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Reflex responses of masseter muscles to sound
Clinical Neurophysiology 121 (2010) 1690–1699
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Invited review
Reflex responses of masseter muscles to sound Franca Deriu a,*, Elena Giaconi a, John C. Rothwell b, Eusebio Tolu a a b
Department of Biomedical Sciences, University of Sassari, Sassari, Italy Sobell Department of Motor Neuroscience and Movement Disorders, Institute of Neurology, University College London, London, UK
a r t i c l e
i n f o
Article history: Accepted 9 November 2009 Available online 5 May 2010 Keywords: Vestibulo-masseteric reflex Acoustic masseteric reflex Acoustic stimulation Jaw muscles Brainstem Trigeminal motor system
a b s t r a c t Acoustic stimuli can evoke reflex EMG responses (acoustic jaw reflex) in the masseter muscle. Although these were previously ascribed to activation of cochlear receptors, high intensity sound can also activate vestibular receptors. Since anatomical and physiological studies, both in animals and humans, have shown that masseter muscles are a target for vestibular inputs we have recently reassessed the vestibular contribution to masseter reflexes. We found that high intensity sound evokes two bilateral and symmetrical short-latency responses in active unrectified masseter EMG of healthy subjects: a high threshold, early p11/n15 wave and a lower threshold, later p16/n21 wave. Both of these reflexes are inhibitory but differ in their threshold, latency and appearance in the rectified EMG average. Experiments in healthy subjects and in patients with selective lesions showed that vestibular receptors were responsible for the p11/n15 wave (vestibulo-masseteric reflex) whereas cochlear receptors were responsible for the p16/n21 wave (acoustic masseteric reflex). The possible functional significance of the double vestibular control over masseter muscles is discussed. Ó 2010 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved.
Contents 1. 2.
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Sound as a stimulus activating cochlear as well as vestibular receptors . . . . . . . . . . . . . . . . . . . . . . . . . 1.1. Reflex responses to sound in cranial muscles . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Masseter responses to vestibular stimulation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.1. Vestibulo-trigeminal responses in animals . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.2. Vestibulo-trigeminal responses in humans . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.3. Vestibular control over masseter muscles . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.4. Summarizing functional remarks . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Masseter responses to acoustic stimulation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.1. Origin of masseter reflex responses to sound . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.2. EMG features of the vestibulo-masseteric reflex. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.3. Possible functional consequences of sound-induced vestibular and cochlear masseter reflexes . Possible role for the vestibulo-masseteric reflex pathways in trigeminal motor control . . . . . . . . . . . . Clinical prospects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
1. Sound as a stimulus activating cochlear as well as vestibular receptors Although the primary receptor specialised for the detection of sound is the cochlea, it has been known for many years that sound * Corresponding author. Address: Department of Biomedical Sciences, University of Sassari, Section of Human Physiology and Bioengineering, Viale San Pietro 43/b, 07100 Sassari, Italy. Tel.: +39 079 22 82 94; fax: +39 079 22 81 56. E-mail address: [email protected] (F. Deriu).
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can also affect the vestibular system. For instance, in humans intense sound is well known to produce vestibular symptoms and illusions of movement (Parker et al., 1975). These probably arise from stimulation of otolith organs in the saccule since this is reported to be the most sensitive part of the vestibular system to sound (Young et al., 1977; Cazals et al., 1983; Mc Cue and Guinan, 1994; Murofushi et al., 1995, 1996; Murofushi and Curthoys, 1997). Indeed the saccular hair cells are activated by high intensity clicks in a way similar to natural linear acceleration (Uchino et al., 1997b; Ogawa et al., 2000).
1388-2457/$36.00 Ó 2010 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.clinph.2009.11.093
F. Deriu et al. / Clinical Neurophysiology 121 (2010) 1690–1699
Acoustic stimulation is now widely accepted as a simple, non-invasive and safe method to activate the otoliths (Clarke, 2001; Welgampola and Colebatch, 2005; Wuyts et al., 2007). However, investigations only began in this field in 1964 when Bickford and colleagues described a reflex response in posterior neck muscles that was induced by high intensity click stimulation. They referred to this as the inion response. It scaled with the level of muscle activation, consistent with a myogenic origin, and it was suggested to arise from activation of the vestibular apparatus rather than from the cochlea (Bickford et al., 1964; Cody et al., 1964). This conclusion was later supported by work of Cody and Bickford (1969) and Townsend and Cody (1971), but was disputed by others (Meier-Ewert et al., 1974). Because of this uncertainty the inion response never achieved acceptance as a useful test of vestibular reflex function (Douek, 1981). It was a further 20 years before Colebatch reinvestigated the reflex responses to high intensity sound in neck (Colebatch et al., 1994). These authors found that high intensity clicks (95–100 dB NHL) evoke a reflex response in active sternocleidomastoid muscles. This response consists of an early, short-latency, high-threshold ipsilateral p13/n23 potential and a late lower threshold, bilateral n34/ p44 response. The earlier response depended on vestibular afferent activation, while the later response depended on cochlear integrity (Colebatch and Halmagyi, 1992). The neurophysiological substrate for the short latency p13/n23 potential, i.e. the sacculo-collic reflex arc, was later described in animals by Uchino and colleagues (Uchino et al., 1997a; Kushiro et al., 1999) and additional methods of evoking vestibular-dependent reflexes in the same pathway have since been published (Halmagyi et al., 1995; Watson and Colebacth, 1998a, b). Studies of the effect of loud sound on the firing of single motor units in the SCM muscle have shown that the underlying effect is inhibitory (Colebatch and Rothwell, 1993, 2004). 1.1. Reflex responses to sound in cranial muscles There is a long history of reflex responses to sound in other cranial muscles (postauricular, frontalis, orbicular oris, orbicular oculi, mylohyoideus, temporalis and masseter muscles) and these were always attributed to activation of cochlear rather than vestibular afferents (Kiang, 1963; Meier-Ewert et al., 1974). In particular an acoustic jaw reflex was originally described by Meier-Ewert and colleagues (1974) in several cranial muscles, including the masseters. Here the reflex consisted of a dual bilateral inhibitory period (approximate latency 14 ms, duration 11 ms) visible in the submaximal interference pattern of the masseter EMG after unilateral stimulation with high intensity clicks or tones. The authors suggested that it might be a local protective reflex and proved that its afferent reflex arc was the acoustic nerve while a vestibular contribution was excluded. They also identified a non-consistent later silent period which was considered as a central part of the startle pattern. Although this work confirms that cochlear receptors provide strong input to cranial muscles, previous work had also shown that trigeminal motoneurones innervating jaw muscles are a target for vestibular inputs, both in animals (Tolu and Pugliatti, 1993; Tolu et al., 1994, 1996; Deriu et al., 1999) and in humans (Hickenbottom et al., 1985; Deriu et al., 2000, 2003). Indeed, Deriu et al. (2003) described a new short-latency, short-duration vestibulo-masseteric reflex (p11/n15 wave) induced in active masseters by transmastoid electrical activation of vestibular afferent fibres. Thus, the question arise as to whether sound also can activate similar vestibular inputs to jaw muscles. 2. Masseter responses to vestibular stimulation There are many investigations into the vestibular interactions with muscles controlling the neck and eye. However, it seems pos-
