- Email: [email protected]
The ocular vestibular-evoked myogenic potential to air-conducted sound; probable superior vestibular nerve origin
Clinical Neurophysiology 122 (2011) 611–616
Contents lists available at ScienceDirect
Clinical Neurophysiology journal homepage: www.elsevier.com/locate/clinph
The ocular vestibular-evoked myogenic potential to air-conducted sound; probable superior vestibular nerve origin Ian S. Curthoys a,*, Shinichi Iwasaki b, Yasuhiro Chihara b, Munetaka Ushio b, Leigh A. McGarvie c, Ann M. Burgess a a b c
Vestibular Research Laboratory, School of Psychology, The University of Sydney, NSW, Australia Department of Otolaryngology, Faculty of Medicine, University of Tokyo, Tokyo, Japan Institute of Clinical Neurosciences, Royal Prince Alfred Hospital, Sydney, NSW, Australia
a r t i c l e
i n f o
Article history: Accepted 21 July 2010 Available online 14 August 2010 Keywords: Vestibular Otolith Utricular Saccular Inferior oblique VOR VEMP oVEMP Vestibulo-ocular
a b s t r a c t Objective: Intense air-conducted sound (ACS) elicits an ocular vestibular-evoked myogenic potential (oVEMP), and it has been suggested that it does so by stimulating saccular receptors and afferents in the inferior vestibular nerve and so activating a crossed sacculo-ocular pathway. Bone conducted vibration (BCV) also elicits an oVEMP probably by activating utricular receptors and a crossed utriculo-ocular pathway. Are there two separate pathways mediating oVEMPs for ACS and BCV? If saccular receptors and afferents are primarily responsible for the oVEMP to ACS, then the oVEMP to ACS should be normal in patients with reduced or absent utricular function – unilateral superior vestibular neuritis (SVN). If utricular receptors and afferents are primarily responsible for oVEMP n10, then oVEMP to ACS should be reduced or absent in SVN patients, and in these patients there should be a close relationship between the size of the oVEMP n10 to BCV and to ACS. Methods: The n10 component of the oVEMP to 500 Hz BCV and to 500 Hz ACS was recorded in 10 patients with unilateral SVN but who had saccular and inferior vestibular nerve function preserved, as shown by their normal cVEMP responses to ACS. Results: In SVN patients with normal saccular and inferior vestibular nerve function, the oVEMP n10 in response to ACS was reduced or absent. Across SVN patients there was a very close correspondence between the size of oVEMP n10 for ACS and for BCV. Conclusions: The n10 component of the oVEMP to ACS is probably mediated predominantly by the superior vestibular nerve and so most likely by utricular receptors and afferents. Significance: The n10 component of the oVEMP to either ACS or BCV probably indicates mainly superior vestibular nerve function. Ó 2010 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved.
1. Introduction Abbreviations: AR, asymmetry ratio for the relative size of the n10 of the oVEMPs for the two eyes; ACS, air conducted sound; BCV, bone conducted vibration; EMG, electromyogram; Fz, the location on the head in the midline at the hairline; Fz BCV, bone conducted vibration delivered to Fz; 4810, the Bruel and Kjaer Mini-Shaker; cVEMPs, cervical vestibular-evoked myogenic potentials; oVEMPs, ocular vestibular-evoked myogenic potentials; n10, the initial negative potential in the oVEMP response at latency of around 10 ms; p13–n23, the initial positive potential of the cVEMP; MTB, Mini Tone Burst, a tone burst (500 Hz for 6 ms) delivered by the Mini-Shaker; uVL, unilateral vestibular loss; SAR, signed asymmetry ratio; SCM, sternocleidomastoid muscles; se, standard error; SVN, superior vestibular neuritis; IO, inferior oblique. * Corresponding author. Address: Vestibular Research Laboratory, School of Psychology, A 18 University of Sydney, Sydney, NSW 2006, Australia. Tel.: +61 2 9351 3570; fax: +61 2 9036 5223. E-mail address: [email protected] (I.S. Curthoys).
Vestibular-evoked myogenic potentials (VEMPs) recorded by surface EMG electrodes are now widely used to assess vestibular function (for recent reviews see Curthoys, 2010; Curthoys et al., 2009; Rosengren et al., 2010). In one testing paradigm the electrodes are placed over tensed sternocleidomastoid muscles (SCM), and the initial positive (inhibitory) myogenic potential (p13–n23) recorded in response to air-conducted sound (ACS) or bone conducted vibration (BCV) is called the cervical vestibularevoked myogenic potential (cVEMP). In another testing paradigm, the electrodes are placed just beneath the eyes over the inferior oblique (IO) and inferior rectus (IR) eye muscles with the subject or patient required to look up during testing, and the myogenic po-
1388-2457/$36.00 Ó 2010 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.clinph.2010.07.018
612
I.S. Curthoys et al. / Clinical Neurophysiology 122 (2011) 611–616
tential recorded in response to ACS or BCV is called the ocular vestibular-evoked myogenic potential (oVEMP). The initial negative (excitatory) component of this potential, peaking at around 10 ms, is called n10. These potentials are called ‘‘vestibular-evoked” rather than ‘‘auditory-evoked” because it has been shown that the stimuli which are effective for evoking them cause selective activation of irregular primary otolith afferents in guinea pigs (Murofushi et al., 1995; Curthoys et al., 2006; Curthoys, 2010) and cats (McCue and Guinan, 1995, 1997). In particular utricular afferents are activated by BCV at very low stimulus levels (close to ABR threshold) (Curthoys et al., 2006). Suzuki et al. (1969) and Tokumasu et al. (1971) showed in cats that electrical stimulation of the utricular nerve resulted in characteristic patterns of activation of eye muscles and eye movements. In healthy human subjects BCV stimulation of the mastoid has been shown to cause very small similar eye movements (Cornell et al., 2009). Control data confirms the vestibular nature of the response. In totally deaf human subjects the oVEMP n10 responses to BCV still persist in the absence of auditory function, whereas patients without vestibular function but with remaining hearing do not show oVEMP n10s (Iwasaki et al., 2008a). In patients with unilateral vestibular loss (uVL) there is a loss of oVEMP n10s to BCV beneath the contralesional eye, showing that the oVEMP n10 is a crossed otolith-ocular response (Iwasaki et al., 2007, 2008b). In patients with unilateral superior vestibular neuritis (SVN) affecting the nerves from the horizontal and anterior canals and the utricular macula, it has been demonstrated that in response to 500 Hz BCV delivered to the midline of the forehead at the hairline (the location called Fz), the oVEMP n10 beneath the contralesional eye is reduced or absent (Iwasaki et al., 2009; Manzari et al., 2010) whilst saccular function is still present (as shown by normal cVEMPs). These results suggest that in human subjects and patients the n10 to 500 Hz Fz BCV is primarily utricular. Air-conducted sound (ACS) also causes oVEMP n10s and it has been suggested that the reason for this is that ACS stimulates a different set of receptors – saccular receptors and afferents predominantly in the inferior vestibular nerve – and so activates a sacculo-ocular pathway (Chihara et al., 2007). In guinea pigs and cats ACS does activate receptors on the saccular macula (Murofushi et al., 1995; Murofushi and Curthoys, 1997; McCue and Guinan, 1994, 1997). However, existing evidence indicates that a sacculo-ocular pathway is polysynaptic and probably weak (Isu et al., 2000; Chan et al., 1977; Hwang and Poon, 1975). An alternative possibility is that the ACS stimulates utricular receptors and afferents in the superior vestibular nerve and so activates the same utriculo-ocular pathway as activated by BCV. In support of the latter: there is now evidence from single neuron recordings of primary vestibular afferents that ACS activates utricular receptors and irregular primary utricular afferents in the superior vestibular nerve of the guinea pig (Curthoys, 2010; Curthoys and Vulovic, 2010, unpublished data). One way of assessing which of these alternative explanations is correct is by measuring cVEMPs and oVEMPs to ACS in patients with superior vestibular neuritis (SVN). A defining characteristic of SVN is that patients have reduced horizontal canal responses to caloric stimulation and also show a head impulse sign for yaw head rotations to the affected side (Halmagyi et al., 2010; Strupp and Brandt, 1999; Nadol, 1995; Fetter and Dichgans, 1996). Since the utricular nerve travels with the nerve from the horizontal canal in the superior division of the vestibular nerve (de Burlet, 1924) it is likely that in most cases SVN affects the entire superior vestibular nerve, including the utricular afferents (Aw et al., 2001; Nadol, 1995; Fetter and Dichgans, 1996; Halmagyi et al., 2010). An important fact is that in SVN patients the saccular receptors and inferior vestibular nerve are still functional since SVN patients show normal cVEMPs to ACS stimulation of their affected ear (Iwasaki
et al., 2009; Murofushi et al., 1996). So in SVN patients it is reasonable to assume that ACS activates the saccular receptors. If saccular activation is primarily responsible for n10 to ACS, one would expect little effect of SVN on contralesional n10, since the presence of the ipsilateral cVEMP shows that the ipsilateral saccular receptors and the sacculo-collic pathway are still functioning and so would be expected to be able to produce a normal oVEMP n10 to ACS. However, if the utricular macula is primarily responsible for the contralesional oVEMP n10 to ACS, then one would expect that, with reduced or absent utricular function in SVN, there should be a reduced or absent contralateral oVEMP n10 response to ACS stimulation. One other prediction can be made: SVN is not an all-or-none phenomenon; some SVN patients have almost complete loss of n10; others have much smaller losses (Iwasaki et al., 2009), presumably reflecting the severity of their neuritis. If the superior vestibular nerve was primarily responsible for oVEMP n10, then the extent of the reduction of the oVEMP n10 should be similar for both BCV and ACS. If the inferior vestibular nerve was primarily responsible there should not be a close relationship because on this hypothesis oVEMP n10s are generated by independent mechanisms: utricular macula for BCV and saccular macula for ACS. Consequently one would expect the amplitude of n10 to ACS should be independent of the amplitude of n10 to BCV.
