 ears) had 100% response rates in both BCV- and GVS–oVEMPs, exhibiting a response rate significantly higher than 80% in ACS–oVEMPs. The mean nI latency was the shortest in the GVS mode, followed by BCV and then ACS modes. The variation among the latencies of the three modes was significant. Likewise, the mean nI–pI amplitudes in ACS-, BCV- and GVS modes varied significantly. However, the mean nI–pI interval did not differ significantly among the three modes. Conclusions: Among the ACS (127 dBSPL), BCV (142 dB force level), and GVS (5 mA) modes, the BCV mode yields a 100% response rate and the largest nI–pI amplitude of oVEMPs. Significance: The oVEMPs in ACS and GVS modes may help to differentiate the saccular from the retrosaccular lesions. If ACS–oVEMPs are normal, then oVEMPs in BCV and GVS modes can distinguish between utricular and retro-utricular disorders. Restated, oVEMPs in ACS, BCV, and GVS modes may promote the topographical delineation of the lesion site of the otolithic–ocular reflex pathway. Ó 2009 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved.
1. Introduction Recently, vestibular-evoked myogenic potentials (VEMPs) have been successfully generated via acoustic (air-conducted sound, ACS), mechanical (bone-conducted vibration, BCV), and galvanic (galvanic vestibular stimulation, GVS) stimulation modes, and recorded on cervical muscles (so-called cVEMPs) and extraocular muscles (so-called oVEMPs) (Welgampola, 2008). The cVEMPs are thought to mediate through the sacculo-collic reflex pathway (Uchino et al., 1997), while the oVEMPs pass along the crossed vestibulo-ocular reflex (VOR) pathway (Iwasaki et al., 2007). Animal studies have demonstrated that acoustic stimulation activates the saccular macula – mostly the type I hair cells – in guinea pigs (Murofushi et al., 1995; Lue et al., 2009). Curthoys et al. (2006) re-
* Corresponding author. Address: Department of Otolaryngology, National Taiwan University Hospital, 1, Chang-Te St., Taipei, Taiwan. Tel.: + 886 2 23123456x65221; fax: + 886 2 23946674. E-mail address: [email protected] (Y.-H. Young).
ported that the firing rate of most irregular saccular and utricular afferents increased significantly in response to BCV stimuli, but canal afferent neurons were not activated by low-intensity BCV. Alternatively, both canal and otolithic afferents are activated by GVS (Goldberg et al., 1984). Thus, these three stimulation modes, acting on different parts of the VOR pathway, may help to identify topographically the site responsible for the VOR deficit. In our previous report (Cheng et al., 2008), GVS with an intensity of 5 mA for a duration of 1 ms elicited high (100%) response rates and large amplitudes of galvanic cVEMPs. Recently, Rosengren et al. (2009) utilized 4 mA for 2 ms to elicit oVEMPs successfully, and compared them with those elicited in ACS and tapping modes. Since head taps using a reflex hammer with an electronic trigger cannot deliver a series of brief, rapid changes in linear acceleration of movement, skull tapping generated by a hand-held electro-mechanical vibrator in BCV mode was performed in this study. Hence, the goal of this study was to compare the characteristic parameters of oVEMPs elicited by the ACS, BCV and GVS modes.
1388-2457/$36.00 Ó 2009 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.clinph.2009.08.002
1842
P.-W. Cheng et al. / Clinical Neurophysiology 120 (2009) 1841–1844
2. Subjects and methods Fifteen healthy volunteers (12 men and 3 women, aged from 24 to 31 years, mean 27 years) from the medical students and resident doctors were enrolled in this study. Each subject denied having previous ear disorders, and underwent oVEMP tests using ACS and BCV modes in a randomized order. On another day, the oVEMP test using the GVS mode was performed in each subject. This study was approved by the institutional review board, and each subject signed the informed consent to participate. 2.1. ACS–oVEMP The oVEMP stimulated by the ACS mode is denoted ACS– oVEMP. The subject was in a sitting position. Surface potentials, predominantly electromyographic (EMG) activities, were recorded (Medelec Synergy N-EP, Oxford Instrument Medicals, Surrey, UK) with five Ag/AgCl electrodes. Each active electrode was placed on the face inferior to each eye, around 1 cm below the center of the lower eyelid. The reference electrodes were positioned 1–2 cm below the corresponding active ones. One ground electrode was placed over the sternum. The electrode impedance was kept under 8 kX. During recording, the subject was instructed to look upward at a small fixed target >2 m from the eyes, with a vertical visual angle of approximately 30°–35° above horizontal. The EMG signals were amplified and bandpass filtered between 1 and 1000 Hz. Acoustic stimuli were 105 dBnHL (127 dB pe SPL) short tone bursts (500 Hz, rise/fall time = 1 ms, plateau time = 2 ms) with rarefaction polarity and were delivered through an insert earphone. Binaural acoustic stimulation with bilateral recordings was employed. The stimulation rate was 5 Hz and analytical time for each response was 50 ms; 100 responses were averaged for each run. The initial negative–positive biphasic waveform comprised the nI and pI peaks. Consecutive runs were performed to confirm the reproducibility of the nI and pI peaks, which were interpreted by two independent observers to determine whether oVEMPs were present. Conversely, oVEMPs were deemed absent when the biphasic waveform was not reproducible. The latencies of the nI and pI peaks, interval and amplitude of nI–pI were measured (Wang et al., 2009).