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sible that motoneurones innervating the masseter muscles might also be a possible target of vestibular inputs since these muscles, in addition to their role in mastication, phonation, respiration and swallowing, are also involved in maintaining the posture of the jaw against gravity (Lund and Olsson, 1983; Miralles et al., 1987). To date this question has only been addressed by the work of Hickenbottom et al. (1985) on the functional relationship between the vestibular and the motor trigeminal systems, and by the reports from Tolu and colleagues in experimental animals (Tolu and Pugliatti, 1993; Tolu et al., 1994, 1996; Deriu et al., 1999). 2.1. Vestibulo-trigeminal responses in animals In anaesthetized guinea pigs Tolu et al. (Tolu and Pugliatti, 1993; Tolu et al., 1994) showed that the activity of trigeminal motoneurones could be affected by stimulation or lesioning of vestibular receptors. The spontaneous firing of single masseter motor units increased tonically during caloric ampullar stimulation whilst it was modulated asymmetrically with otolith stimulation, with excitation during contralateral tilt and inhibition during ipsilateral tilt. Responses of identified masseter and digastric motoneurones to electrical stimulation of ampullar receptors revealed a bilateral excitatory action on these antagonist muscles (Tolu et al., 1996). They were coactivated by vestibular stimulation, but masseter responses occurred slightly earlier than digastric responses. Furthermore, ipsilateral responses in both muscles occurred later than contralateral responses (Deriu et al., 1999). The data allowed the authors to conclude that trigeminal motoneurones are tonically and bilaterally excited by ampullar receptor activation and that macular inputs exert a bilateral asymmetrical control on jaw muscles, in relation to head displacements in space. The latency and duration of the vestibular-induced trigeminal responses suggested that they were due to activity in polysynaptic pathways from vestibular receptors to the motor trigeminal nuclei, with the contralateral pathway being more powerful and shorter than the ipsilateral pathway. This hypothesis was confirmed later by a neuroanatomical study using a transsynaptic retrograde tracer, the pseudorabies virus Bartha (Card et al., 1992; Aston-Jones and Card, 2000). This study showed that neurones in the caudal portion of the parvicellular division of the medial vestibular nuclei, in the caudal part of the spinal vestibular nucleus and in the ventromedial portion of the caudal part of the prepositus hypoglossi nucleus project bilaterally to populations of motoneurones innervating the lower third of the superficial layer of the masseter muscle of rats (Giaconi et al., 2006). Several pathways could have been involved in this connection with potential relays in the pontomedullary reticular formation, the intertrigeminal nucleus, the supratrigeminal nucleus, the peritrigeminal zone and the premotor zone included in the trigeminal sensory complex. Although a di- or monosynaptic vestibulo-masseteric pathway could not be excluded, this study provided, for the first time, support for the postulated bilateral polysynaptic vestibulo-trigeminal pathways that had been inferred from physiological data obtained in animal experiments. An outline of the anatomical pathways surrounding the vestibulo-trigeminal multisynaptic connections is shown in Fig. 1. 2.2. Vestibulo-trigeminal responses in humans There have been very few studies into the vestibular action on human jaw muscles. Hickenbottom et al. (1985) studied the effects on the monosynaptic jaw jerk and provided quantitative evidence that the dynamic input from vestibular ampullar receptors caused by whole-body rotation enhances masseteric motoneurone output. Other authors studied the effect of static tilt on active masseters as well as on the exteroceptive masseter silent period and
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Multisynaptic vestibulo-trigeminal pathway
peritrigeminal zone supratrigeminal nucleus
PONS
trigeminal complex
trigeminal motor nucleus intertrigeminal nucleus
V nerve
principal trigeminal nucleus spinal trigeminal nucleus
MEDULLA
superior vestibular nucleus lateral vestibular nucleus
vestibular complex
VIII nerve
spinal vestibular nucleus medial vestibular nucleus prepositus hypoglossi nucleus
pontomedullary reticular formation
Fig. 1. Schematic representation of vestibulo-trigeminal multisynaptic pathways. For simplicity, only ipsilateral connections are outlined in the diagram. Nervous structures represented in white are relay stations mediating multisynaptic vestibulo-trigeminal connections. Arrows with broken lines represent vestibular inputs to them. The broken vertical line represents the midline.
demonstrated a bilateral and asymmetrical control from macular inputs in these muscles (Deriu et al., 2000). Both these studies confirmed that the bilateral, excitatory asymmetric vestibulo-trigeminal relationship described in the animal model, also operates in humans. More recently a new vestibulo-masseteric reflex (VMR), with properties different from the responses reported above, has been described in healthy humans (Deriu et al., 2003). This was evoked with transmastoid electrical vestibular stimulation (EVS) which has been reported to act upon the most distal part of the vestibular nerve: cathodal stimulation increases and anodal stimulation decreases the resting discharge rate of primary afferent fibres (Goldberg et al., 1984; Courjon et al., 1987; Baird et al., 1988; Nissim et al., 1994). Studies on humans support an action at the same site (Watson and Colebacth, 1997, 1998b; Watson et al., 1998). In active masseter muscles, responses to unilateral or bilateral EVS consisted of a positive–negative biphasic potential (p11/n15 wave) following cathodal stimulation and of a wave of opposite polarity (n11/p15) following anodal stimulation. The inhibitory nature of the p11/n15 response was clarified by single motor unit studies (Deriu et al., 2003, 2005). The VMR is very similar in onset and peak latencies, as well as in its inhibitory nature, to the EVS-induced vestibulo-collic reflex described by Watson and Colebacth (1998a) in active sternocleidomastoid muscles. Like the vestibulo-collic reflex, the magnitude of the VMR is linearly related to current intensity and scales with the mean level of EMG activity (Deriu et al., 2003). Some differences related to the recording-stimulation side (cathodal responses in masseter are positive–negative on both sides, while in sternocleidomastoids they are positive–negative ipsilaterally and negative–positive contralaterally) were suggested to relate to the different functional role played by these muscles: sternocleidomastoid muscles working as antagonists in head rotation, while masseters operate together on the mandible. The short-duration p11/n15 cathodal response was thought to be produced by synaptic activation of an inhibitory projection to
masseter motoneurones by a sudden discharge in the vestibular nerve. Given its short onset latency (7.2–8.8 ms) and the abrupt onset of inhibition of single motor unit firing (Deriu et al., 2003), it was suggested that this bilateral vestibulo-trigeminal pathway involved no more than three synaptic relays. This hypothesis has recently received anatomical support from a double labelling study performed in rats, where a combination of anterograde and retrograde monosynaptic tracers was used (Cuccurazzu et al., 2007). Vestibular terminals were found to make contact with masseter motoneurones in the ipsilateral and contralateral trigeminal motor nucleus, demonstrating the existence of a crossed monosynaptic pathway that links the dorsomedial part of the parvicellular division of the medial vestibular nucleus and the ventromedial part of the prepositus hypoglossi nucleus to motoneurones innervating the masseter muscle (Fig. 2). It must be recalled that these anatomical data were obtained in rats, and must be applied to humans with due caution, until further data are available from localised lesions in clinical studies. 2.3. Vestibular control over masseter muscles Interestingly, the anatomical studies above noted that both the multisynaptic (Giaconi et al., 2006) and the monosynaptic (Cuccurazzu et al., 2007) vestibulo-trigeminal pathways only terminated on motoneurones innervating the lower third of the superficial layer of the masseter muscle. Why this is the case is unclear. However, the masseter muscle is multipennate (Eriksson, 1982; Eriksson and Thornell, 1983; Stålberg et al., 1986) with a complex organisation that has been investigated in several species, like the rabbit (Weijs, 1996; Widmer et al., 1997; Westberg et al., 1998), pig (Herring et al., 1979) and human (Godaux and Desmedt, 1975; Stålberg et al., 1986; Widmer and Lund, 1989). In all cases, the muscle consists of multiple anatomical partitions that each produce different mechanical actions (Herring et al., 1979; Widmer et al., 2003). Moreover, the muscle fibres associated with each masseter motor unit are limited to a relatively small region of
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Monosynaptic vestibulo-trigeminal pathway
trigeminal motor nucleus
PONS
V nerve superior vestibular nucleus
MEDULLA
lateral vestibular nucleus
vestibular complex
VIII nerve
spinal vestibular nucleus medial vestibular nucleus prepositus hypoglossi nucleus
Fig. 2. Schematic representation of vestibulo-trigeminal monosynaptic pathways. The direct and crossed vestibulo-trigeminal connections are reported in the anatomical diagram. The broken vertical line represents the midline.