2. Patients and methods Twelve patients identified as having SVN according to the criteria below were enrolled in this study at the University of Tokyo Hospital. However, in only 10 of these patients was it possible to obtain a response to ACS, so the data reported below is only from these 10 patients. Others have noted the fact that even not all healthy subjects show an n10 response to ACS (Chihara et al., 2007; Cheng et al., 2009). Table 1 summarizes the relevant demographics of the 10 patients and their audiometric and vestibular test results. Most patients were tested in the acute stage of SVN. The criteria for selecting the patients were based on standard definitions (Nadol, 1995): (1) that they had absent or markedly reduced horizontal canal function (absent or reduced caloric responses (canal paresis score of >22%)) and the presence of a head impulse sign for horizontal head rotations towards the affected ear (Halmagyi and Curthoys, 1988) both indicating the superior vestibular nerve was not functional; (2) that normal cVEMPs in response to ACS of the affected ear were still present, indicating that saccular receptors and those saccular otolithic afferents coursing in the inferior vestibular nerve were still functional; (3) absence of auditory signs. All procedures were in accordance with the Helsinki declaration and were approved by the University of Tokyo Human Ethics Committee, and patients gave informed consent. The methods have been described in detail (Iwasaki et al., 2008a). In brief, the patients lay supine and oVEMP potentials were recorded from surface EMG electrodes placed just beneath the eyes as the patient looked upward (toward the top of their head) during the test. A small fixation point was positioned 25–30 deg above the patient’s visual straight ahead. The active EMG electrodes were placed on the cleaned skin over the infra-orbital ridges at the centre of each lower eye lid and the reference electrodes were placed 3 cm below that (Iwasaki et al., 2008a). To record cVEMPs the EMG electrodes were placed over the belly of the SCM and the patient contracted the SCM by lifting their head off the pillow. The EMG potentials were amplified, band-pass filtered at 20–500 Hz (BCV) or 20–3000 Hz (ACS), sampled at 20 kHz and the data from stimulus onset to 50 ms was averaged. For the n10 the amplitude was defined as baseline to peak, for the cVEMPs the amplitude was defined as the value of the difference between p13 and n23.
613
I.S. Curthoys et al. / Clinical Neurophysiology 122 (2011) 611–616 Table 1 The age, gender and summaries of the audiometric and vestibular test results for the 12 SVN patients reported. PTA = average of the pure tone thresholds at 500 Hz, 1 kHz, and 2 kHz; CP = horizontal canal paresis score.
*
Patient
Age, gender
Side of lesion
PTA healthy side
PTA affected side
CP %
ACS cVEMP signed AR %
ACS oVEMP signed AR %
BCV oVEMP signed AR %
1* 2* 3* 4 5 6 7 8 9 10
57 M 30 M 70 F 34 M 23 M 60 M 31 M 58 M 61 M 41 M
L R R R L R R L R R
16.3 5 16.7 8.8 7.5 5 6.7 13.3 23.3 6.7
13.8 3.3 16.7 7.5 6.7 3.8 10 11.7 23.3 10
65 100 50 73 81.6 100 62.8 58 100 100
3.52 9.75 11.24 11.25 11.96 5.92 13.13 18.38 1.29 8.09
50.00 81.63 100.00 4.92 15.46 70.63 100.00 100.00 23.08 65.19
70.73 69.19 68.60 9.86 41.04 78.43 100.00 56.25 20.00 61.98
The BCV unsigned AR data for these patients has been reported previously (Iwasaki et al., 2009).
The ACS stimuli for oVEMPs and cVEMPs were 95 dBnHL tone bursts of 4 ms duration. ACS was presented through a calibrated headphone (type DR-531, Elega Acoustics Co., Ltd., Tokyo, Japan). The stimulus intensity was set at 135 dB SPL. The stimulation rate was 5 Hz. The stimulus was 500 Hz short tone bursts (rise/fall time = 1 ms and plateau time = 2 ms). The ACS stimulus was presented separately to the affected ear and the unaffected ear. When using ACS, the n10 responses were measured beneath the eye contralateral to the stimulated ear (Chihara et al., 2007); and the amplitudes of these contralateral responses were used for calculation of asymmetry when using ACS (see below for further explanation). BCV stimuli were 500 Hz tone bursts (6 ms in duration: rise/ fall time = 1 ms and plateau time = 4 ms) delivered to the midline forehead of the patient at the hairline (Fz). The stimulator was a Bruel and Kjaer Mini-Shaker (4810) (Naerum, Denmark), fitted with a 2 cm long machine screw (M5) terminated in a bakelite cap 1.5 cm in diameter. This cap was placed at Fz, without pressure, and the potentials measured to 50 stimulus presentations. There are problems in directly comparing the absolute amplitude of n10 for ACS with the absolute amplitude of n10 for BCV. Previously published data have shown that the amplitude of n10 to 500 Hz Fz BCV and ACS varies in absolute size considerably between people (Iwasaki et al., 2008a; Chihara et al., 2007). Also the average amplitude of n10 to ACS is only approximately 3.5 lV baseline to peak (Chihara et al., 2007) which is systematically smaller than the average amplitude of n10 to BCV stimuli, approximately 8.5 lV baseline to peak (Iwasaki et al., 2008a). The average amplitude of oVEMP n10 to 500 Hz Fz BCV decreases with age (Iwasaki et al., 2008a). These problems can be overcome by using an Asymmetry Ratio (AR) for comparisons of the response to BCV and ACS. The AR for 500 Hz Fz BCV does not vary with age (Iwasaki et al., 2008a). In previous studies we have calculated the absolute asymmetry ratio (AR) by using the formula:
AR ¼ ½ðlarger n10 smaller n10Þ=ðlarger n10 þ smaller n10Þ 100 However, in this study it is necessary to take account of the side more explicitly, because the affected ear may generate a larger n10 or a smaller n10 response than the n10 response generated by the healthy ear and an absolute AR would not show such sideness. To overcome that drawback in this study we have used a signed asymmetry ratio (SAR) defined by the formula:
oVEMP Signed AR ¼ ½ðipsilesional n10 contralesional n10Þ=ðipsilesional n10 þ contralesional n10Þ 100 This Signed AR (SAR) varies from 100% to +100%. A case where the contralesional n10 is absent, but the ipsilesional n10 is present would yield a SAR of +100%; a case where the contralesional n10 is present and the ipsilesional n10 is absent would yield a SAR of
100%; and a case where the ipsilesional and contralesional n10s are of equal amplitude would yield a SAR of 0%. The ACS data gathering and SAR calculation for ACS was rather different than for BCV since in the present study each ear was stimulated with ACS separately (unilateral or monaural stimulation), as opposed to BCV where both ears were stimulated simultaneously. To ensure comparability between the SAR calculations for BCV and ACS we used the following approach for ACS: in the above equation the term ‘‘contralesional n10” refers to the amplitude of n10 beneath the eye opposite the affected ear when the affected ear was stimulated by ACS. Similarly the term ‘‘ipsilesional n10” refers to the amplitude of n10 beneath the eye opposite the healthy ear, when the healthy ear was stimulated. In this way the ipsilesional and contralesional responses (and the signed ARs) were directly comparable between BCV and ACS. The Signed Asymmetry Ratio of the cVEMP was calculated in a similar fashion:
cVEMPSignedAR ¼ ½ðcontralesionalfp13 n23g ipsilesionalfp13 n23gÞ= ðcontralesionalfp13 n23g þ ipsilesionalfp13 n23gÞ 100 The values are expressed below as means ± standard error (Winer et al., 1991). The significance level was set at 0.05. The value of the n10 used for the analysis was baseline-to-peak and the value of the cVEMP p13–n23 was the value of the voltage difference between p13 and n23. The n10 varies considerably between individuals (Iwasaki et al., 2008a), probably depending on factors such as skull size, but we have shown that with Fz stimulation (which stimulates both ears about equally (Iwasaki et al., 2008a)) the amplitude of n10 is about equal beneath both eyes in healthy subjects. A previous paper on oVEMPs in SVN patients (Iwasaki et al., 2009) reported only BCV data in SVN patients. The BCV AR values for 3 of the patients in that study have been recalculated (as SAR values) and are presented here, together with their corresponding ACS SAR data which has not been previously presented. The Manzari et al. (2010) study on SVN patients was conducted in a different country (Italy) on a totally different set of patients and only concerned n10 to 500 Hz Fz BCV. 3. Results The results for a typical patient with a right sided SVN for cVEMPs and oVEMPs are shown in Fig. 1. This patient is number 7 in Table 1. Panel (a) shows the cVEMPs for ACS are about equal for ACS stimulation of each ear. Panel (b) shows the patient has a major asymmetry of oVEMP n10s for 500 Hz Fz, confirming previous evidence for SVN patients (Iwasaki et al., 2009). Although both ears are stimulated about equally by