sides of the mastoid process (cathode) and the forehead (anode) in all subjects. All EMG recording conditions were the same as in the ACS mode, except that the subjects received galvanic stimulations while they gazed up or down. A direct 5 mA current was applied for 1.0 ms. During stimulation, eye movements were observed by videonystagmoscopy (Ulmer type Synapsys Co., Marseille, France). Responses to 100 galvanic stimuli were averaged for each run and the results of two duplicate runs were averaged. Since an original GVS–oVEMP waveform might contain large electrical artifacts (Watson and Colebatch, 1998), the response obtained upon gazing downward was subtracted from those upon gazing upward to provide the final GVS–oVEMP (Fig. 1). 2.4. Statistical methods The response rate, defined as the percentage of ears in which a clear response was identified, was compared between ACS–, BCV– and GVS–oVEMPs using the McNemar test. The latencies, interpeak intervals, and amplitudes were compared, respectively, using repeated-measures ANOVA among ACS–, BCV– and GVS–oVEMPs, followed by paired t-test if it reaches a significant difference. The level of significance was set at p < 0.05. 3. Results All 15 healthy subjects (30 ears) showed 100% response rates in both BCV– and GVS–oVEMPs, but only 80% response rate in ACS– oVEMPs (Fig. 2). Therefore, the response rate was significantly lower in ACS mode than in the other two modes (p < 0.05, McNemar’s test). Five subjects with absent ACS–oVEMPs in one or both ears were excluded, leaving 10 subjects (20 ears) enrolled to perform comparative analyses between ACS–, BCV– and GVS–oVEMPs. The mean latencies of nI in ACS, BCV and GVS modes were 9.5 ± 0.7 (mean ± SD), 8.9 ± 0.7 and 8.2 ± 0.6 ms, respectively, revealing that the nI latency was the shortest in the GVS mode, followed by the BCV mode, and the longest in the ACS mode; these
2.2. BCV–oVEMP The oVEMP stimulated by the BCV mode is denoted BCV– oVEMP. The BCV mode utilized a hand-held electro-mechanical vibrator (V201 shaker, Ling Dynamic Systems, Royston, England) fitted with a short M4 bolt (2 cm in length) terminated in a bakelite cap (1.6 cm in diameter). The input signal was a condensation square wave (0.5 ms in duration), which was driven by a custom amplifier combination. The drive voltage was adjusted and fixed to produce a peak force of 12 Newton, about 142 dB force level (FL) from the vibrator, as measured by an artificial mastoid (model 4930, Bruel & Kjaer P/L, Denmark). The initial impulse of the BCV was approximately a half-cycle of a 600 Hz sine wave. The operator held the vibrator by hand and supported most of its weight such that the axis of the connected bakelite cap perpendicularly delivered a repeatable tap on the subject’s head at Fz (midline forehead at the hairline) for the oVEMP test. The other setting was the same as the ACS mode, except that the ground electrode was placed on the right clavicle. A total of 50 responses were averaged for each run of oVEMP. 2.3. GVS–oVEMP The oVEMP elicited by the GVS mode is denoted GVS–oVEMP. Electrodes for delivering galvanic stimuli were placed on both
Fig. 1. Typical configuration of GVS–oVEMP. To remove electrical artifacts, the responses on downward gaze (A) are subtracted from those on upward gaze (B), when using galvanic stimulation 5 mA/1 ms. Thus, a final GVS–oVEMP waveform (C) is obtained after subtracting (A) from (B).
1843
P.-W. Cheng et al. / Clinical Neurophysiology 120 (2009) 1841–1844
Fig. 2. Illustration of oVEMPs induced by air-conducted sound (ACS), boneconducted vibration (BCV), and galvanic vestibular stimulation (GVS) modes.
latencies varied significantly (p < 0.05, two-tailed paired t-test; repeated-measures ANOVA, Table 1). Likewise, the pI latency followed the same trend among the three modes (p < 0.05, twotailed paired t-test, Table 1). However, the mean nI–pI interval did not vary significantly among the three modes (p > 0.05, repeated-measures ANOVA). The mean nI–pI amplitudes in ACS–, BCV– and GVS modes were 4.4 ± 1.5, 16.7 ± 6.7 and 13.7 ± 5.4 lV, respectively; they varied significantly among the three modes (p < 0.05, repeated-measures ANOVA, Table 1). The trend of nI–pI amplitude differed from that of latencies; the BCV mode exhibited the largest nI–pI amplitude, followed by the GVS mode, and the ACS mode had the smallest amplitude (p < 0.05, two-tailed paired t-test, Table 1). Fig. 3 illustrates the ACS–cVEMPs as well as oVEMPs under three modes in a unilateral Meniere’s disease patient, showing absent ACS–cVEMPs and ACS–oVEMPs, but present BCV–oVEMPs and GVS–oVEMPs.
4. Discussion The use of cVEMPs for evaluating the integrity of sacculo-collic reflex has gained popularity in the recent decade (Young, 2006). When cVEMPs are absent in response to ACS stimulation, cVEMPs by the GVS mode may help to distinguish labyrinthine lesions from retro-labyrinthine ones (Watson and Colebatch, 1998). Recently, the oVEMP test has been introduced to assess if the crossed VOR pathway is intact, which could be triggered by activating either saccular afferents by ACS mode, or both saccular and utricular afferents by BCV mode (Curthoys et al., 2006). Hence, the oVEMP test coupled with the cVEMP test may help to differentiate be-
Fig. 3. Illustration of cVEMPs and oVEMPs in a 38-year-old female patient with right Meniere’s disease. Both ACS–cVEMPs and ACS–oVEMPs are absent, but both BCV–oVEMPs and GVS–oVEMPs are present.