the muscle, such that each masseter motoneurone provides innervation to a restricted territory (Weijs et al., 1993). In humans the masseter compartment receiving the heaviest motor innervation is the lower third of the superficial layer of the muscle (Godaux and Desmedt, 1975; Widmer and Lund, 1989; Widmer et al., 1997). This is also the region from which the largest vestibular-induced EMG responses were recorded with surface EMG (Deriu et al., 2003). However, further experiments will be required to determine whether there is a functional topography in vestibular influences on the compartments of the human masseter muscle. At first sight, the recent results obtained in humans with electrical vestibular stimulation (Deriu et al., 2003) appear to contradict previous data obtained from animal (Tolu and Pugliatti, 1993; Tolu et al., 1994, 1996; Deriu et al., 1999) and human experiments (Hickenbottom et al., 1985; Deriu et al., 2000). The latter showed a bilateral vestibulo-trigeminal response which is late, prolonged, asymmetric and excitatory whereas the VMR is short-latency, short-duration, symmetrical and predominantly inhibitory. However, it may be that the two sets of physiological responses are mediated by different portions of the multisynaptic and monosynaptic anatomical connections. Perhaps the VMR represents activity in the monosynaptic pathway whereas the asymmetric excitatory responses are due to activity in the longer multisynaptic pathway. 2.4. Summarizing functional remarks Taken all together, physiological and anatomical data indicate that there are two sets of functional connections between the vestibular system and the masseter motoneurones: a short latency pathway, preferentially activated by phasic inputs and indirect pathways that operate in a tonic fashion. Such a situation is not unique. For example, mastoid electric vestibular stimulation evokes two sets of responses in leg and arm muscles (Britton et al., 1993; Fitzpatrick et al., 1994; Watson and Colebacth, 1997): a short-latency, short-duration response followed by a longer lasting response of opposite polarity. The latter sustained effect is more powerful and is responsible for the postural sway that mastoid
electric vestibular stimulation evokes in standing subjects. We speculate that the same type of functional organisation may occur in masseter. The short latency pathway, activated by phasic inputs, may be of minor importance in postural control, but it may be more important in fine-tuning voluntary motor output by allowing vestibular inputs rapid access to jaw muscle control. The second sustained, and more powerful control, activated by tonic inputs may be of importance in postural control of masseters by stabilizing the jaw during head movements in space. 3. Masseter responses to acoustic stimulation Responses to loud sounds were first recorded in the average surface EMG of voluntarily contracted masseter muscles using acoustic click stimuli (Deriu et al., 2005). Unilateral stimulation evokes a bilateral and symmetrical short-latency response that consists of two overlapping components distinguished by their threshold, latency and by their appearance in the rectified EMG, as summarized in Table 1. Responses to bilateral stimulation are similar, but larger. The lower threshold response is a p16 wave in the averaged unrectified EMG, where it is clearly visible only when the click
Table 1 Physiological features of the p11 wave and of the p16 wave induced in averaged unrectified masseter EMG by bilateral click stimulation. Sound-induced masseter EMG waves
p11
p16
Threshold (intensity of click stimuli) Onset latency
High (>85–90 dB NHL)
Low
8.4 ± 0.5 ms (no significant side differences) 11.9 ± 0.8 ms Usually not (sometimes small upward peak)
12 ± 1.2 ms (no significant side differences) 16.6 ± 1.2 ms Always (downward deflection: latency: 11–14 ms, duration 10–12 ms, peak 16–20 ms) Inhibitory
Peak latency Appearance in the rectified mean EMG Nature
Inhibitory
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Right Masseter Muscle n21
Left Masseter Muscle n21
100 dB NHL
Bilateral Clicks
p11
p11
140 µV
147 µV
n21 n21
Right Clicks
p11
p11
85 µV
94 µV n21 n21
50 µV
Left Clicks
10 ms
p11
p11
122 µV
120 µV
70 dB NHL n21 n21
50 µV
Biateral Clicks
p16
128 µV
p16
10 ms
136 µV
Fig. 3. Responses induced by click stimulation in averaged EMG recorded from surface electrodes over the left and right masseter muscles in a subject. Simultaneous averages of unrectified and rectified EMGs are reported. Responses to clicks of intensity suprathreshold (100 dB NHL) and subthreshold (70 dB NHL) for vestibular receptor activation are shown in the upper and lower panel, respectively. Every set of averages (each of 300 trials) was obtained with the same click duration (0.1 ms) and frequency (3 Hz) and during a tonic activation of masseters at 50% of maximal voluntary contraction. In all traces arrows indicate the time of stimulus application. Horizontal calibration at the bottom of the figure refers to all unrectified and rectified traces (500 runs per average). Peak size of waves in the unrectified EMG is indicated by vertical calibration on the right side of the last unrectified EMG trace in each panel. The values below the rectified EMG average indicate the background level of EMG prestimulus activity. (Modified from Deriu et al., 2007).
intensity is lower than 80–90 dB NHL. In contrast, it appears in the rectified EMG at all stimulation intensities, as a bilateral decrease (Fig. 3), whose latency and time course are very similar to the acoustic jaw reflex (Meier-Ewert et al., 1974). The higher threshold response is an earlier p11 wave in the unrectified EMG which is sometimes visible in the rectified mean EMG as an initial short period of excitation prior to the longer lasting suppression. The initial p11 wave is sometimes followed by a small n15 wave and by a later variable n21 wave. However, the n15 wave is often just a deflection in a simple biphasic p11/n21 wave (Fig. 3). Short-latency responses are often followed by later potentials (n28, p34, n44), which have not been investigated in detail. They correspond in
time to the later inhibitory responses described by Meier-Ewert et al. (1974) and which were thought to be part of the central startle pattern. Studies of the effect of click stimuli on the firing pattern of single motor units have shown that both of these responses are inhibitory. Clicks of 80 dB intensity (below the threshold for the p11 wave) suppress the firing of motor unit for 3–8 ms with an onset latency of 14–17 ms. Increasing the intensity to 100 dB recruits an earlier suppression at 10–13 ms with a deeper and longer lasting (8–12 ms) effect than at lower intensities (Fig. 4A). This would be consistent with the idea that at high click intensities an additional early ‘‘vestibular” response merges with a late ‘‘cochlear”
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A. Click Stimulation at 100 dB vs Click Stimulation at 80 dB SMU 3: Right Masseter
Bilateral Clicks 100 dB
Counts/bin
30 20 10 0 -50
-25
0
25 ms
50
75
100
-50
-25
0
25 ms
50
75
100
Bilateral Clicks 80 dB
Counts/bin
30 20 10 0
B. Electrical Vestibular Stimulation vs Click Stimulation at 100 dB SMU 1: Left Masseter
Right EVS 5 mA
Counts/bin
20
10
0 -50
-25
0
25
50
75
100
50
75
100
ms
Right Clicks 100 dB
Counts/bin
20
10
0 -50
-25
0
25 ms
Fig. 4. The same masseter single motor unit showed an inhibitory period of different latency and duration depending on intensity and on type of stimuli (sound or electrical) used to activate the vestibular system. (A) Effects induced on the same SMU by clicks of intensity suprathreshold (100 dB NHL) and subthreshold (80 dB NHL) for vestibular activation are shown. PSTHs report the response of a SMU recorded from the right masseter muscle to 800 consecutive bilateral click stimuli. Silent period in SMU firing induced by 100 dB clicks, occurred at a latency shorter and lasted longer than that induced by click stimulation at 80 dB. (B) PSTHs report the response of a SMU recorded from the left masseter to 800 consecutive cathodal stimuli (5 mA, 2 ms, 3 Hz) applied to the contralateral mastoid process and to 800 consecutive click stimuli (100 dB, 0.1 ms, 3 Hz) applied to the contralateral ear are reported. SMU inhibition, induced by click stimulation, occurred at the same latency but lasted longer than that induced by cathodal EVS. Stimuli were given at the time zero indicated by arrows. Bin duration = 1 ms. (Modified from Deriu et al., 2005).