614
I.S. Curthoys et al. / Clinical Neurophysiology 122 (2011) 611–616
Fig. 1. The responses of a typical patient with a right SVN showing (a) ACS cVEMPs, (b) BCV oVEMPs (Fz BCV), and (c) ACS oVEMPs. (a) The cVEMP p13–n23 response to 500 Hz ACS on the affected right side shows normal amplitude (short lines) and so gives evidence that the stimulus is working and that the saccular macula on the affected right side is functioning and responding to ACS. It also shows that this patient does not have a conductive hearing loss which would affect the 500 Hz ACS stimulus. However, despite that functioning saccular macula, the n10 of the oVEMP on the contralateral (left side – from the affected right ear) is absent, both for 500 Hz Fz BCV (b – left eye upper trace) and also for 500 Hz ACS stimulation of the affected ear (c – left eye upper trace).
the Fz BCV stimulus (Iwasaki et al., 2008a) there is a clear n10 beneath the right eye (from the healthy (left) labyrinth), but no n10 is discernible beneath the left eye (from the affected (right) labyrinth). So this patient has an SAR of 100% for Fz BCV. The third panel (c) shows that in this patient ACS of each ear results in a very similar asymmetrical oVEMP n10 just as found for BCV stimulation; the n10 beneath the right eye (from monaural ACS stimulation of the healthy labyrinth) is normal, whereas the n10 beneath the left eye (from monaural stimulation of the affected labyrinth) is not detectable. So this patient also has an SAR of 100% for ACS (Fig. 2). All patients had cVEMPs in the normal range from ACS stimulation. The average SAR for cVEMPs to ACS was 0.50% ±3.52 (standard error = se). In contrast there was a marked asymmetry in oVEMPs for both BCV and ACS stimuli. The average SAR for BCV oVEMPs was 51.63% ±12.10 (se) and for ACS was 55.49% ±14.30 (se). The correlation between the SAR for ACS and BCV oVEMPs was 0.88; the correlation between the ACS oVEMPs and ACS cVEMPs was 0.13. On a paired t-test there was no significant difference between the oVEMP SARs to BCV and ACS (t = 0.57, df = 9, p > 0.05). There is a highly significant linear relationship for the SAR for ACS oVEMPs and the SAR for BCV oVEMPs (linear regression F = 28.17, p < 0.01) in contrast to the non-significant relationship (linear regression F = 0.14, p > 0.05) between the SAR for ACS oVEMPs and the SAR for ACS cVEMPs. In one patient (patient 4) the size of the n10 to 500 Hz Fz BCV was about equal in both eyes, and we considered this was probably because the SVN had minimally affected the superior vestibular nerve on the affected side. In such a case the signed asymmetry ratio (SAR) for oVEMP n10 was very small for both BCV and ACS stimuli (Table 1). In another patient (7) the oVEMPs to both Fz BCV and ACS were reduced or absent beneath the contralesional eye, resulting in a large SAR for both ACS and BCV stimuli. One patient (9) diagnosed as SVN on the basis of CP and cVEMPs unexpectedly had a larger n10 beneath the contralesional eye than beneath the ipsilesional eye to BCV, resulting in a negative signed asymmetry value for BCV. However, this patient also had a similar pattern of n10 responses to ACS and so also had a negative signed asymmetry ratio for ACS. 4. Discussion The results show that in SVN patients (1) Unilateral loss of function of the superior vestibular nerve, with functioning inferior vestibular nerve, leads to loss of contralesional oVEMP n10 to both BCV and ACS stimuli.
The same ACS stimulus which is effective in eliciting a clear cVEMP response in the ipsilesional SCM can only generate a reduced or absent oVEMP n10 beneath the contralesional eye. The symmetry of the cVEMP response validates the fact that the stimulus was delivered, there was no conductive hearing loss and the saccular receptors were functional. (2) The magnitude of the loss of n10 for ACS closely corresponds to the magnitude of the loss of n10 for BCV. Both results confirm the hypothesis that oVEMP n10s arise from activation of the superior vestibular nerve. The results are not consistent with the hypothesis that n10 to ACS arises from afferents in the inferior vestibular nerve. Given that all utricular afferents course in the superior vestibular nerve and that ACS can activate utricular afferents, it is reasonable to infer that n10 to both ACS and BCV probably arises from utricular receptors. That result shows that the saccular receptors and inferior vestibular nerve have a very minor role in generating oVEMP n10, since it was predicted that if saccular receptors and afferents were the cause of contralesional n10 to ACS there would be a large SAR for BCV oVEMPs but a small SAR for ACS oVEMPs. Our result shows there is no significant difference between the SARs for BCV and ACS. There is one proviso: a small bundle of nerve fibres from the ‘‘hook” region of the saccular macula travels in the superior vestibular nerve (de Burlet, 1924). These fibres would probably be affected by SVN so their contribution to the n10 to both ACS and BCV would be reduced, and so could result in the close relationship between BCV and ACS which we have observed. We think this is unlikely, because it is unlikely that only the hook region of the saccular macula, rather than the utricular macula, is responsible for the very short-latency oVEMP n10, because of the demonstrably weak polysynaptic sacculo-ocular pathways (Isu et al., 2000). The results of this study apply to 500 Hz Fz BCV and 500 Hz ACS. Recently it has been reported that the frequencies for eliciting optimal oVEMPs from BCV and from ACS are rather different – the BCV response is optimized by low-frequency stimulation whereas the ACS response is optimized by higher frequencies (Chihara et al., 2009). That difference has been interpreted as indicating that the labyrinthine mechanisms for generating oVEMP n10 for ACS and BCV are different, and such an interpretation is inconsistent with the interpretation we have used here. The following addresses considerations relevant for this matter. Both BCV and ACS cause hair cell deflection and afferent activation, but the way in which each stimulus generates hair cell deflec-
I.S. Curthoys et al. / Clinical Neurophysiology 122 (2011) 611–616
A
ACS
ACS
B
615
characteristics of middle-ear transmission which almost certainly has a higher tuned frequency than operates for BCV. In sum, the totally different transduction mechanisms with different frequency responses for ACS and BCV suggest that there will be different optimum frequencies for eliciting oVEMP n10s for the two stimulus modes, and indeed Chihara et al. reported that result (2009). For these reasons the presence of different optimal frequencies for oVEMP n10s from ACS and BCV cannot be taken to support the different contribution of saccular macula and utricular macula to oVEMP n10 generation. Whilst ACS can be used to evoke oVEMP n10, it should be noted that even in healthy subjects ACS does not always evoke an oVEMP n10. Cheng et al. (2009) reported that the response prevalence of oVEMP n10 to ACS was about 80%; similarly Chihara et al. (2007) reported a response prevalence of 90% of oVEMP n10 to ACS, whereas the response prevalence of oVEMPs to BCV was 100% (also Iwasaki et al., 2008a). Similar results were found by Park et al. (2010) and confirmed by our own observations in this study: in two patients of the 12 originally enrolled in the study it was not possible to elicit an n10 to ACS and so they were excluded from the study. BCV is a much more efficacious stimulus than ACS for evoking an oVEMP n10 response. 5. Conclusion Despite the saccular macula being functional, as shown by the presence of cVEMPs in response to ACS stimulation, it is not capable of generating an n10 response. The present results point to oVEMP n10 being due to superior vestibular nerve function and most probably utricular receptors as has been reported (Iwasaki et al., 2009; Manzari et al., 2010). Acknowledgements We are grateful for the support of NH&MRC of Australia and the Garnett Passe and Rodney Williams Memorial Foundation. References
ACS Fig. 2. (A) The relationship between the signed asymmetry ratio for oVEMP n10 to BCV and oVEMP n10 for ACS. The line shows an ordinary least-squares linear regression fit to the BCV oVEMP SAR ratio as a function of the ACS oVEMP SAR: the slope of the line is 0.75, the y intercept is 10.21, with a coefficient of determination of 0.78. It is significant (F = 28.17). (B) The relationship between the signed asymmetry ratio for ACS cVEMPS and ACS oVEMPs. The slope is 0.03, the y intercept is 2.30, with a coefficient of determination of 0.02. It is not significant (F = 0.14).