tween utricular and saccular disorders, or between upper and lower brainstem lesions. However, oVEMPs in ACS and BCV modes can not identify any lesion that affects the afferents between the otolithic organs and vestibular nuclei. Alternatively, oVEMPs in the GVS mode may solve this problem, and further assess the integrity of the crossed VOR pathway originating from the otolithic organs. In this study, both BCV and GVS modes elicited 100% clear oVEMPs in 15 healthy subjects, while ACS mode had a 80% response rate for oVEMPs, suggesting that the ACS mode is not a reliable tool for eliciting oVEMPs. For example, high intensity ACS failed to elicit a clear oVEMP in 5 of those healthy subjects, and these subjects would have been diagnosed as having absent otolithic function, when in fact they do have otolithic function as shown by the presence of BCV–oVEMPs. Subsequently, the latencies of nI and pI were compared: the GVS mode had the shortest latencies, followed by the BCV mode, and the ACS mode had the longest ones (Table 1). Unlike BCV directly activates the otolithic receptors, ACS may activate saccular receptors after the combined transfer function of the outer and middle ears. This discrepancy might explain why the mean nI latency of BCV–oVEMPs is 0.6 ms shorter than that of ACS–oVEMPs. Furthermore, the mean nI latency of GVS–oVEMPs is 0.7 ms less than that of BCV–oVEMPs, possibly due to the total latencies of receptor activation, synaptic transmission, and subsequent action potential propagation to the distal vestibular afferents. Given the insignificant variation of the interpeak nI–pI interval among the three modes, ACS–, BCV–, and GVS–oVEMPs may, at least in part, share a common VOR pathway.
Table 1 Comparison of characteristic parameters of oVEMPs triggered by ACS, BCV and GVS modes. Stimulation mode
N (ears)
nI latency (ms)
pI latency (ms)
nI–pI interval (ms)
nI–pI amplitude (lV)
ACS BCV GVS p value
20 20 20
9.5 ± 0.7 8.9 ± 0.7 8.2 ± 0.6 <0.05
13.3 ± 0.8 12.6 ± 0.7 11.8 ± 0.6 <0.05
3.8 ± 0.4 3.7 ± 0.5 3.6 ± 0.4 >0.05
4.4 ± 1.5 16.7 ± 6.7 13.7 ± 5.4 <0.05
Data are expressed as mean ± SD; ACS, air-conducted sound; BCV, bone-conducted vibration; GVS, galvanic vestibular stimulation. p value: two-tailed paired t-test; repeated-measures ANOVA.
1844
P.-W. Cheng et al. / Clinical Neurophysiology 120 (2009) 1841–1844
The nI–pI amplitude of BCV–oVEMPs significantly exceeds that of ACS–oVEMPs. This phenomenon reflects the fact that the BCV mode is more efficient than the ACS mode in activating the otolithic receptors and then firing more fibers. Although ACS mode does have the advantage of being able to stimulate each ear separately, it has the disadvantage that responses elicited by ACS are small and unreliable, especially in comparison to BCV–oVEMPs. Notably, to elicit even an unreliable ACS–oVEMP requires high intensity, unpleasant and possibly damaging sound intensities. On the other hand, oVEMPs can be elicited reliably by BCV stimuli at modest levels without unpleasant effect. The trend of the nI–pI amplitudes in the three modes differs from that of the latencies: the BCV mode had significantly larger nI–pI amplitude of the oVEMPs than did the GVS mode. According to the optimal stimulation for each mode at our laboratory, we utilized 127dBSPL for ACS mode, 142 dBFL for BCV mode, and 5 mA for GVS mode (Hsu et al., 2009; Cheng et al, 2008). Since the stimulating reference levels are different from each other, comparison of these absolute amplitudes is not useful. Restated, measures and comparisons of absolute oVEMP amplitudes among three modes are useless, because manipulating the stimulus intensity will change these amplitudes. Curthoys et al. (2006) reported that the irregular primary otolithic afferent neurons of guinea pigs are especially sensitive to BCV. Additionally, physiological evidence has shown that these irregular afferents contact with type I hair cells preferentially (Goldberg, 2000). Thus, the BCV mode may selectively activate the irregular afferents of the otolithic organs, while afferents that arise from all vestibular sensory organs are uniformly stimulated by the GVS mode (Kim and Curthoys, 2004). Since this study utilized a 5 mA pulse (1 ms) to elicit oVEMPs that was much shorter than the 5 mA pulse (100 ms) that was used for eliciting eye movements (Aw et al., 2006), no eye movement was observed during the experiment. Moreover, the oVEMPs are thought to have begun prior to the eye movement (Todd et al., 2007), possibly because more synapses are required for the canal–ocular reflex than the oligosynaptic pathway for the otolithic–ocular reflex (Rosengren et al., 2009). When the possible effects of the canal afferents have been excluded, GVS might be considered to activate both irregular and regular afferents of the otolithic organs. Thus, the value of the GVS–oVEMPs is to test whether there are residual vestibular afferents. Clinically, patients with unilateral Meniere’s disease may show absent ACS–cVEMPs and ACS–oVEMPs, but present BCV–oVEMPs and GVS–oVEMPs (Fig. 3), possibly because both ACS–cVEMPs and ACS–oVEMPs are primarily originated from the saccular macula. Since the saccule is the second most frequent site for hydrops formation, and severe hydrops is observed most frequently in the saccule (Okuno and Sando, 1987), abnormal ACS–cVEMPs and ACS–oVEMPs may indicate saccular hydrops in patients with Meniere’s disease (Young et al., 2003). Restated, in cases of Meniere’s disease, normal ACS–oVEMPs may indicate intact saccular function, leading to normal ACS–cVEMPs as well. Since hydrops formation occurred less frequently in the utricle, normal BCV–oVEMPs and GVS–oVEMPs may imply the integrity of utriculo-ocular reflex pathway.