response that can be evoked by low intensity stimulation (Deriu et al., 2005). Figs. 4B and 5 compare the effects of low and high intensity clicks with transmastoid EVS, which is known to activate the vestibular nerve directly (Goldberg et al., 1984; Watson and Colebacth, 1997, 1998a; Watson et al., 1998). They show that sound elicits in active masseter muscles two different reflex responses, which partially overlap in the unrectified mean EMG (Fig. 5) but merge into a continuous suppression of single motor unit activity (Fig. 4B). The earlier high-threshold response evoked by loud clicks has the same latency and form as the p11/n15 VMR evoked by trans-
mastoid EVS (Deriu et al., 2003). It scales with background EMG level, is larger at higher stimulus intensity and following bilateral stimuli, is modulated asymmetrically by static tilt of the body and corresponds to an inhibitory period in single motor unit discharge rate. In addition, like the EVS-induced VMR, the p11 wave induced by loud clicks does not appear in the rectified mean EMG, although it is sometimes visible as a small upward deflection (Fig. 5). Interestingly, single motor unit studies (Fig. 4B) showed that the duration of inhibition evoked by EVS (2–3 ms) was shorter than that evoked by high intensity clicks (5–7 ms). This was interpreted as due to the fact that clicks cause a later, lower threshold
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Electrical Vestibular Stimulation vs Click Stimulation n15
25 µV
Bilateral EVS (5 mA) p11 150 µV 20 ms 0
n21
two sternocleidomastoid muscles working as antagonists in head rotation, while the masseters work together to set the appropriate position of the mandible. Another notable difference between effects induced by loud clicks in masseters and in sternocleidomastoids is in the magnitude of responses to the same stimulus. A comparison between corrected amplitudes (normalised to the mean level of ongoing rectified EMG) of the masseter p11 wave and of the sternocleidomastoid p13 wave induced by 100 dB ipsilateral clicks, showed that the latter response was 30% larger than the former. This indicates that the strength of the vestibular projection to sternocleidomastoid muscles is more powerful than its projection to masseters and is compatible with the predominant role played by neck muscles in postural control compared to that played by jaw-closing muscles. 3.1. Origin of masseter reflex responses to sound
25 µV
Bilateral Clicks 100 dB 150
p11
µV 20 ms 0
25 µV
Bilateral Clicks 80 dB
p16 150
The best evidence for the vestibular origin of the p11/n15 and the cochlear origin of the p16/n21 comes from studies on patients with selective lesions. Patients with cochlear lesions and deafness had clear p11/n15 responses but little or no p16/n21 response whereas a patient with a selective vestibular lesion and normal hearing had no p11/n15, but a preserved p16/n21 (Deriu et al., 2007). Faithful transmission of sound stimuli to the inner ear is required to produce both masseter responses since they were absent in a subject with conductive hearing loss due to pathology of the middle ear. Thus, they cannot be due to stimulation of receptors in the ear drum or canal. Interestingly, the negative n15 wave of the vestibular component is usually unclear or absent in healthy people following loud clicks, because it overlaps with the concurrent p16 wave, induced by cochlear stimulation. However, since the p16 is absent in subjects with cochlear deafness, their n15 wave is much clearer than in healthy subjects. Indeed, their p11/n15 response to clicks is very similar to the response evoked by electrical vestibular stimulation (Deriu et al., 2003).
µV 20 ms
3.2. EMG features of the vestibulo-masseteric reflex
0
Fig. 5. Reflex responses induced in active masseter surface EMG by transmastoid electrical vestibular stimulation and by click stimulation. A selection of averaged (500 runs per average) unrectified and rectified EMGs recorded simultaneously from the left masseter muscle of a representative subject is reported. Masseter response to bilateral electrical vestibular stimulation (EVS: 5 mA, 2 ms, 3 Hz, cathode on the left mastoid) in the unrectified EMG consisted of a p11/n15 wave which was not detectable in the rectified EMG. Response to 100 dB clicks, activating both vestibular and cochlear receptors, begins with a p11 wave with onset and amplitude similar to that induced by EVS, but differs from the VMR as for the absence of the n15 wave in the unrectified EMG and for a clear decrease in mean rectified EMG level. This silent period in the rectified EMG exhibited a time course different from those of p11/n15 potentials but similar to the p16 response visible in the unrectified EMG when clicks of a subthreshold intensity (80 dB) for the p11 wave were delivered. (Modified from Deriu et al., 2005).
The single motor unit studies confirmed that the VMR elicited by EVS (Deriu et al., 2003) or by high intensity sound (Deriu et al., 2005, 2007) is inhibitory, making it similar to the vestibulo-collic reflex (Watson and Colebacth, 1998a; Colebatch et al., 1994) and the trigemino-collic reflex evoked by stimulation of the infraorbital nerve (Di Lazzaro et al., 1995). All these reflexes have rather unusual characteristics: they are visible as a biphasic potential in averaged unrectified EMG but do not appear in the average rectified EMG. The reason for this was originally explored by Colebatch and Rothwell (1993, 2004) and more recently by Colebatch (2009) using the vestibular-evoked potential as a model.
acoustic reflex that prolongs the single unit inhibition beyond that seen after transmastoid electrical vestibular stimulation. The p11/n15 response to clicks is also similar to the vestibulocollic reflex (also known as vestibular evoked myogenic potential, VEMPs) induced in sternocleidomastoid muscles by same stimuli (Colebatch et al., 1994). Both have the same high threshold (90– 100 dB NHL), both correspond to a period of inhibition in single unit activity (Colebatch and Rothwell, 1993, 2004) and both scale in amplitude with the background level of tonic EMG activity. It should be noted that although the masseter p11/n15 wave is bilateral and symmetric following unilateral stimulation, the VEMP is predominantly ipsilateral (Colebatch et al., 1994). This is likely due to the different functional role played by these muscles, the
(i) The unrectified EMG is a complex signal formed of many partially overlapping positive/negative action potentials. The average of a set of unrectified traces is flat since on average all the positive phases of the potentials are balanced by the negative phase (see Fig. 6). Imagine now that motor unit inhibition occurs at the same time ‘‘t” in every sweep, and that the inhibition only lasts for a short period of time, as in all the reflexes described above. Thus, while action potentials occur at random times over most of each sweep, no action potentials ever begin over this time ‘‘t” in every sweep. The fact that these action potentials are missing, means that there is no cancellation of the positive tails of action potentials that start before time ‘‘t”. Similarly, there is nothing to cancel the negative peaks of action potentials
F. Deriu et al. / Clinical Neurophysiology 121 (2010) 1690–1699
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t
Sweep 1
Sweep 2
Average
Fig. 6. Single motor unit inhibition and surface unrectified EMG average. The middle two traces are separate single sweeps (sweep 1 and sweep 2) of unrectified surface EMG activity. They show the discharge of a number of identical motor units. Imagine that no units can ever fire for time ‘‘t” delineated by the two vertical lines. When the average is made of the two sweeps, there is a probability that the upgoing phases of the discharge of a unit in one sweep will be cancelled out by the downgoing phases of another unit in the second sweep (and vice versa). Some examples of this are outlined by the shaded boxes. However, the downgoing phases of units that start just before the period of inhibition, and the upgoing phases of units that start just after the end of the period of inhibition (like units outlined in bold in sweep 1), can never be cancelled out because no units ever start to discharge over time ‘‘t”. What will remain, after averaging a much larger number of sweeps than illustrated, is that most of the grand average will be flat apart from a downgoing/upgoing potential that starts at the time of motor unit inhibition (like the thick unit illustrated in the average). This potential is effectively the inverse of all the motor unit activity that would have appeared in time ‘‘t” (see top trace). (By courtesy of Prof. John C. Rothwell.)
that start just after time ‘‘t”. There is thus a ‘‘failure of cancellation” because action potentials are always missing at the same time in every sweep. Effectively what is seen in the average unrectified EMG (Fig. 3) is a ‘‘missing action potential” that has the opposite polarity (positive–negative) to the normal motor unit potential (M wave, negative– positive). (ii) In the rectified EMG average there is no sign of inhibition. Going back to the model (Fig. 6), we can see that although no motor units begin to fire during time ‘‘t”, there is still activity in that period, due to the tails of motor units that begin to discharge before time ‘‘t”. As we have seen, because no motor units start to fire during time ‘‘t”, these tails are not cancelled out by the upgoing peaks in other sweeps of the average, and hence they ‘‘fill” in activity during time ‘‘t” in the rectified average. Inhibition in the average rectified EMG only becomes evident when the duration of motor unit inhibition exceeds approximately half the duration of a motor unit action potential. When the period of inhibition is shorter than half the duration of the action potentials, there is no sign of any response in the rectified average, although the failure of cancellation produces a clear positive–negative potential in the unrectified average. As the period of inhibition is lengthened, the lack of activity becomes evident in the rectified average. So, the reason why the short period of unit inhibition (2–3 ms), corresponding to the p11/n15 wave in the unrectified EMG, gives no obvious deflections in the rectified EMG average is because the period of inhibition ‘‘t” is much shorter than the duration of a typical action potential in the surface EMG. However, as noted by Widmer and Lund (1989), a sudden onset of motor unit inhibition can sometimes lead to a paradoxical early increase in rectified EMG activity arising
from failure of cancellation of the tails of unit action potentials that had begun to discharge before the inhibition began. Indeed, very short periods of inhibition, such as the VEMP and the VMR, may appear as an increase of the rectified average (see Colebatch (2009) for a complete formulation of this argument). 3.3. Possible functional consequences of sound-induced vestibular and cochlear masseter reflexes At this stage there is no definitive conclusion as to the role of the reflexes we describe here. Both produce EMG inhibition at approximately the same latency. A local protective function was attributed to the acoustic jaw reflex by Meier-Ewert et al. (1974). Indeed, the fact that it is inhibitory may allow it to play a role in preventing the subject biting his/her tongue and/or cheek when startled. The brief vestibular inhibition preceding the cochlear inhibition may have some role in adjusting or prepare masseter muscle tone to sustain the acoustic response following immediately after.