tion is totally different. The 500 Hz Fz BCV initiates a rostro-caudally directed pressure wave whose effective stimulation parameters depend heavily on the direction of the stimulus and on inherent skull characteristics such as the size, mass, resonance, and reflections from the back of the skull. This stimulus will result in hair cell deflections in particular regions of the macula, and those regions will change depending on the direction of the stimulus and on the parameters we have specified above. These particular regions of the macula stimulated are probably frequency dependent because of the frequency dependence of the parameters listed above. In contrast ACS is mediated solely by stapes movement initiating a pressure wave into the fluid-filled inner ear. The direction of that pressure wave is independent of frequency. Furthermore it is unlikely that stapes movement would ever generate skull resonance at physiological ACS levels. The efficacy of transmission via the stapes will depend heavily on the frequency
Aw ST, Fetter M, Cremer PD, Karlberg M, Halmagyi GM. Individual semicircular canal function in superior and inferior vestibular neuritis. Neurology 2001;57:768–74. Chan YS, Hwang JC, Cheung YM. Crossed sacculo-ocular pathway via the Deiters’ nucleus in cats. Brain Res Bull 1977;2:1–6. Cheng P-W, Chen C-C, Wang S-J, Young Y-H. Acoustic, mechanical and galvanic stimulation modes elicit ocular vestibular-evoked myogenic potentials. Clin Neurophysiol 2009;120:1841–4. Chihara Y, Iwasaki S, Ushio M, Murofushi T. Vestibular-evoked extraocular potentials by air-conducted sound: another clinical test for vestibular function. Clin Neurophysiol 2007;118:2745–51. Chihara Y, Iwasaki S, Fujimoto C, Ushio M, Yamasoba T, Murofushi T. Frequency tuning properties of ocular vestibular evoked myogenic potentials. Neuroreport 2009;20:1491–5. Cornell ED, Burgess AM, MacDougall HG, Curthoys IS. Vertical and horizontal eye movement responses to unilateral and bilateral bone conducted vibration to the mastoid. J Vestib Res 2009;19:41–7. Curthoys IS. A critical review of the neurophysiological evidence underlying clinical vestibular testing using sound, vibration and galvanic stimuli. Clin Neurophysiol 2010;121:132–44. 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. Curthoys IS, Manzari L, Smulders YE, Burgess AM. A review of the scientific basis and practical application of a new test of utricular function – ocular vestibularevoked myogenic potentials to bone conducted vibration. Acta Otorhinolaryngol Ital 2009;29:179–86. de Burlet HM. Zur Innervation der Macula sacculi bei Säugetieren. Anat Anzeig 1924;58:26–32. Fetter M, Dichgans J. Vestibular neuritis spares the inferior division of the vestibular nerve. Brain 1996;119:755–63. Halmagyi GM, Curthoys IS. A clinical sign of canal paresis. Arch Neurol 1988;45:737–9. Halmagyi GM, Weber KP, Curthoys IS. Vestibular function after acute vestibular neuritis. Restor Neurol Neurosci 2010;28:37–46.
616
I.S. Curthoys et al. / Clinical Neurophysiology 122 (2011) 611–616
Hwang JC, Poon WF. An electrophysiological study of the sacculo-ocular pathways in cats. Jpn J Physiol 1975;25:241–51. Isu N, Graf W, Sato H, Kushiro K, Zakir M, Imagawa M, Uchino Y. Sacculo-ocular reflex connectivity in cats. Exp Brain Res 2000;131:262–8. Iwasaki S, McGarvie LA, Halmagyi GM, Burgess AM, Kim J, Colebatch JG, Curthoys IS. Head taps evoke a crossed vestibulo-ocular reflex. Neurology 2007;68:1227–9. Iwasaki S, Smulders YE, Burgess AM, McGarvie AL, MacDougall H, Halmagyi GM, Curthoys IS. Ocular vestibular evoked myogenic potentials to bone conducted vibration of the midline forehead at Fz in healthy subjects. Clin Neurophysiol 2008a;119:2135–47. Iwasaki S, Smulders YE, Burgess AM, McGarvie AL, MacDougall H, Halmagyi GM, Curthoys IS. Ocular vestibular evoked myogenic potentials in response to bone conducted vibration of the midline forehead at Fz – a new indicator of unilateral otolithic loss. Audiol Neurotol 2008b;13:396–404. Iwasaki S, Chihara Y, Smulders YE, Burgess AM, Halmagyi GM, Curthoys IS, Murofushi T. The role of the superior vestibular nerve in generating ocular vestibular-evoked myogenic potentials to bone conducted vibration at Fz. Clin Neurophysiol 2009;120:588–93. Manzari L, Tedesco AR, Burgess AM, Curthoys IS. Ocular vestibular-evoked myogenic potentials to bone conducted vibration in superior vestibular neuritis show utricular function. Otolaryngol Head Neck Surg 2010;143:274–80. McCue MP, Guinan JJ. Acoustically responsive fibers in the vestibular nerve of the cat. J Neurosci 1994;14:6058–70. McCue MP, Guinan Jr JJ. Spontaneous activity and frequency selectivity of acoustically responsive vestibular afferents in the cat. J Neurophysiol 1995;74:1563–72.
McCue MP, Guinan Jr JJ. Sound evoked activity in primary afferent neurons of a mammalian vestibular system. Am J Otol 1997;18:355–60. 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. Murofushi T, Halmagyi GM, Yavor RA, Colebatch JG. Absent vestibular evoked myogenic potentials in vestibular neurolabyrinthitis. An indicator of inferior vestibular nerve involvement? Arch Otolaryngol Head Neck Surg 1996;122:845–8. Murofushi T, Curthoys IS. Physiological and anatomical study of click-sensitive primary vestibular afferents in the guinea pig. Acta Otolaryngol 1997;17:66–72. Nadol JB. Vestibular neuritis. Otolaryngol Head Neck Surg 1995;112:162–72. Park HJ, Lee I-S, Shin JE, Lee YJ, Park MS. Frequency-tuning characteristics of cervical and ocular vestibular evoked myogenic potentials induced by air-conducted tone bursts. Clin Neurophysiol 2010;121:85–9. Rosengren SM, Welgampola MS, Colebatch JG. Vestibular evoked myogenic potentials: past, present and future. Clin Neurophysiol 2010;121:636–51. Strupp M, Brandt T. Vestibular neuritis. In: Büttner U, editor. Vestibular dysfunction and its therapy. Adv Otorhinolaryngol 1999; 55, pp. 111–36. Suzuki JI, Tokumasu K, Goto K. Eye movements from single utricular nerve stimulation in the cat. Acta Otolaryngol 1969;68:350–62. Tokumasu K, Suzuki JI, Goto K. A study of the current spread on electric stimulation of the individual utricular and ampullary nerves. Acta Otolaryngol 1971;71:313–8. Winer BJ, Brown DR, Michels KM. Statistical principles in experimental design. 3rd ed. New York: McGraw-Hill; 1991.