Additionally, GVS–oVEMPs may be useful in investigating the integrity of central vestibular projection from the otolithic afferents to the extraocular muscles. For example, ACS– and GVS–oVEMP tests may help to differentiate the saccular from the retro-saccular lesions. If ACS–oVEMPs are normal, then BCV and GVS modes can distinguish between utricular and retro-utricular disorders. Restated, ACS and BCV coupled with GVS modes may be effective in topographically delineating the lesion site of the otolithic–ocular reflex pathway. 5. Conclusion Among the ACS (127 dBSPL), BCV (142 dB force level), and GVS (5 mA) modes, the BCV mode yields a 100% response rate and the largest nI–pI amplitude of oVEMPs. The oVEMPs in ACS, BCV, and GVS modes may promote the topographical delineation of the lesion site of the otolithic–ocular reflex pathway. References Aw ST, Todd MJ, Halmagyi GM. Latency and initiation of the human vestibuloocular reflex to pulsed galvanic stimulation. J Neurophysiol 2006;96:925–30. Cheng PW, Yang CS, Huang TW, Young YH. Optimal stimulation mode for galvanicevoked myogenic potentials. Ear Hear 2008;29:942–6. Curthoys IS, Kim J, McPhedran SK, Camp AJ. Bone conducted vibration selectively activates irregular primary otolithic vestibular neurons in the guinea pig. Exp Brain Res 2006;175:256–67. Goldberg JM. Afferent diversity and the organization of central vestibular pathways. Exp Brain Res 2000;130:277–97. Goldberg JM, Smith CE, Fernández C. Relation between discharge regularity and responses to externally applied galvanic currents in vestibular nerve afferents of the squirrel monkey. J Neurophysiol 1984;51:1236–56. Hsu YS, Wang SJ, Young YH. Ocular vestibular-evoked myogenic potentials in children using air conducted sound stimulation. Clin. Neurophysiol 2009;120:420–3. Iwasaki S, McGarvie LA, Halmagyi GM, Burgess AM, Kim J, Colebatch JG, et al. Head taps evoke a crossed vestibulo-ocular reflex. Neurology 2007;68:1227–9. Kim J, Curthoys IS. Responses of primary vestibular neurons to galvanic vestibular stimulation (GVS) in the anesthetised guinea pig. Brain Res Bull 2004;64:265–71. Lue JH, Day AS, Cheng PW, Young YH. Vestibular evoked myogenic potentials are heavily dependent on type I hair cell activity of the saccular macula in guinea pigs. Audiol Neurotol 2009;14:59–66. Murofushi T, Curthoys IS, Topple AN, Colebatch JG, Halmagyi GM. Responses of guinea pig primary vestibular neurons to clicks. Exp Brain Res 1995;103:174–8. Okuno T, Sando I. Localization, frequency and severity of endolymphatic hydrops and the pathology of the labyrinthine membrane in Meniere’s disease. Ann Otol Rhinol Laryngol 1987;96:438–45. Rosengren SM, Jombik P, Halmagyi GM, Colebatch JG. Galvanic ocular vestibular evoked myogenic potentials provide new insight into vestibulo-ocular reflexes and unilateral vestibular loss. Clin Neurophysiol 2009;120:569–80. Todd NP, Rosengren SM, Aw ST, Colebatch JG. Ocular vestibular evoked myogenic potentials (OVEMPs) produced by air- and bone-conducted sound. Clin Neurophysiol 2007;118:381–90. Uchino Y, Sato H, Sasaki M, Imagawa M, Ikegami H, Isu N, et al. Sacculocollic reflex arcs in cats. J Neurophysiol 1997;77:3003–12. Wang SJ, Jaw FS, Young YH. Ocular vestibular evoked myogenic potentials elicited from monaural versus binaural acoustic stimulation. Clin Neurophysiol 2009;120:420–3. Watson SR, Colebatch JG. Vestibulocollic reflexes evoked by short-duration galvanic stimulation in man. J Physiol 1998;513:587–97. Welgampola MS. Evoked potential testing in neuro-otology. Curr Opin Neurol 2008;21:29–35. Young YH. Vestibular evoked myogenic potentials: optimal stimulation and clinical application. J Biomed Sci 2006;13:745–51. Young YH, Huang TW, Cheng PW. Assessing the stage of Meniere’s disease using vestibular evoked myogenic potentials. Arch Otolaryngol Head Neck Surg 2003;129:815–8.