4. Possible role for the vestibulo-masseteric reflex pathways in trigeminal motor control In addition to mastication, the masseter muscle is involved in speech, swallowing, respiration and maintenance of the position of the mandible, by bringing it back to its physiological axis. Each of these functions require jaw muscles to perform motor tasks that differ in force produced, as well as rapidity, shape and precision of mouth movements. Furthermore, they are often required to perform these multiple and very different actions simultaneously, so that we are able, for instance to speak and laugh while chewing. To be able to achieve its many complex functions jaw muscle
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motor command is modulated by volition and by peripheral afferent feedback. So what role could there be for vestibular inputs? One possibility is that they may play a role in the adjustment of masticatory muscle tone during angular acceleration of the head in spatial planes, and also in postural adjustment of the mandible during changes in head position with respect to the gravity, such as when chewing with the head tilted or during extreme laterotrusion and protrusion/retrusion of the jaw (Goto et al., 2001). It seems plausible that this ‘‘postural” function is a prerogative for the multisynaptic, asymmetric, tonic, excitatory vestibular projection, which may control masseter muscle tone the same way as it does with all the other antigravity muscles of the body. The role of the monosynaptic, symmetric, phasic, inhibitory vestibulo-masseteric projection is more difficult to understand. One possibility is that it is involved in responding to sudden head tilt upwards or downwards. For instance, if the head is suddenly dropped, it may be of value to inhibit the masseters, and vice versa if the head is suddenly pitched upwards. However, the reflex appears to be weak, requiring the average of many trials to become evident (Deriu et al., 2003, 2005, 2007), so that whether the reflex does have a true functional relevance is unclear. A last perhaps unsatisfactory possibility is that the neural pathway is an evolutionary leftover that has no role in normal human activities.
5. Clinical prospects The study of the vestibulo-masseteric reflex and of the acoustic masseteric reflex in people with selective lesion of vestibular or cochlear receptors definitely demonstrated that these end organs originate the p11/n15 and the p16/n21 waves, respectively (Deriu et al., 2007). This study also shows that masseter responses to sound can be used as additional tools to test saccular and cochlear function in human otological investigations. However, it seems unlikely that these responses will replace the click-induced VEMPs which are commonly used in the clinical practice to study vestibular function. The advantage of the VEMPs, respect to the VMR is that they need a smaller number of trials to become evident (300 vs 500 sweeps) and are larger in magnitude (around 30% bigger). However, a possible application for the VMR is its assessment as an alternative to the SCM in patients who are unable to hold their neck up or who have had surgery to or congenital abnormalities of the SCM. The lack of normative data for latency, amplitudes and symmetry does limit this at present. In addition, if the clinical purpose is testing brainstem function, the investigation of masseter responses to sound, can be of some value. The partial knowledge available on the anatomical substrate for these reflexes is based on animal studies, so they cannot be applied to humans until anatomical–functional correlation studies, aided by neuroimaging, are done, similarly to those performed for trigeminal reflexes (Ongerboer de Visser et al., 1990; Cruccu et al., 2005). Nevertheless, both the vestibulo-masseteric and the acoustic masseteric reflex can be considered as new additional neurophysiological tools in the exploration of brainstem circuits in physiological as well as pathological conditions. Their evaluation may add useful information especially if it is combined with other neurophysiological methods already standardized in this field (Ref. in Aramideh and Ongerboer de Visser (2002)) and with neuroimaging data. Acknowledgements This work was supported by grants from the Ministero dell’Istruzione, dell’Università e della Ricerca (MIUR) and from Fondazione Italiana Sclerosi Multipla (FISM 2008/R/9). Dr. Elena Giaconi was supported by a grant from MIUR (PRIN).
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Clinical Neurophysiology journal homepage: www.elsevier.com/locate/clinph
Invited review
Reflex responses of masseter muscles to sound Franca Deriu a,*, Elena Giaconi a, John C. Rothwell b, Eusebio Tolu a a b
Department of Biomedical Sciences, University of Sassari, Sassari, Italy Sobell Department of Motor Neuroscience and Movement Disorders, Institute of Neurology, University College London, London, UK
a r t i c l e
i n f o
Article history: Accepted 9 November 2009 Available online 5 May 2010 Keywords: Vestibulo-masseteric reflex Acoustic masseteric reflex Acoustic stimulation Jaw muscles Brainstem Trigeminal motor system
a b s t r a c t Acoustic stimuli can evoke reflex EMG responses (acoustic jaw reflex) in the masseter muscle. Although these were previously ascribed to activation of cochlear receptors, high intensity sound can also activate vestibular receptors. Since anatomical and physiological studies, both in animals and humans, have shown that masseter muscles are a target for vestibular inputs we have recently reassessed the vestibular contribution to masseter reflexes. We found that high intensity sound evokes two bilateral and symmetrical short-latency responses in active unrectified masseter EMG of healthy subjects: a high threshold, early p11/n15 wave and a lower threshold, later p16/n21 wave. Both of these reflexes are inhibitory but differ in their threshold, latency and appearance in the rectified EMG average. Experiments in healthy subjects and in patients with selective lesions showed that vestibular receptors were responsible for the p11/n15 wave (vestibulo-masseteric reflex) whereas cochlear receptors were responsible for the p16/n21 wave (acoustic masseteric reflex). The possible functional significance of the double vestibular control over masseter muscles is discussed. Ó 2010 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved.
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Sound as a stimulus activating cochlear as well as vestibular receptors . . . . . . . . . . . . . . . . . . . . . . . . . 1.1. Reflex responses to sound in cranial muscles . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Masseter responses to vestibular stimulation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.1. Vestibulo-trigeminal responses in animals . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.2. Vestibulo-trigeminal responses in humans . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.3. Vestibular control over masseter muscles . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.4. Summarizing functional remarks . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Masseter responses to acoustic stimulation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.1. Origin of masseter reflex responses to sound . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.2. EMG features of the vestibulo-masseteric reflex. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.3. Possible functional consequences of sound-induced vestibular and cochlear masseter reflexes . Possible role for the vestibulo-masseteric reflex pathways in trigeminal motor control . . . . . . . . . . . . Clinical prospects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
1. Sound as a stimulus activating cochlear as well as vestibular receptors Although the primary receptor specialised for the detection of sound is the cochlea, it has been known for many years that sound * Corresponding author. Address: Department of Biomedical Sciences, University of Sassari, Section of Human Physiology and Bioengineering, Viale San Pietro 43/b, 07100 Sassari, Italy. Tel.: +39 079 22 82 94; fax: +39 079 22 81 56. E-mail address: [email protected] (F. Deriu).
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can also affect the vestibular system. For instance, in humans intense sound is well known to produce vestibular symptoms and illusions of movement (Parker et al., 1975). These probably arise from stimulation of otolith organs in the saccule since this is reported to be the most sensitive part of the vestibular system to sound (Young et al., 1977; Cazals et al., 1983; Mc Cue and Guinan, 1994; Murofushi et al., 1995, 1996; Murofushi and Curthoys, 1997). Indeed the saccular hair cells are activated by high intensity clicks in a way similar to natural linear acceleration (Uchino et al., 1997b; Ogawa et al., 2000).