Contents lists available at ScienceDirect
Clinical Neurophysiology journal homepage: www.elsevier.com/locate/clinph
The ocular vestibular-evoked myogenic potential to air-conducted sound; probable superior vestibular nerve origin Ian S. Curthoys a,*, Shinichi Iwasaki b, Yasuhiro Chihara b, Munetaka Ushio b, Leigh A. McGarvie c, Ann M. Burgess a a b c
Vestibular Research Laboratory, School of Psychology, The University of Sydney, NSW, Australia Department of Otolaryngology, Faculty of Medicine, University of Tokyo, Tokyo, Japan Institute of Clinical Neurosciences, Royal Prince Alfred Hospital, Sydney, NSW, Australia
a r t i c l e
i n f o
Article history: Accepted 21 July 2010 Available online 14 August 2010 Keywords: Vestibular Otolith Utricular Saccular Inferior oblique VOR VEMP oVEMP Vestibulo-ocular
a b s t r a c t Objective: Intense air-conducted sound (ACS) elicits an ocular vestibular-evoked myogenic potential (oVEMP), and it has been suggested that it does so by stimulating saccular receptors and afferents in the inferior vestibular nerve and so activating a crossed sacculo-ocular pathway. Bone conducted vibration (BCV) also elicits an oVEMP probably by activating utricular receptors and a crossed utriculo-ocular pathway. Are there two separate pathways mediating oVEMPs for ACS and BCV? If saccular receptors and afferents are primarily responsible for the oVEMP to ACS, then the oVEMP to ACS should be normal in patients with reduced or absent utricular function – unilateral superior vestibular neuritis (SVN). If utricular receptors and afferents are primarily responsible for oVEMP n10, then oVEMP to ACS should be reduced or absent in SVN patients, and in these patients there should be a close relationship between the size of the oVEMP n10 to BCV and to ACS. Methods: The n10 component of the oVEMP to 500 Hz BCV and to 500 Hz ACS was recorded in 10 patients with unilateral SVN but who had saccular and inferior vestibular nerve function preserved, as shown by their normal cVEMP responses to ACS. Results: In SVN patients with normal saccular and inferior vestibular nerve function, the oVEMP n10 in response to ACS was reduced or absent. Across SVN patients there was a very close correspondence between the size of oVEMP n10 for ACS and for BCV. Conclusions: The n10 component of the oVEMP to ACS is probably mediated predominantly by the superior vestibular nerve and so most likely by utricular receptors and afferents. Significance: The n10 component of the oVEMP to either ACS or BCV probably indicates mainly superior vestibular nerve function. Ó 2010 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved.
1. Introduction Abbreviations: AR, asymmetry ratio for the relative size of the n10 of the oVEMPs for the two eyes; ACS, air conducted sound; BCV, bone conducted vibration; EMG, electromyogram; Fz, the location on the head in the midline at the hairline; Fz BCV, bone conducted vibration delivered to Fz; 4810, the Bruel and Kjaer Mini-Shaker; cVEMPs, cervical vestibular-evoked myogenic potentials; oVEMPs, ocular vestibular-evoked myogenic potentials; n10, the initial negative potential in the oVEMP response at latency of around 10 ms; p13–n23, the initial positive potential of the cVEMP; MTB, Mini Tone Burst, a tone burst (500 Hz for 6 ms) delivered by the Mini-Shaker; uVL, unilateral vestibular loss; SAR, signed asymmetry ratio; SCM, sternocleidomastoid muscles; se, standard error; SVN, superior vestibular neuritis; IO, inferior oblique. * Corresponding author. Address: Vestibular Research Laboratory, School of Psychology, A 18 University of Sydney, Sydney, NSW 2006, Australia. Tel.: +61 2 9351 3570; fax: +61 2 9036 5223. E-mail address: [email protected] (I.S. Curthoys).
Vestibular-evoked myogenic potentials (VEMPs) recorded by surface EMG electrodes are now widely used to assess vestibular function (for recent reviews see Curthoys, 2010; Curthoys et al., 2009; Rosengren et al., 2010). In one testing paradigm the electrodes are placed over tensed sternocleidomastoid muscles (SCM), and the initial positive (inhibitory) myogenic potential (p13–n23) recorded in response to air-conducted sound (ACS) or bone conducted vibration (BCV) is called the cervical vestibularevoked myogenic potential (cVEMP). In another testing paradigm, the electrodes are placed just beneath the eyes over the inferior oblique (IO) and inferior rectus (IR) eye muscles with the subject or patient required to look up during testing, and the myogenic po-
1388-2457/$36.00 Ó 2010 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.clinph.2010.07.018
612
I.S. Curthoys et al. / Clinical Neurophysiology 122 (2011) 611–616
tential recorded in response to ACS or BCV is called the ocular vestibular-evoked myogenic potential (oVEMP). The initial negative (excitatory) component of this potential, peaking at around 10 ms, is called n10. These potentials are called ‘‘vestibular-evoked” rather than ‘‘auditory-evoked” because it has been shown that the stimuli which are effective for evoking them cause selective activation of irregular primary otolith afferents in guinea pigs (Murofushi et al., 1995; Curthoys et al., 2006; Curthoys, 2010) and cats (McCue and Guinan, 1995, 1997). In particular utricular afferents are activated by BCV at very low stimulus levels (close to ABR threshold) (Curthoys et al., 2006). Suzuki et al. (1969) and Tokumasu et al. (1971) showed in cats that electrical stimulation of the utricular nerve resulted in characteristic patterns of activation of eye muscles and eye movements. In healthy human subjects BCV stimulation of the mastoid has been shown to cause very small similar eye movements (Cornell et al., 2009). Control data confirms the vestibular nature of the response. In totally deaf human subjects the oVEMP n10 responses to BCV still persist in the absence of auditory function, whereas patients without vestibular function but with remaining hearing do not show oVEMP n10s (Iwasaki et al., 2008a). In patients with unilateral vestibular loss (uVL) there is a loss of oVEMP n10s to BCV beneath the contralesional eye, showing that the oVEMP n10 is a crossed otolith-ocular response (Iwasaki et al., 2007, 2008b). In patients with unilateral superior vestibular neuritis (SVN) affecting the nerves from the horizontal and anterior canals and the utricular macula, it has been demonstrated that in response to 500 Hz BCV delivered to the midline of the forehead at the hairline (the location called Fz), the oVEMP n10 beneath the contralesional eye is reduced or absent (Iwasaki et al., 2009; Manzari et al., 2010) whilst saccular function is still present (as shown by normal cVEMPs). These results suggest that in human subjects and patients the n10 to 500 Hz Fz BCV is primarily utricular. Air-conducted sound (ACS) also causes oVEMP n10s and it has been suggested that the reason for this is that ACS stimulates a different set of receptors – saccular receptors and afferents predominantly in the inferior vestibular nerve – and so activates a sacculo-ocular pathway (Chihara et al., 2007). In guinea pigs and cats ACS does activate receptors on the saccular macula (Murofushi et al., 1995; Murofushi and Curthoys, 1997; McCue and Guinan, 1994, 1997). However, existing evidence indicates that a sacculo-ocular pathway is polysynaptic and probably weak (Isu et al., 2000; Chan et al., 1977; Hwang and Poon, 1975). An alternative possibility is that the ACS stimulates utricular receptors and afferents in the superior vestibular nerve and so activates the same utriculo-ocular pathway as activated by BCV. In support of the latter: there is now evidence from single neuron recordings of primary vestibular afferents that ACS activates utricular receptors and irregular primary utricular afferents in the superior vestibular nerve of the guinea pig (Curthoys, 2010; Curthoys and Vulovic, 2010, unpublished data). One way of assessing which of these alternative explanations is correct is by measuring cVEMPs and oVEMPs to ACS in patients with superior vestibular neuritis (SVN). A defining characteristic of SVN is that patients have reduced horizontal canal responses to caloric stimulation and also show a head impulse sign for yaw head rotations to the affected side (Halmagyi et al., 2010; Strupp and Brandt, 1999; Nadol, 1995; Fetter and Dichgans, 1996). Since the utricular nerve travels with the nerve from the horizontal canal in the superior division of the vestibular nerve (de Burlet, 1924) it is likely that in most cases SVN affects the entire superior vestibular nerve, including the utricular afferents (Aw et al., 2001; Nadol, 1995; Fetter and Dichgans, 1996; Halmagyi et al., 2010). An important fact is that in SVN patients the saccular receptors and inferior vestibular nerve are still functional since SVN patients show normal cVEMPs to ACS stimulation of their affected ear (Iwasaki
et al., 2009; Murofushi et al., 1996). So in SVN patients it is reasonable to assume that ACS activates the saccular receptors. If saccular activation is primarily responsible for n10 to ACS, one would expect little effect of SVN on contralesional n10, since the presence of the ipsilateral cVEMP shows that the ipsilateral saccular receptors and the sacculo-collic pathway are still functioning and so would be expected to be able to produce a normal oVEMP n10 to ACS. However, if the utricular macula is primarily responsible for the contralesional oVEMP n10 to ACS, then one would expect that, with reduced or absent utricular function in SVN, there should be a reduced or absent contralateral oVEMP n10 response to ACS stimulation. One other prediction can be made: SVN is not an all-or-none phenomenon; some SVN patients have almost complete loss of n10; others have much smaller losses (Iwasaki et al., 2009), presumably reflecting the severity of their neuritis. If the superior vestibular nerve was primarily responsible for oVEMP n10, then the extent of the reduction of the oVEMP n10 should be similar for both BCV and ACS. If the inferior vestibular nerve was primarily responsible there should not be a close relationship because on this hypothesis oVEMP n10s are generated by independent mechanisms: utricular macula for BCV and saccular macula for ACS. Consequently one would expect the amplitude of n10 to ACS should be independent of the amplitude of n10 to BCV.