Contents lists available at ScienceDirect
Clinical Neurophysiology journal homepage: www.elsevier.com/locate/clinph
Acoustic, mechanical and galvanic stimulation modes elicit ocular vestibular-evoked myogenic potentials Po-Wen Cheng a, Chien-Cheng Chen a, Shou-Jen Wang b, Yi-Ho Young c,* a
Department of Otolaryngology, Far Eastern Memorial Hospital, Taipei, Taiwan Institute of Biomedical Engineering, College of Medicine and College of Engineering, National Taiwan University, Taipei, Taiwan c Department of Otolaryngology, National Taiwan University Hospital, Taipei, Taiwan b
a r t i c l e
i n f o
Article history: Accepted 3 August 2009 Available online 29 August 2009 Keywords: Air-conducted sound Bone-conducted vibration Galvanic vestibular stimulation Vestibular-evoked myogenic potential Ocular
a b s t r a c t Objective: This study compared the characteristic parameters of ocular vestibular-evoked myogenic potentials (oVEMPs) elicited by the air-conducted sound (ACS) and bone-conducted vibration (BCV) stimulation modes as well as the galvanic vestibular stimulation (GVS) mode. Design: Fifteen healthy subjects underwent oVEMP tests using ACS (127 dBSPL), BCV (142 dB force level), and GVS (5 mA) modes. The response rate, latencies of nI and pI, nI–pI interval and amplitude were measured for each mode and compared among modes. Results: All 15 healthy subjects (30 ears) had 100% response rates in both BCV- and GVS–oVEMPs, exhibiting a response rate significantly higher than 80% in ACS–oVEMPs. The mean nI latency was the shortest in the GVS mode, followed by BCV and then ACS modes. The variation among the latencies of the three modes was significant. Likewise, the mean nI–pI amplitudes in ACS-, BCV- and GVS modes varied significantly. However, the mean nI–pI interval did not differ significantly among the three modes. Conclusions: Among the ACS (127 dBSPL), BCV (142 dB force level), and GVS (5 mA) modes, the BCV mode yields a 100% response rate and the largest nI–pI amplitude of oVEMPs. Significance: The oVEMPs in ACS and GVS modes may help to differentiate the saccular from the retrosaccular lesions. If ACS–oVEMPs are normal, then oVEMPs in BCV and GVS modes can distinguish between utricular and retro-utricular disorders. Restated, oVEMPs in ACS, BCV, and GVS modes may promote the topographical delineation of the lesion site of the otolithic–ocular reflex pathway. Ó 2009 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved.
1. Introduction Recently, vestibular-evoked myogenic potentials (VEMPs) have been successfully generated via acoustic (air-conducted sound, ACS), mechanical (bone-conducted vibration, BCV), and galvanic (galvanic vestibular stimulation, GVS) stimulation modes, and recorded on cervical muscles (so-called cVEMPs) and extraocular muscles (so-called oVEMPs) (Welgampola, 2008). The cVEMPs are thought to mediate through the sacculo-collic reflex pathway (Uchino et al., 1997), while the oVEMPs pass along the crossed vestibulo-ocular reflex (VOR) pathway (Iwasaki et al., 2007). Animal studies have demonstrated that acoustic stimulation activates the saccular macula – mostly the type I hair cells – in guinea pigs (Murofushi et al., 1995; Lue et al., 2009). Curthoys et al. (2006) re-
* Corresponding author. Address: Department of Otolaryngology, National Taiwan University Hospital, 1, Chang-Te St., Taipei, Taiwan. Tel.: + 886 2 23123456x65221; fax: + 886 2 23946674. E-mail address: [email protected] (Y.-H. Young).
ported that the firing rate of most irregular saccular and utricular afferents increased significantly in response to BCV stimuli, but canal afferent neurons were not activated by low-intensity BCV. Alternatively, both canal and otolithic afferents are activated by GVS (Goldberg et al., 1984). Thus, these three stimulation modes, acting on different parts of the VOR pathway, may help to identify topographically the site responsible for the VOR deficit. In our previous report (Cheng et al., 2008), GVS with an intensity of 5 mA for a duration of 1 ms elicited high (100%) response rates and large amplitudes of galvanic cVEMPs. Recently, Rosengren et al. (2009) utilized 4 mA for 2 ms to elicit oVEMPs successfully, and compared them with those elicited in ACS and tapping modes. Since head taps using a reflex hammer with an electronic trigger cannot deliver a series of brief, rapid changes in linear acceleration of movement, skull tapping generated by a hand-held electro-mechanical vibrator in BCV mode was performed in this study. Hence, the goal of this study was to compare the characteristic parameters of oVEMPs elicited by the ACS, BCV and GVS modes.
1388-2457/$36.00 Ó 2009 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.clinph.2009.08.002
1842
P.-W. Cheng et al. / Clinical Neurophysiology 120 (2009) 1841–1844
2. Subjects and methods Fifteen healthy volunteers (12 men and 3 women, aged from 24 to 31 years, mean 27 years) from the medical students and resident doctors were enrolled in this study. Each subject denied having previous ear disorders, and underwent oVEMP tests using ACS and BCV modes in a randomized order. On another day, the oVEMP test using the GVS mode was performed in each subject. This study was approved by the institutional review board, and each subject signed the informed consent to participate. 2.1. ACS–oVEMP The oVEMP stimulated by the ACS mode is denoted ACS– oVEMP. The subject was in a sitting position. Surface potentials, predominantly electromyographic (EMG) activities, were recorded (Medelec Synergy N-EP, Oxford Instrument Medicals, Surrey, UK) with five Ag/AgCl electrodes. Each active electrode was placed on the face inferior to each eye, around 1 cm below the center of the lower eyelid. The reference electrodes were positioned 1–2 cm below the corresponding active ones. One ground electrode was placed over the sternum. The electrode impedance was kept under 8 kX. During recording, the subject was instructed to look upward at a small fixed target >2 m from the eyes, with a vertical visual angle of approximately 30°–35° above horizontal. The EMG signals were amplified and bandpass filtered between 1 and 1000 Hz. Acoustic stimuli were 105 dBnHL (127 dB pe SPL) short tone bursts (500 Hz, rise/fall time = 1 ms, plateau time = 2 ms) with rarefaction polarity and were delivered through an insert earphone. Binaural acoustic stimulation with bilateral recordings was employed. The stimulation rate was 5 Hz and analytical time for each response was 50 ms; 100 responses were averaged for each run. The initial negative–positive biphasic waveform comprised the nI and pI peaks. Consecutive runs were performed to confirm the reproducibility of the nI and pI peaks, which were interpreted by two independent observers to determine whether oVEMPs were present. Conversely, oVEMPs were deemed absent when the biphasic waveform was not reproducible. The latencies of the nI and pI peaks, interval and amplitude of nI–pI were measured (Wang et al., 2009).