1388-2457/$36.00 Ó 2010 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.clinph.2009.11.093
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Acoustic stimulation is now widely accepted as a simple, non-invasive and safe method to activate the otoliths (Clarke, 2001; Welgampola and Colebatch, 2005; Wuyts et al., 2007). However, investigations only began in this field in 1964 when Bickford and colleagues described a reflex response in posterior neck muscles that was induced by high intensity click stimulation. They referred to this as the inion response. It scaled with the level of muscle activation, consistent with a myogenic origin, and it was suggested to arise from activation of the vestibular apparatus rather than from the cochlea (Bickford et al., 1964; Cody et al., 1964). This conclusion was later supported by work of Cody and Bickford (1969) and Townsend and Cody (1971), but was disputed by others (Meier-Ewert et al., 1974). Because of this uncertainty the inion response never achieved acceptance as a useful test of vestibular reflex function (Douek, 1981). It was a further 20 years before Colebatch reinvestigated the reflex responses to high intensity sound in neck (Colebatch et al., 1994). These authors found that high intensity clicks (95–100 dB NHL) evoke a reflex response in active sternocleidomastoid muscles. This response consists of an early, short-latency, high-threshold ipsilateral p13/n23 potential and a late lower threshold, bilateral n34/ p44 response. The earlier response depended on vestibular afferent activation, while the later response depended on cochlear integrity (Colebatch and Halmagyi, 1992). The neurophysiological substrate for the short latency p13/n23 potential, i.e. the sacculo-collic reflex arc, was later described in animals by Uchino and colleagues (Uchino et al., 1997a; Kushiro et al., 1999) and additional methods of evoking vestibular-dependent reflexes in the same pathway have since been published (Halmagyi et al., 1995; Watson and Colebacth, 1998a, b). Studies of the effect of loud sound on the firing of single motor units in the SCM muscle have shown that the underlying effect is inhibitory (Colebatch and Rothwell, 1993, 2004). 1.1. Reflex responses to sound in cranial muscles There is a long history of reflex responses to sound in other cranial muscles (postauricular, frontalis, orbicular oris, orbicular oculi, mylohyoideus, temporalis and masseter muscles) and these were always attributed to activation of cochlear rather than vestibular afferents (Kiang, 1963; Meier-Ewert et al., 1974). In particular an acoustic jaw reflex was originally described by Meier-Ewert and colleagues (1974) in several cranial muscles, including the masseters. Here the reflex consisted of a dual bilateral inhibitory period (approximate latency 14 ms, duration 11 ms) visible in the submaximal interference pattern of the masseter EMG after unilateral stimulation with high intensity clicks or tones. The authors suggested that it might be a local protective reflex and proved that its afferent reflex arc was the acoustic nerve while a vestibular contribution was excluded. They also identified a non-consistent later silent period which was considered as a central part of the startle pattern. Although this work confirms that cochlear receptors provide strong input to cranial muscles, previous work had also shown that trigeminal motoneurones innervating jaw muscles are a target for vestibular inputs, both in animals (Tolu and Pugliatti, 1993; Tolu et al., 1994, 1996; Deriu et al., 1999) and in humans (Hickenbottom et al., 1985; Deriu et al., 2000, 2003). Indeed, Deriu et al. (2003) described a new short-latency, short-duration vestibulo-masseteric reflex (p11/n15 wave) induced in active masseters by transmastoid electrical activation of vestibular afferent fibres. Thus, the question arise as to whether sound also can activate similar vestibular inputs to jaw muscles. 2. Masseter responses to vestibular stimulation There are many investigations into the vestibular interactions with muscles controlling the neck and eye. However, it seems pos-
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sible that motoneurones innervating the masseter muscles might also be a possible target of vestibular inputs since these muscles, in addition to their role in mastication, phonation, respiration and swallowing, are also involved in maintaining the posture of the jaw against gravity (Lund and Olsson, 1983; Miralles et al., 1987). To date this question has only been addressed by the work of Hickenbottom et al. (1985) on the functional relationship between the vestibular and the motor trigeminal systems, and by the reports from Tolu and colleagues in experimental animals (Tolu and Pugliatti, 1993; Tolu et al., 1994, 1996; Deriu et al., 1999). 2.1. Vestibulo-trigeminal responses in animals In anaesthetized guinea pigs Tolu et al. (Tolu and Pugliatti, 1993; Tolu et al., 1994) showed that the activity of trigeminal motoneurones could be affected by stimulation or lesioning of vestibular receptors. The spontaneous firing of single masseter motor units increased tonically during caloric ampullar stimulation whilst it was modulated asymmetrically with otolith stimulation, with excitation during contralateral tilt and inhibition during ipsilateral tilt. Responses of identified masseter and digastric motoneurones to electrical stimulation of ampullar receptors revealed a bilateral excitatory action on these antagonist muscles (Tolu et al., 1996). They were coactivated by vestibular stimulation, but masseter responses occurred slightly earlier than digastric responses. Furthermore, ipsilateral responses in both muscles occurred later than contralateral responses (Deriu et al., 1999). The data allowed the authors to conclude that trigeminal motoneurones are tonically and bilaterally excited by ampullar receptor activation and that macular inputs exert a bilateral asymmetrical control on jaw muscles, in relation to head displacements in space. The latency and duration of the vestibular-induced trigeminal responses suggested that they were due to activity in polysynaptic pathways from vestibular receptors to the motor trigeminal nuclei, with the contralateral pathway being more powerful and shorter than the ipsilateral pathway. This hypothesis was confirmed later by a neuroanatomical study using a transsynaptic retrograde tracer, the pseudorabies virus Bartha (Card et al., 1992; Aston-Jones and Card, 2000). This study showed that neurones in the caudal portion of the parvicellular division of the medial vestibular nuclei, in the caudal part of the spinal vestibular nucleus and in the ventromedial portion of the caudal part of the prepositus hypoglossi nucleus project bilaterally to populations of motoneurones innervating the lower third of the superficial layer of the masseter muscle of rats (Giaconi et al., 2006). Several pathways could have been involved in this connection with potential relays in the pontomedullary reticular formation, the intertrigeminal nucleus, the supratrigeminal nucleus, the peritrigeminal zone and the premotor zone included in the trigeminal sensory complex. Although a di- or monosynaptic vestibulo-masseteric pathway could not be excluded, this study provided, for the first time, support for the postulated bilateral polysynaptic vestibulo-trigeminal pathways that had been inferred from physiological data obtained in animal experiments. An outline of the anatomical pathways surrounding the vestibulo-trigeminal multisynaptic connections is shown in Fig. 1. 2.2. Vestibulo-trigeminal responses in humans There have been very few studies into the vestibular action on human jaw muscles. Hickenbottom et al. (1985) studied the effects on the monosynaptic jaw jerk and provided quantitative evidence that the dynamic input from vestibular ampullar receptors caused by whole-body rotation enhances masseteric motoneurone output. Other authors studied the effect of static tilt on active masseters as well as on the exteroceptive masseter silent period and
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Multisynaptic vestibulo-trigeminal pathway
peritrigeminal zone supratrigeminal nucleus
PONS
trigeminal complex
trigeminal motor nucleus intertrigeminal nucleus
V nerve
principal trigeminal nucleus spinal trigeminal nucleus
MEDULLA
superior vestibular nucleus lateral vestibular nucleus
vestibular complex
VIII nerve
spinal vestibular nucleus medial vestibular nucleus prepositus hypoglossi nucleus
pontomedullary reticular formation
Fig. 1. Schematic representation of vestibulo-trigeminal multisynaptic pathways. For simplicity, only ipsilateral connections are outlined in the diagram. Nervous structures represented in white are relay stations mediating multisynaptic vestibulo-trigeminal connections. Arrows with broken lines represent vestibular inputs to them. The broken vertical line represents the midline.