2. Patients and methods Twelve patients identified as having SVN according to the criteria below were enrolled in this study at the University of Tokyo Hospital. However, in only 10 of these patients was it possible to obtain a response to ACS, so the data reported below is only from these 10 patients. Others have noted the fact that even not all healthy subjects show an n10 response to ACS (Chihara et al., 2007; Cheng et al., 2009). Table 1 summarizes the relevant demographics of the 10 patients and their audiometric and vestibular test results. Most patients were tested in the acute stage of SVN. The criteria for selecting the patients were based on standard definitions (Nadol, 1995): (1) that they had absent or markedly reduced horizontal canal function (absent or reduced caloric responses (canal paresis score of >22%)) and the presence of a head impulse sign for horizontal head rotations towards the affected ear (Halmagyi and Curthoys, 1988) both indicating the superior vestibular nerve was not functional; (2) that normal cVEMPs in response to ACS of the affected ear were still present, indicating that saccular receptors and those saccular otolithic afferents coursing in the inferior vestibular nerve were still functional; (3) absence of auditory signs. All procedures were in accordance with the Helsinki declaration and were approved by the University of Tokyo Human Ethics Committee, and patients gave informed consent. The methods have been described in detail (Iwasaki et al., 2008a). In brief, the patients lay supine and oVEMP potentials were recorded from surface EMG electrodes placed just beneath the eyes as the patient looked upward (toward the top of their head) during the test. A small fixation point was positioned 25–30 deg above the patient’s visual straight ahead. The active EMG electrodes were placed on the cleaned skin over the infra-orbital ridges at the centre of each lower eye lid and the reference electrodes were placed 3 cm below that (Iwasaki et al., 2008a). To record cVEMPs the EMG electrodes were placed over the belly of the SCM and the patient contracted the SCM by lifting their head off the pillow. The EMG potentials were amplified, band-pass filtered at 20–500 Hz (BCV) or 20–3000 Hz (ACS), sampled at 20 kHz and the data from stimulus onset to 50 ms was averaged. For the n10 the amplitude was defined as baseline to peak, for the cVEMPs the amplitude was defined as the value of the difference between p13 and n23.
613
I.S. Curthoys et al. / Clinical Neurophysiology 122 (2011) 611–616 Table 1 The age, gender and summaries of the audiometric and vestibular test results for the 12 SVN patients reported. PTA = average of the pure tone thresholds at 500 Hz, 1 kHz, and 2 kHz; CP = horizontal canal paresis score.
*
Patient
Age, gender
Side of lesion
PTA healthy side
PTA affected side
CP %
ACS cVEMP signed AR %
ACS oVEMP signed AR %
BCV oVEMP signed AR %
1* 2* 3* 4 5 6 7 8 9 10
57 M 30 M 70 F 34 M 23 M 60 M 31 M 58 M 61 M 41 M
L R R R L R R L R R
16.3 5 16.7 8.8 7.5 5 6.7 13.3 23.3 6.7
13.8 3.3 16.7 7.5 6.7 3.8 10 11.7 23.3 10
65 100 50 73 81.6 100 62.8 58 100 100
3.52 9.75 11.24 11.25 11.96 5.92 13.13 18.38 1.29 8.09
50.00 81.63 100.00 4.92 15.46 70.63 100.00 100.00 23.08 65.19
70.73 69.19 68.60 9.86 41.04 78.43 100.00 56.25 20.00 61.98
The BCV unsigned AR data for these patients has been reported previously (Iwasaki et al., 2009).
The ACS stimuli for oVEMPs and cVEMPs were 95 dBnHL tone bursts of 4 ms duration. ACS was presented through a calibrated headphone (type DR-531, Elega Acoustics Co., Ltd., Tokyo, Japan). The stimulus intensity was set at 135 dB SPL. The stimulation rate was 5 Hz. The stimulus was 500 Hz short tone bursts (rise/fall time = 1 ms and plateau time = 2 ms). The ACS stimulus was presented separately to the affected ear and the unaffected ear. When using ACS, the n10 responses were measured beneath the eye contralateral to the stimulated ear (Chihara et al., 2007); and the amplitudes of these contralateral responses were used for calculation of asymmetry when using ACS (see below for further explanation). BCV stimuli were 500 Hz tone bursts (6 ms in duration: rise/ fall time = 1 ms and plateau time = 4 ms) delivered to the midline forehead of the patient at the hairline (Fz). The stimulator was a Bruel and Kjaer Mini-Shaker (4810) (Naerum, Denmark), fitted with a 2 cm long machine screw (M5) terminated in a bakelite cap 1.5 cm in diameter. This cap was placed at Fz, without pressure, and the potentials measured to 50 stimulus presentations. There are problems in directly comparing the absolute amplitude of n10 for ACS with the absolute amplitude of n10 for BCV. Previously published data have shown that the amplitude of n10 to 500 Hz Fz BCV and ACS varies in absolute size considerably between people (Iwasaki et al., 2008a; Chihara et al., 2007). Also the average amplitude of n10 to ACS is only approximately 3.5 lV baseline to peak (Chihara et al., 2007) which is systematically smaller than the average amplitude of n10 to BCV stimuli, approximately 8.5 lV baseline to peak (Iwasaki et al., 2008a). The average amplitude of oVEMP n10 to 500 Hz Fz BCV decreases with age (Iwasaki et al., 2008a). These problems can be overcome by using an Asymmetry Ratio (AR) for comparisons of the response to BCV and ACS. The AR for 500 Hz Fz BCV does not vary with age (Iwasaki et al., 2008a). In previous studies we have calculated the absolute asymmetry ratio (AR) by using the formula:
AR ¼ ½ðlarger n10 smaller n10Þ=ðlarger n10 þ smaller n10Þ 100 However, in this study it is necessary to take account of the side more explicitly, because the affected ear may generate a larger n10 or a smaller n10 response than the n10 response generated by the healthy ear and an absolute AR would not show such sideness. To overcome that drawback in this study we have used a signed asymmetry ratio (SAR) defined by the formula:
oVEMP Signed AR ¼ ½ðipsilesional n10 contralesional n10Þ=ðipsilesional n10 þ contralesional n10Þ 100 This Signed AR (SAR) varies from 100% to +100%. A case where the contralesional n10 is absent, but the ipsilesional n10 is present would yield a SAR of +100%; a case where the contralesional n10 is present and the ipsilesional n10 is absent would yield a SAR of
100%; and a case where the ipsilesional and contralesional n10s are of equal amplitude would yield a SAR of 0%. The ACS data gathering and SAR calculation for ACS was rather different than for BCV since in the present study each ear was stimulated with ACS separately (unilateral or monaural stimulation), as opposed to BCV where both ears were stimulated simultaneously. To ensure comparability between the SAR calculations for BCV and ACS we used the following approach for ACS: in the above equation the term ‘‘contralesional n10” refers to the amplitude of n10 beneath the eye opposite the affected ear when the affected ear was stimulated by ACS. Similarly the term ‘‘ipsilesional n10” refers to the amplitude of n10 beneath the eye opposite the healthy ear, when the healthy ear was stimulated. In this way the ipsilesional and contralesional responses (and the signed ARs) were directly comparable between BCV and ACS. The Signed Asymmetry Ratio of the cVEMP was calculated in a similar fashion:
cVEMPSignedAR ¼ ½ðcontralesionalfp13 n23g ipsilesionalfp13 n23gÞ= ðcontralesionalfp13 n23g þ ipsilesionalfp13 n23gÞ 100 The values are expressed below as means ± standard error (Winer et al., 1991). The significance level was set at 0.05. The value of the n10 used for the analysis was baseline-to-peak and the value of the cVEMP p13–n23 was the value of the voltage difference between p13 and n23. The n10 varies considerably between individuals (Iwasaki et al., 2008a), probably depending on factors such as skull size, but we have shown that with Fz stimulation (which stimulates both ears about equally (Iwasaki et al., 2008a)) the amplitude of n10 is about equal beneath both eyes in healthy subjects. A previous paper on oVEMPs in SVN patients (Iwasaki et al., 2009) reported only BCV data in SVN patients. The BCV AR values for 3 of the patients in that study have been recalculated (as SAR values) and are presented here, together with their corresponding ACS SAR data which has not been previously presented. The Manzari et al. (2010) study on SVN patients was conducted in a different country (Italy) on a totally different set of patients and only concerned n10 to 500 Hz Fz BCV. 3. Results The results for a typical patient with a right sided SVN for cVEMPs and oVEMPs are shown in Fig. 1. This patient is number 7 in Table 1. Panel (a) shows the cVEMPs for ACS are about equal for ACS stimulation of each ear. Panel (b) shows the patient has a major asymmetry of oVEMP n10s for 500 Hz Fz, confirming previous evidence for SVN patients (Iwasaki et al., 2009). Although both ears are stimulated about equally by