sides of the mastoid process (cathode) and the forehead (anode) in all subjects. All EMG recording conditions were the same as in the ACS mode, except that the subjects received galvanic stimulations while they gazed up or down. A direct 5 mA current was applied for 1.0 ms. During stimulation, eye movements were observed by videonystagmoscopy (Ulmer type Synapsys Co., Marseille, France). Responses to 100 galvanic stimuli were averaged for each run and the results of two duplicate runs were averaged. Since an original GVS–oVEMP waveform might contain large electrical artifacts (Watson and Colebatch, 1998), the response obtained upon gazing downward was subtracted from those upon gazing upward to provide the final GVS–oVEMP (Fig. 1). 2.4. Statistical methods The response rate, defined as the percentage of ears in which a clear response was identified, was compared between ACS–, BCV– and GVS–oVEMPs using the McNemar test. The latencies, interpeak intervals, and amplitudes were compared, respectively, using repeated-measures ANOVA among ACS–, BCV– and GVS–oVEMPs, followed by paired t-test if it reaches a significant difference. The level of significance was set at p < 0.05. 3. Results All 15 healthy subjects (30 ears) showed 100% response rates in both BCV– and GVS–oVEMPs, but only 80% response rate in ACS– oVEMPs (Fig. 2). Therefore, the response rate was significantly lower in ACS mode than in the other two modes (p < 0.05, McNemar’s test). Five subjects with absent ACS–oVEMPs in one or both ears were excluded, leaving 10 subjects (20 ears) enrolled to perform comparative analyses between ACS–, BCV– and GVS–oVEMPs. The mean latencies of nI in ACS, BCV and GVS modes were 9.5 ± 0.7 (mean ± SD), 8.9 ± 0.7 and 8.2 ± 0.6 ms, respectively, revealing that the nI latency was the shortest in the GVS mode, followed by the BCV mode, and the longest in the ACS mode; these
2.2. BCV–oVEMP The oVEMP stimulated by the BCV mode is denoted BCV– oVEMP. The BCV mode utilized a hand-held electro-mechanical vibrator (V201 shaker, Ling Dynamic Systems, Royston, England) fitted with a short M4 bolt (2 cm in length) terminated in a bakelite cap (1.6 cm in diameter). The input signal was a condensation square wave (0.5 ms in duration), which was driven by a custom amplifier combination. The drive voltage was adjusted and fixed to produce a peak force of 12 Newton, about 142 dB force level (FL) from the vibrator, as measured by an artificial mastoid (model 4930, Bruel & Kjaer P/L, Denmark). The initial impulse of the BCV was approximately a half-cycle of a 600 Hz sine wave. The operator held the vibrator by hand and supported most of its weight such that the axis of the connected bakelite cap perpendicularly delivered a repeatable tap on the subject’s head at Fz (midline forehead at the hairline) for the oVEMP test. The other setting was the same as the ACS mode, except that the ground electrode was placed on the right clavicle. A total of 50 responses were averaged for each run of oVEMP. 2.3. GVS–oVEMP The oVEMP elicited by the GVS mode is denoted GVS–oVEMP. Electrodes for delivering galvanic stimuli were placed on both
Fig. 1. Typical configuration of GVS–oVEMP. To remove electrical artifacts, the responses on downward gaze (A) are subtracted from those on upward gaze (B), when using galvanic stimulation 5 mA/1 ms. Thus, a final GVS–oVEMP waveform (C) is obtained after subtracting (A) from (B).
1843
P.-W. Cheng et al. / Clinical Neurophysiology 120 (2009) 1841–1844
Fig. 2. Illustration of oVEMPs induced by air-conducted sound (ACS), boneconducted vibration (BCV), and galvanic vestibular stimulation (GVS) modes.
latencies varied significantly (p < 0.05, two-tailed paired t-test; repeated-measures ANOVA, Table 1). Likewise, the pI latency followed the same trend among the three modes (p < 0.05, twotailed paired t-test, Table 1). However, the mean nI–pI interval did not vary significantly among the three modes (p > 0.05, repeated-measures ANOVA). The mean nI–pI amplitudes in ACS–, BCV– and GVS modes were 4.4 ± 1.5, 16.7 ± 6.7 and 13.7 ± 5.4 lV, respectively; they varied significantly among the three modes (p < 0.05, repeated-measures ANOVA, Table 1). The trend of nI–pI amplitude differed from that of latencies; the BCV mode exhibited the largest nI–pI amplitude, followed by the GVS mode, and the ACS mode had the smallest amplitude (p < 0.05, two-tailed paired t-test, Table 1). Fig. 3 illustrates the ACS–cVEMPs as well as oVEMPs under three modes in a unilateral Meniere’s disease patient, showing absent ACS–cVEMPs and ACS–oVEMPs, but present BCV–oVEMPs and GVS–oVEMPs.