demonstrated a bilateral and asymmetrical control from macular inputs in these muscles (Deriu et al., 2000). Both these studies confirmed that the bilateral, excitatory asymmetric vestibulo-trigeminal relationship described in the animal model, also operates in humans. More recently a new vestibulo-masseteric reflex (VMR), with properties different from the responses reported above, has been described in healthy humans (Deriu et al., 2003). This was evoked with transmastoid electrical vestibular stimulation (EVS) which has been reported to act upon the most distal part of the vestibular nerve: cathodal stimulation increases and anodal stimulation decreases the resting discharge rate of primary afferent fibres (Goldberg et al., 1984; Courjon et al., 1987; Baird et al., 1988; Nissim et al., 1994). Studies on humans support an action at the same site (Watson and Colebacth, 1997, 1998b; Watson et al., 1998). In active masseter muscles, responses to unilateral or bilateral EVS consisted of a positive–negative biphasic potential (p11/n15 wave) following cathodal stimulation and of a wave of opposite polarity (n11/p15) following anodal stimulation. The inhibitory nature of the p11/n15 response was clarified by single motor unit studies (Deriu et al., 2003, 2005). The VMR is very similar in onset and peak latencies, as well as in its inhibitory nature, to the EVS-induced vestibulo-collic reflex described by Watson and Colebacth (1998a) in active sternocleidomastoid muscles. Like the vestibulo-collic reflex, the magnitude of the VMR is linearly related to current intensity and scales with the mean level of EMG activity (Deriu et al., 2003). Some differences related to the recording-stimulation side (cathodal responses in masseter are positive–negative on both sides, while in sternocleidomastoids they are positive–negative ipsilaterally and negative–positive contralaterally) were suggested to relate to the different functional role played by these muscles: sternocleidomastoid muscles working as antagonists in head rotation, while masseters operate together on the mandible. The short-duration p11/n15 cathodal response was thought to be produced by synaptic activation of an inhibitory projection to
masseter motoneurones by a sudden discharge in the vestibular nerve. Given its short onset latency (7.2–8.8 ms) and the abrupt onset of inhibition of single motor unit firing (Deriu et al., 2003), it was suggested that this bilateral vestibulo-trigeminal pathway involved no more than three synaptic relays. This hypothesis has recently received anatomical support from a double labelling study performed in rats, where a combination of anterograde and retrograde monosynaptic tracers was used (Cuccurazzu et al., 2007). Vestibular terminals were found to make contact with masseter motoneurones in the ipsilateral and contralateral trigeminal motor nucleus, demonstrating the existence of a crossed monosynaptic pathway that links the dorsomedial part of the parvicellular division of the medial vestibular nucleus and the ventromedial part of the prepositus hypoglossi nucleus to motoneurones innervating the masseter muscle (Fig. 2). It must be recalled that these anatomical data were obtained in rats, and must be applied to humans with due caution, until further data are available from localised lesions in clinical studies. 2.3. Vestibular control over masseter muscles Interestingly, the anatomical studies above noted that both the multisynaptic (Giaconi et al., 2006) and the monosynaptic (Cuccurazzu et al., 2007) vestibulo-trigeminal pathways only terminated on motoneurones innervating the lower third of the superficial layer of the masseter muscle. Why this is the case is unclear. However, the masseter muscle is multipennate (Eriksson, 1982; Eriksson and Thornell, 1983; Stålberg et al., 1986) with a complex organisation that has been investigated in several species, like the rabbit (Weijs, 1996; Widmer et al., 1997; Westberg et al., 1998), pig (Herring et al., 1979) and human (Godaux and Desmedt, 1975; Stålberg et al., 1986; Widmer and Lund, 1989). In all cases, the muscle consists of multiple anatomical partitions that each produce different mechanical actions (Herring et al., 1979; Widmer et al., 2003). Moreover, the muscle fibres associated with each masseter motor unit are limited to a relatively small region of
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Monosynaptic vestibulo-trigeminal pathway
trigeminal motor nucleus
PONS
V nerve superior vestibular nucleus
MEDULLA
lateral vestibular nucleus
vestibular complex
VIII nerve
spinal vestibular nucleus medial vestibular nucleus prepositus hypoglossi nucleus
Fig. 2. Schematic representation of vestibulo-trigeminal monosynaptic pathways. The direct and crossed vestibulo-trigeminal connections are reported in the anatomical diagram. The broken vertical line represents the midline.
the muscle, such that each masseter motoneurone provides innervation to a restricted territory (Weijs et al., 1993). In humans the masseter compartment receiving the heaviest motor innervation is the lower third of the superficial layer of the muscle (Godaux and Desmedt, 1975; Widmer and Lund, 1989; Widmer et al., 1997). This is also the region from which the largest vestibular-induced EMG responses were recorded with surface EMG (Deriu et al., 2003). However, further experiments will be required to determine whether there is a functional topography in vestibular influences on the compartments of the human masseter muscle. At first sight, the recent results obtained in humans with electrical vestibular stimulation (Deriu et al., 2003) appear to contradict previous data obtained from animal (Tolu and Pugliatti, 1993; Tolu et al., 1994, 1996; Deriu et al., 1999) and human experiments (Hickenbottom et al., 1985; Deriu et al., 2000). The latter showed a bilateral vestibulo-trigeminal response which is late, prolonged, asymmetric and excitatory whereas the VMR is short-latency, short-duration, symmetrical and predominantly inhibitory. However, it may be that the two sets of physiological responses are mediated by different portions of the multisynaptic and monosynaptic anatomical connections. Perhaps the VMR represents activity in the monosynaptic pathway whereas the asymmetric excitatory responses are due to activity in the longer multisynaptic pathway. 2.4. Summarizing functional remarks Taken all together, physiological and anatomical data indicate that there are two sets of functional connections between the vestibular system and the masseter motoneurones: a short latency pathway, preferentially activated by phasic inputs and indirect pathways that operate in a tonic fashion. Such a situation is not unique. For example, mastoid electric vestibular stimulation evokes two sets of responses in leg and arm muscles (Britton et al., 1993; Fitzpatrick et al., 1994; Watson and Colebacth, 1997): a short-latency, short-duration response followed by a longer lasting response of opposite polarity. The latter sustained effect is more powerful and is responsible for the postural sway that mastoid
electric vestibular stimulation evokes in standing subjects. We speculate that the same type of functional organisation may occur in masseter. The short latency pathway, activated by phasic inputs, may be of minor importance in postural control, but it may be more important in fine-tuning voluntary motor output by allowing vestibular inputs rapid access to jaw muscle control. The second sustained, and more powerful control, activated by tonic inputs may be of importance in postural control of masseters by stabilizing the jaw during head movements in space. 3. Masseter responses to acoustic stimulation Responses to loud sounds were first recorded in the average surface EMG of voluntarily contracted masseter muscles using acoustic click stimuli (Deriu et al., 2005). Unilateral stimulation evokes a bilateral and symmetrical short-latency response that consists of two overlapping components distinguished by their threshold, latency and by their appearance in the rectified EMG, as summarized in Table 1. Responses to bilateral stimulation are similar, but larger. The lower threshold response is a p16 wave in the averaged unrectified EMG, where it is clearly visible only when the click
Table 1 Physiological features of the p11 wave and of the p16 wave induced in averaged unrectified masseter EMG by bilateral click stimulation. Sound-induced masseter EMG waves
p11
p16
Threshold (intensity of click stimuli) Onset latency
High (>85–90 dB NHL)
Low
8.4 ± 0.5 ms (no significant side differences) 11.9 ± 0.8 ms Usually not (sometimes small upward peak)
12 ± 1.2 ms (no significant side differences) 16.6 ± 1.2 ms Always (downward deflection: latency: 11–14 ms, duration 10–12 ms, peak 16–20 ms) Inhibitory
Peak latency Appearance in the rectified mean EMG Nature
Inhibitory
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Right Masseter Muscle n21
Left Masseter Muscle n21
100 dB NHL
Bilateral Clicks
p11
p11
140 µV
147 µV
n21 n21
Right Clicks
p11
p11
85 µV
94 µV n21 n21
50 µV
Left Clicks
10 ms
p11
p11
122 µV
120 µV
70 dB NHL n21 n21
50 µV
Biateral Clicks
p16
128 µV
p16
10 ms
136 µV
Fig. 3. Responses induced by click stimulation in averaged EMG recorded from surface electrodes over the left and right masseter muscles in a subject. Simultaneous averages of unrectified and rectified EMGs are reported. Responses to clicks of intensity suprathreshold (100 dB NHL) and subthreshold (70 dB NHL) for vestibular receptor activation are shown in the upper and lower panel, respectively. Every set of averages (each of 300 trials) was obtained with the same click duration (0.1 ms) and frequency (3 Hz) and during a tonic activation of masseters at 50% of maximal voluntary contraction. In all traces arrows indicate the time of stimulus application. Horizontal calibration at the bottom of the figure refers to all unrectified and rectified traces (500 runs per average). Peak size of waves in the unrectified EMG is indicated by vertical calibration on the right side of the last unrectified EMG trace in each panel. The values below the rectified EMG average indicate the background level of EMG prestimulus activity. (Modified from Deriu et al., 2007).