614
I.S. Curthoys et al. / Clinical Neurophysiology 122 (2011) 611–616
Fig. 1. The responses of a typical patient with a right SVN showing (a) ACS cVEMPs, (b) BCV oVEMPs (Fz BCV), and (c) ACS oVEMPs. (a) The cVEMP p13–n23 response to 500 Hz ACS on the affected right side shows normal amplitude (short lines) and so gives evidence that the stimulus is working and that the saccular macula on the affected right side is functioning and responding to ACS. It also shows that this patient does not have a conductive hearing loss which would affect the 500 Hz ACS stimulus. However, despite that functioning saccular macula, the n10 of the oVEMP on the contralateral (left side – from the affected right ear) is absent, both for 500 Hz Fz BCV (b – left eye upper trace) and also for 500 Hz ACS stimulation of the affected ear (c – left eye upper trace).
the Fz BCV stimulus (Iwasaki et al., 2008a) there is a clear n10 beneath the right eye (from the healthy (left) labyrinth), but no n10 is discernible beneath the left eye (from the affected (right) labyrinth). So this patient has an SAR of 100% for Fz BCV. The third panel (c) shows that in this patient ACS of each ear results in a very similar asymmetrical oVEMP n10 just as found for BCV stimulation; the n10 beneath the right eye (from monaural ACS stimulation of the healthy labyrinth) is normal, whereas the n10 beneath the left eye (from monaural stimulation of the affected labyrinth) is not detectable. So this patient also has an SAR of 100% for ACS (Fig. 2). All patients had cVEMPs in the normal range from ACS stimulation. The average SAR for cVEMPs to ACS was 0.50% ±3.52 (standard error = se). In contrast there was a marked asymmetry in oVEMPs for both BCV and ACS stimuli. The average SAR for BCV oVEMPs was 51.63% ±12.10 (se) and for ACS was 55.49% ±14.30 (se). The correlation between the SAR for ACS and BCV oVEMPs was 0.88; the correlation between the ACS oVEMPs and ACS cVEMPs was 0.13. On a paired t-test there was no significant difference between the oVEMP SARs to BCV and ACS (t = 0.57, df = 9, p > 0.05). There is a highly significant linear relationship for the SAR for ACS oVEMPs and the SAR for BCV oVEMPs (linear regression F = 28.17, p < 0.01) in contrast to the non-significant relationship (linear regression F = 0.14, p > 0.05) between the SAR for ACS oVEMPs and the SAR for ACS cVEMPs. In one patient (patient 4) the size of the n10 to 500 Hz Fz BCV was about equal in both eyes, and we considered this was probably because the SVN had minimally affected the superior vestibular nerve on the affected side. In such a case the signed asymmetry ratio (SAR) for oVEMP n10 was very small for both BCV and ACS stimuli (Table 1). In another patient (7) the oVEMPs to both Fz BCV and ACS were reduced or absent beneath the contralesional eye, resulting in a large SAR for both ACS and BCV stimuli. One patient (9) diagnosed as SVN on the basis of CP and cVEMPs unexpectedly had a larger n10 beneath the contralesional eye than beneath the ipsilesional eye to BCV, resulting in a negative signed asymmetry value for BCV. However, this patient also had a similar pattern of n10 responses to ACS and so also had a negative signed asymmetry ratio for ACS. 4. Discussion The results show that in SVN patients (1) Unilateral loss of function of the superior vestibular nerve, with functioning inferior vestibular nerve, leads to loss of contralesional oVEMP n10 to both BCV and ACS stimuli.
The same ACS stimulus which is effective in eliciting a clear cVEMP response in the ipsilesional SCM can only generate a reduced or absent oVEMP n10 beneath the contralesional eye. The symmetry of the cVEMP response validates the fact that the stimulus was delivered, there was no conductive hearing loss and the saccular receptors were functional. (2) The magnitude of the loss of n10 for ACS closely corresponds to the magnitude of the loss of n10 for BCV. Both results confirm the hypothesis that oVEMP n10s arise from activation of the superior vestibular nerve. The results are not consistent with the hypothesis that n10 to ACS arises from afferents in the inferior vestibular nerve. Given that all utricular afferents course in the superior vestibular nerve and that ACS can activate utricular afferents, it is reasonable to infer that n10 to both ACS and BCV probably arises from utricular receptors. That result shows that the saccular receptors and inferior vestibular nerve have a very minor role in generating oVEMP n10, since it was predicted that if saccular receptors and afferents were the cause of contralesional n10 to ACS there would be a large SAR for BCV oVEMPs but a small SAR for ACS oVEMPs. Our result shows there is no significant difference between the SARs for BCV and ACS. There is one proviso: a small bundle of nerve fibres from the ‘‘hook” region of the saccular macula travels in the superior vestibular nerve (de Burlet, 1924). These fibres would probably be affected by SVN so their contribution to the n10 to both ACS and BCV would be reduced, and so could result in the close relationship between BCV and ACS which we have observed. We think this is unlikely, because it is unlikely that only the hook region of the saccular macula, rather than the utricular macula, is responsible for the very short-latency oVEMP n10, because of the demonstrably weak polysynaptic sacculo-ocular pathways (Isu et al., 2000). The results of this study apply to 500 Hz Fz BCV and 500 Hz ACS. Recently it has been reported that the frequencies for eliciting optimal oVEMPs from BCV and from ACS are rather different – the BCV response is optimized by low-frequency stimulation whereas the ACS response is optimized by higher frequencies (Chihara et al., 2009). That difference has been interpreted as indicating that the labyrinthine mechanisms for generating oVEMP n10 for ACS and BCV are different, and such an interpretation is inconsistent with the interpretation we have used here. The following addresses considerations relevant for this matter. Both BCV and ACS cause hair cell deflection and afferent activation, but the way in which each stimulus generates hair cell deflec-
I.S. Curthoys et al. / Clinical Neurophysiology 122 (2011) 611–616
A
ACS
ACS
B
615
characteristics of middle-ear transmission which almost certainly has a higher tuned frequency than operates for BCV. In sum, the totally different transduction mechanisms with different frequency responses for ACS and BCV suggest that there will be different optimum frequencies for eliciting oVEMP n10s for the two stimulus modes, and indeed Chihara et al. reported that result (2009). For these reasons the presence of different optimal frequencies for oVEMP n10s from ACS and BCV cannot be taken to support the different contribution of saccular macula and utricular macula to oVEMP n10 generation. Whilst ACS can be used to evoke oVEMP n10, it should be noted that even in healthy subjects ACS does not always evoke an oVEMP n10. Cheng et al. (2009) reported that the response prevalence of oVEMP n10 to ACS was about 80%; similarly Chihara et al. (2007) reported a response prevalence of 90% of oVEMP n10 to ACS, whereas the response prevalence of oVEMPs to BCV was 100% (also Iwasaki et al., 2008a). Similar results were found by Park et al. (2010) and confirmed by our own observations in this study: in two patients of the 12 originally enrolled in the study it was not possible to elicit an n10 to ACS and so they were excluded from the study. BCV is a much more efficacious stimulus than ACS for evoking an oVEMP n10 response. 5. Conclusion Despite the saccular macula being functional, as shown by the presence of cVEMPs in response to ACS stimulation, it is not capable of generating an n10 response. The present results point to oVEMP n10 being due to superior vestibular nerve function and most probably utricular receptors as has been reported (Iwasaki et al., 2009; Manzari et al., 2010). Acknowledgements We are grateful for the support of NH&MRC of Australia and the Garnett Passe and Rodney Williams Memorial Foundation. References
ACS Fig. 2. (A) The relationship between the signed asymmetry ratio for oVEMP n10 to BCV and oVEMP n10 for ACS. The line shows an ordinary least-squares linear regression fit to the BCV oVEMP SAR ratio as a function of the ACS oVEMP SAR: the slope of the line is 0.75, the y intercept is 10.21, with a coefficient of determination of 0.78. It is significant (F = 28.17). (B) The relationship between the signed asymmetry ratio for ACS cVEMPS and ACS oVEMPs. The slope is 0.03, the y intercept is 2.30, with a coefficient of determination of 0.02. It is not significant (F = 0.14).