4. Discussion The use of cVEMPs for evaluating the integrity of sacculo-collic reflex has gained popularity in the recent decade (Young, 2006). When cVEMPs are absent in response to ACS stimulation, cVEMPs by the GVS mode may help to distinguish labyrinthine lesions from retro-labyrinthine ones (Watson and Colebatch, 1998). Recently, the oVEMP test has been introduced to assess if the crossed VOR pathway is intact, which could be triggered by activating either saccular afferents by ACS mode, or both saccular and utricular afferents by BCV mode (Curthoys et al., 2006). Hence, the oVEMP test coupled with the cVEMP test may help to differentiate be-
Fig. 3. Illustration of cVEMPs and oVEMPs in a 38-year-old female patient with right Meniere’s disease. Both ACS–cVEMPs and ACS–oVEMPs are absent, but both BCV–oVEMPs and GVS–oVEMPs are present.
tween utricular and saccular disorders, or between upper and lower brainstem lesions. However, oVEMPs in ACS and BCV modes can not identify any lesion that affects the afferents between the otolithic organs and vestibular nuclei. Alternatively, oVEMPs in the GVS mode may solve this problem, and further assess the integrity of the crossed VOR pathway originating from the otolithic organs. In this study, both BCV and GVS modes elicited 100% clear oVEMPs in 15 healthy subjects, while ACS mode had a 80% response rate for oVEMPs, suggesting that the ACS mode is not a reliable tool for eliciting oVEMPs. For example, high intensity ACS failed to elicit a clear oVEMP in 5 of those healthy subjects, and these subjects would have been diagnosed as having absent otolithic function, when in fact they do have otolithic function as shown by the presence of BCV–oVEMPs. Subsequently, the latencies of nI and pI were compared: the GVS mode had the shortest latencies, followed by the BCV mode, and the ACS mode had the longest ones (Table 1). Unlike BCV directly activates the otolithic receptors, ACS may activate saccular receptors after the combined transfer function of the outer and middle ears. This discrepancy might explain why the mean nI latency of BCV–oVEMPs is 0.6 ms shorter than that of ACS–oVEMPs. Furthermore, the mean nI latency of GVS–oVEMPs is 0.7 ms less than that of BCV–oVEMPs, possibly due to the total latencies of receptor activation, synaptic transmission, and subsequent action potential propagation to the distal vestibular afferents. Given the insignificant variation of the interpeak nI–pI interval among the three modes, ACS–, BCV–, and GVS–oVEMPs may, at least in part, share a common VOR pathway.
Table 1 Comparison of characteristic parameters of oVEMPs triggered by ACS, BCV and GVS modes. Stimulation mode
N (ears)
nI latency (ms)
pI latency (ms)
nI–pI interval (ms)
nI–pI amplitude (lV)
ACS BCV GVS p value
20 20 20
9.5 ± 0.7 8.9 ± 0.7 8.2 ± 0.6 <0.05
13.3 ± 0.8 12.6 ± 0.7 11.8 ± 0.6 <0.05
3.8 ± 0.4 3.7 ± 0.5 3.6 ± 0.4 >0.05
4.4 ± 1.5 16.7 ± 6.7 13.7 ± 5.4 <0.05
Data are expressed as mean ± SD; ACS, air-conducted sound; BCV, bone-conducted vibration; GVS, galvanic vestibular stimulation. p value: two-tailed paired t-test; repeated-measures ANOVA.
1844
P.-W. Cheng et al. / Clinical Neurophysiology 120 (2009) 1841–1844
The nI–pI amplitude of BCV–oVEMPs significantly exceeds that of ACS–oVEMPs. This phenomenon reflects the fact that the BCV mode is more efficient than the ACS mode in activating the otolithic receptors and then firing more fibers. Although ACS mode does have the advantage of being able to stimulate each ear separately, it has the disadvantage that responses elicited by ACS are small and unreliable, especially in comparison to BCV–oVEMPs. Notably, to elicit even an unreliable ACS–oVEMP requires high intensity, unpleasant and possibly damaging sound intensities. On the other hand, oVEMPs can be elicited reliably by BCV stimuli at modest levels without unpleasant effect. The trend of the nI–pI amplitudes in the three modes differs from that of the latencies: the BCV mode had significantly larger nI–pI amplitude of the oVEMPs than did the GVS mode. According to the optimal stimulation for each mode at our laboratory, we utilized 127dBSPL for ACS mode, 142 dBFL for BCV mode, and 5 mA for GVS mode (Hsu et al., 2009; Cheng et al, 2008). Since the stimulating reference levels are different from each other, comparison of these absolute amplitudes is not useful. Restated, measures and comparisons of absolute oVEMP amplitudes among three modes are useless, because manipulating the stimulus intensity will change these amplitudes. Curthoys et al. (2006) reported that the irregular primary otolithic afferent neurons of guinea pigs are especially sensitive to BCV. Additionally, physiological evidence has shown that these irregular afferents contact with type I hair cells preferentially (Goldberg, 2000). Thus, the BCV mode may selectively activate the irregular afferents of the otolithic organs, while afferents that arise from all vestibular sensory organs are uniformly stimulated by the GVS mode (Kim and Curthoys, 2004). Since this study utilized a 5 mA pulse (1 ms) to elicit oVEMPs that was much shorter than the 5 mA pulse (100 ms) that was used for eliciting eye movements (Aw et al., 2006), no eye movement was observed during the experiment. Moreover, the oVEMPs are thought to have begun prior to the eye movement (Todd et al., 2007), possibly because more synapses are required for the canal–ocular reflex than the oligosynaptic pathway for the otolithic–ocular reflex (Rosengren et al., 2009). When the possible effects of the canal afferents have been excluded, GVS might be considered to activate both irregular and regular afferents of the otolithic organs. Thus, the value of the GVS–oVEMPs is to test whether there are residual vestibular afferents. Clinically, patients with unilateral Meniere’s disease may show absent ACS–cVEMPs and ACS–oVEMPs, but present BCV–oVEMPs and GVS–oVEMPs (Fig. 3), possibly because both ACS–cVEMPs and ACS–oVEMPs are primarily originated from the saccular macula. Since the saccule is the second most frequent site for hydrops formation, and severe hydrops is observed most frequently in the saccule (Okuno and Sando, 1987), abnormal ACS–cVEMPs and ACS–oVEMPs may indicate saccular hydrops in patients with Meniere’s disease (Young et al., 2003). Restated, in cases of Meniere’s disease, normal ACS–oVEMPs may indicate intact saccular function, leading to normal ACS–cVEMPs as well. Since hydrops formation occurred less frequently in the utricle, normal BCV–oVEMPs and GVS–oVEMPs may imply the integrity of utriculo-ocular reflex pathway.
Additionally, GVS–oVEMPs may be useful in investigating the integrity of central vestibular projection from the otolithic afferents to the extraocular muscles. For example, ACS– and GVS–oVEMP tests may help to differentiate the saccular from the retro-saccular lesions. If ACS–oVEMPs are normal, then BCV and GVS modes can distinguish between utricular and retro-utricular disorders. Restated, ACS and BCV coupled with GVS modes may be effective in topographically delineating the lesion site of the otolithic–ocular reflex pathway. 5. Conclusion Among the ACS (127 dBSPL), BCV (142 dB force level), and GVS (5 mA) modes, the BCV mode yields a 100% response rate and the largest nI–pI amplitude of oVEMPs. The oVEMPs in ACS, BCV, and GVS modes may promote the topographical delineation of the lesion site of the otolithic–ocular reflex pathway. References Aw ST, Todd MJ, Halmagyi GM. Latency and initiation of the human vestibuloocular reflex to pulsed galvanic stimulation. J Neurophysiol 2006;96:925–30. Cheng PW, Yang CS, Huang TW, Young YH. Optimal stimulation mode for galvanicevoked myogenic potentials. Ear Hear 2008;29:942–6. Curthoys IS, Kim J, McPhedran SK, Camp AJ. Bone conducted vibration selectively activates irregular primary otolithic vestibular neurons in the guinea pig. Exp Brain Res 2006;175:256–67. Goldberg JM. Afferent diversity and the organization of central vestibular pathways. Exp Brain Res 2000;130:277–97. Goldberg JM, Smith CE, Fernández C. Relation between discharge regularity and responses to externally applied galvanic currents in vestibular nerve afferents of the squirrel monkey. J Neurophysiol 1984;51:1236–56. Hsu YS, Wang SJ, Young YH. Ocular vestibular-evoked myogenic potentials in children using air conducted sound stimulation. Clin. Neurophysiol 2009;120:420–3. Iwasaki S, McGarvie LA, Halmagyi GM, Burgess AM, Kim J, Colebatch JG, et al. Head taps evoke a crossed vestibulo-ocular reflex. Neurology 2007;68:1227–9. Kim J, Curthoys IS. Responses of primary vestibular neurons to galvanic vestibular stimulation (GVS) in the anesthetised guinea pig. Brain Res Bull 2004;64:265–71. Lue JH, Day AS, Cheng PW, Young YH. Vestibular evoked myogenic potentials are heavily dependent on type I hair cell activity of the saccular macula in guinea pigs. Audiol Neurotol 2009;14:59–66. Murofushi T, Curthoys IS, Topple AN, Colebatch JG, Halmagyi GM. Responses of guinea pig primary vestibular neurons to clicks. Exp Brain Res 1995;103:174–8. Okuno T, Sando I. Localization, frequency and severity of endolymphatic hydrops and the pathology of the labyrinthine membrane in Meniere’s disease. Ann Otol Rhinol Laryngol 1987;96:438–45. Rosengren SM, Jombik P, Halmagyi GM, Colebatch JG. Galvanic ocular vestibular evoked myogenic potentials provide new insight into vestibulo-ocular reflexes and unilateral vestibular loss. Clin Neurophysiol 2009;120:569–80. Todd NP, Rosengren SM, Aw ST, Colebatch JG. Ocular vestibular evoked myogenic potentials (OVEMPs) produced by air- and bone-conducted sound. Clin Neurophysiol 2007;118:381–90. Uchino Y, Sato H, Sasaki M, Imagawa M, Ikegami H, Isu N, et al. Sacculocollic reflex arcs in cats. J Neurophysiol 1997;77:3003–12. Wang SJ, Jaw FS, Young YH. Ocular vestibular evoked myogenic potentials elicited from monaural versus binaural acoustic stimulation. Clin Neurophysiol 2009;120:420–3. Watson SR, Colebatch JG. Vestibulocollic reflexes evoked by short-duration galvanic stimulation in man. J Physiol 1998;513:587–97. Welgampola MS. Evoked potential testing in neuro-otology. Curr Opin Neurol 2008;21:29–35. Young YH. Vestibular evoked myogenic potentials: optimal stimulation and clinical application. J Biomed Sci 2006;13:745–51. Young YH, Huang TW, Cheng PW. Assessing the stage of Meniere’s disease using vestibular evoked myogenic potentials. Arch Otolaryngol Head Neck Surg 2003;129:815–8.