tion is totally different. The 500 Hz Fz BCV initiates a rostro-caudally directed pressure wave whose effective stimulation parameters depend heavily on the direction of the stimulus and on inherent skull characteristics such as the size, mass, resonance, and reflections from the back of the skull. This stimulus will result in hair cell deflections in particular regions of the macula, and those regions will change depending on the direction of the stimulus and on the parameters we have specified above. These particular regions of the macula stimulated are probably frequency dependent because of the frequency dependence of the parameters listed above. In contrast ACS is mediated solely by stapes movement initiating a pressure wave into the fluid-filled inner ear. The direction of that pressure wave is independent of frequency. Furthermore it is unlikely that stapes movement would ever generate skull resonance at physiological ACS levels. The efficacy of transmission via the stapes will depend heavily on the frequency
Aw ST, Fetter M, Cremer PD, Karlberg M, Halmagyi GM. Individual semicircular canal function in superior and inferior vestibular neuritis. Neurology 2001;57:768–74. Chan YS, Hwang JC, Cheung YM. Crossed sacculo-ocular pathway via the Deiters’ nucleus in cats. Brain Res Bull 1977;2:1–6. Cheng P-W, Chen C-C, Wang S-J, Young Y-H. Acoustic, mechanical and galvanic stimulation modes elicit ocular vestibular-evoked myogenic potentials. Clin Neurophysiol 2009;120:1841–4. Chihara Y, Iwasaki S, Ushio M, Murofushi T. Vestibular-evoked extraocular potentials by air-conducted sound: another clinical test for vestibular function. Clin Neurophysiol 2007;118:2745–51. Chihara Y, Iwasaki S, Fujimoto C, Ushio M, Yamasoba T, Murofushi T. Frequency tuning properties of ocular vestibular evoked myogenic potentials. Neuroreport 2009;20:1491–5. Cornell ED, Burgess AM, MacDougall HG, Curthoys IS. Vertical and horizontal eye movement responses to unilateral and bilateral bone conducted vibration to the mastoid. J Vestib Res 2009;19:41–7. Curthoys IS. A critical review of the neurophysiological evidence underlying clinical vestibular testing using sound, vibration and galvanic stimuli. Clin Neurophysiol 2010;121:132–44. 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. Curthoys IS, Manzari L, Smulders YE, Burgess AM. A review of the scientific basis and practical application of a new test of utricular function – ocular vestibularevoked myogenic potentials to bone conducted vibration. Acta Otorhinolaryngol Ital 2009;29:179–86. de Burlet HM. Zur Innervation der Macula sacculi bei Säugetieren. Anat Anzeig 1924;58:26–32. Fetter M, Dichgans J. Vestibular neuritis spares the inferior division of the vestibular nerve. Brain 1996;119:755–63. Halmagyi GM, Curthoys IS. A clinical sign of canal paresis. Arch Neurol 1988;45:737–9. Halmagyi GM, Weber KP, Curthoys IS. Vestibular function after acute vestibular neuritis. Restor Neurol Neurosci 2010;28:37–46.
616
I.S. Curthoys et al. / Clinical Neurophysiology 122 (2011) 611–616
Hwang JC, Poon WF. An electrophysiological study of the sacculo-ocular pathways in cats. Jpn J Physiol 1975;25:241–51. Isu N, Graf W, Sato H, Kushiro K, Zakir M, Imagawa M, Uchino Y. Sacculo-ocular reflex connectivity in cats. Exp Brain Res 2000;131:262–8. Iwasaki S, McGarvie LA, Halmagyi GM, Burgess AM, Kim J, Colebatch JG, Curthoys IS. Head taps evoke a crossed vestibulo-ocular reflex. Neurology 2007;68:1227–9. Iwasaki S, Smulders YE, Burgess AM, McGarvie AL, MacDougall H, Halmagyi GM, Curthoys IS. Ocular vestibular evoked myogenic potentials to bone conducted vibration of the midline forehead at Fz in healthy subjects. Clin Neurophysiol 2008a;119:2135–47. Iwasaki S, Smulders YE, Burgess AM, McGarvie AL, MacDougall H, Halmagyi GM, Curthoys IS. Ocular vestibular evoked myogenic potentials in response to bone conducted vibration of the midline forehead at Fz – a new indicator of unilateral otolithic loss. Audiol Neurotol 2008b;13:396–404. Iwasaki S, Chihara Y, Smulders YE, Burgess AM, Halmagyi GM, Curthoys IS, Murofushi T. The role of the superior vestibular nerve in generating ocular vestibular-evoked myogenic potentials to bone conducted vibration at Fz. Clin Neurophysiol 2009;120:588–93. Manzari L, Tedesco AR, Burgess AM, Curthoys IS. Ocular vestibular-evoked myogenic potentials to bone conducted vibration in superior vestibular neuritis show utricular function. Otolaryngol Head Neck Surg 2010;143:274–80. McCue MP, Guinan JJ. Acoustically responsive fibers in the vestibular nerve of the cat. J Neurosci 1994;14:6058–70. McCue MP, Guinan Jr JJ. Spontaneous activity and frequency selectivity of acoustically responsive vestibular afferents in the cat. J Neurophysiol 1995;74:1563–72.
McCue MP, Guinan Jr JJ. Sound evoked activity in primary afferent neurons of a mammalian vestibular system. Am J Otol 1997;18:355–60. 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. Murofushi T, Halmagyi GM, Yavor RA, Colebatch JG. Absent vestibular evoked myogenic potentials in vestibular neurolabyrinthitis. An indicator of inferior vestibular nerve involvement? Arch Otolaryngol Head Neck Surg 1996;122:845–8. Murofushi T, Curthoys IS. Physiological and anatomical study of click-sensitive primary vestibular afferents in the guinea pig. Acta Otolaryngol 1997;17:66–72. Nadol JB. Vestibular neuritis. Otolaryngol Head Neck Surg 1995;112:162–72. Park HJ, Lee I-S, Shin JE, Lee YJ, Park MS. Frequency-tuning characteristics of cervical and ocular vestibular evoked myogenic potentials induced by air-conducted tone bursts. Clin Neurophysiol 2010;121:85–9. Rosengren SM, Welgampola MS, Colebatch JG. Vestibular evoked myogenic potentials: past, present and future. Clin Neurophysiol 2010;121:636–51. Strupp M, Brandt T. Vestibular neuritis. In: Büttner U, editor. Vestibular dysfunction and its therapy. Adv Otorhinolaryngol 1999; 55, pp. 111–36. Suzuki JI, Tokumasu K, Goto K. Eye movements from single utricular nerve stimulation in the cat. Acta Otolaryngol 1969;68:350–62. Tokumasu K, Suzuki JI, Goto K. A study of the current spread on electric stimulation of the individual utricular and ampullary nerves. Acta Otolaryngol 1971;71:313–8. Winer BJ, Brown DR, Michels KM. Statistical principles in experimental design. 3rd ed. New York: McGraw-Hill; 1991.