intensity is lower than 80–90 dB NHL. In contrast, it appears in the rectified EMG at all stimulation intensities, as a bilateral decrease (Fig. 3), whose latency and time course are very similar to the acoustic jaw reflex (Meier-Ewert et al., 1974). The higher threshold response is an earlier p11 wave in the unrectified EMG which is sometimes visible in the rectified mean EMG as an initial short period of excitation prior to the longer lasting suppression. The initial p11 wave is sometimes followed by a small n15 wave and by a later variable n21 wave. However, the n15 wave is often just a deflection in a simple biphasic p11/n21 wave (Fig. 3). Short-latency responses are often followed by later potentials (n28, p34, n44), which have not been investigated in detail. They correspond in
time to the later inhibitory responses described by Meier-Ewert et al. (1974) and which were thought to be part of the central startle pattern. Studies of the effect of click stimuli on the firing pattern of single motor units have shown that both of these responses are inhibitory. Clicks of 80 dB intensity (below the threshold for the p11 wave) suppress the firing of motor unit for 3–8 ms with an onset latency of 14–17 ms. Increasing the intensity to 100 dB recruits an earlier suppression at 10–13 ms with a deeper and longer lasting (8–12 ms) effect than at lower intensities (Fig. 4A). This would be consistent with the idea that at high click intensities an additional early ‘‘vestibular” response merges with a late ‘‘cochlear”
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A. Click Stimulation at 100 dB vs Click Stimulation at 80 dB SMU 3: Right Masseter
Bilateral Clicks 100 dB
Counts/bin
30 20 10 0 -50
-25
0
25 ms
50
75
100
-50
-25
0
25 ms
50
75
100
Bilateral Clicks 80 dB
Counts/bin
30 20 10 0
B. Electrical Vestibular Stimulation vs Click Stimulation at 100 dB SMU 1: Left Masseter
Right EVS 5 mA
Counts/bin
20
10
0 -50
-25
0
25
50
75
100
50
75
100
ms
Right Clicks 100 dB
Counts/bin
20
10
0 -50
-25
0
25 ms
Fig. 4. The same masseter single motor unit showed an inhibitory period of different latency and duration depending on intensity and on type of stimuli (sound or electrical) used to activate the vestibular system. (A) Effects induced on the same SMU by clicks of intensity suprathreshold (100 dB NHL) and subthreshold (80 dB NHL) for vestibular activation are shown. PSTHs report the response of a SMU recorded from the right masseter muscle to 800 consecutive bilateral click stimuli. Silent period in SMU firing induced by 100 dB clicks, occurred at a latency shorter and lasted longer than that induced by click stimulation at 80 dB. (B) PSTHs report the response of a SMU recorded from the left masseter to 800 consecutive cathodal stimuli (5 mA, 2 ms, 3 Hz) applied to the contralateral mastoid process and to 800 consecutive click stimuli (100 dB, 0.1 ms, 3 Hz) applied to the contralateral ear are reported. SMU inhibition, induced by click stimulation, occurred at the same latency but lasted longer than that induced by cathodal EVS. Stimuli were given at the time zero indicated by arrows. Bin duration = 1 ms. (Modified from Deriu et al., 2005).
response that can be evoked by low intensity stimulation (Deriu et al., 2005). Figs. 4B and 5 compare the effects of low and high intensity clicks with transmastoid EVS, which is known to activate the vestibular nerve directly (Goldberg et al., 1984; Watson and Colebacth, 1997, 1998a; Watson et al., 1998). They show that sound elicits in active masseter muscles two different reflex responses, which partially overlap in the unrectified mean EMG (Fig. 5) but merge into a continuous suppression of single motor unit activity (Fig. 4B). The earlier high-threshold response evoked by loud clicks has the same latency and form as the p11/n15 VMR evoked by trans-
mastoid EVS (Deriu et al., 2003). It scales with background EMG level, is larger at higher stimulus intensity and following bilateral stimuli, is modulated asymmetrically by static tilt of the body and corresponds to an inhibitory period in single motor unit discharge rate. In addition, like the EVS-induced VMR, the p11 wave induced by loud clicks does not appear in the rectified mean EMG, although it is sometimes visible as a small upward deflection (Fig. 5). Interestingly, single motor unit studies (Fig. 4B) showed that the duration of inhibition evoked by EVS (2–3 ms) was shorter than that evoked by high intensity clicks (5–7 ms). This was interpreted as due to the fact that clicks cause a later, lower threshold
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Electrical Vestibular Stimulation vs Click Stimulation n15
25 µV
Bilateral EVS (5 mA) p11 150 µV 20 ms 0
n21
two sternocleidomastoid muscles working as antagonists in head rotation, while the masseters work together to set the appropriate position of the mandible. Another notable difference between effects induced by loud clicks in masseters and in sternocleidomastoids is in the magnitude of responses to the same stimulus. A comparison between corrected amplitudes (normalised to the mean level of ongoing rectified EMG) of the masseter p11 wave and of the sternocleidomastoid p13 wave induced by 100 dB ipsilateral clicks, showed that the latter response was 30% larger than the former. This indicates that the strength of the vestibular projection to sternocleidomastoid muscles is more powerful than its projection to masseters and is compatible with the predominant role played by neck muscles in postural control compared to that played by jaw-closing muscles. 3.1. Origin of masseter reflex responses to sound
25 µV
Bilateral Clicks 100 dB 150
p11
µV 20 ms 0
25 µV
Bilateral Clicks 80 dB
p16 150
The best evidence for the vestibular origin of the p11/n15 and the cochlear origin of the p16/n21 comes from studies on patients with selective lesions. Patients with cochlear lesions and deafness had clear p11/n15 responses but little or no p16/n21 response whereas a patient with a selective vestibular lesion and normal hearing had no p11/n15, but a preserved p16/n21 (Deriu et al., 2007). Faithful transmission of sound stimuli to the inner ear is required to produce both masseter responses since they were absent in a subject with conductive hearing loss due to pathology of the middle ear. Thus, they cannot be due to stimulation of receptors in the ear drum or canal. Interestingly, the negative n15 wave of the vestibular component is usually unclear or absent in healthy people following loud clicks, because it overlaps with the concurrent p16 wave, induced by cochlear stimulation. However, since the p16 is absent in subjects with cochlear deafness, their n15 wave is much clearer than in healthy subjects. Indeed, their p11/n15 response to clicks is very similar to the response evoked by electrical vestibular stimulation (Deriu et al., 2003).
µV 20 ms
3.2. EMG features of the vestibulo-masseteric reflex
0
Fig. 5. Reflex responses induced in active masseter surface EMG by transmastoid electrical vestibular stimulation and by click stimulation. A selection of averaged (500 runs per average) unrectified and rectified EMGs recorded simultaneously from the left masseter muscle of a representative subject is reported. Masseter response to bilateral electrical vestibular stimulation (EVS: 5 mA, 2 ms, 3 Hz, cathode on the left mastoid) in the unrectified EMG consisted of a p11/n15 wave which was not detectable in the rectified EMG. Response to 100 dB clicks, activating both vestibular and cochlear receptors, begins with a p11 wave with onset and amplitude similar to that induced by EVS, but differs from the VMR as for the absence of the n15 wave in the unrectified EMG and for a clear decrease in mean rectified EMG level. This silent period in the rectified EMG exhibited a time course different from those of p11/n15 potentials but similar to the p16 response visible in the unrectified EMG when clicks of a subthreshold intensity (80 dB) for the p11 wave were delivered. (Modified from Deriu et al., 2005).
The single motor unit studies confirmed that the VMR elicited by EVS (Deriu et al., 2003) or by high intensity sound (Deriu et al., 2005, 2007) is inhibitory, making it similar to the vestibulo-collic reflex (Watson and Colebacth, 1998a; Colebatch et al., 1994) and the trigemino-collic reflex evoked by stimulation of the infraorbital nerve (Di Lazzaro et al., 1995). All these reflexes have rather unusual characteristics: they are visible as a biphasic potential in averaged unrectified EMG but do not appear in the average rectified EMG. The reason for this was originally explored by Colebatch and Rothwell (1993, 2004) and more recently by Colebatch (2009) using the vestibular-evoked potential as a model.
acoustic reflex that prolongs the single unit inhibition beyond that seen after transmastoid electrical vestibular stimulation. The p11/n15 response to clicks is also similar to the vestibulocollic reflex (also known as vestibular evoked myogenic potential, VEMPs) induced in sternocleidomastoid muscles by same stimuli (Colebatch et al., 1994). Both have the same high threshold (90– 100 dB NHL), both correspond to a period of inhibition in single unit activity (Colebatch and Rothwell, 1993, 2004) and both scale in amplitude with the background level of tonic EMG activity. It should be noted that although the masseter p11/n15 wave is bilateral and symmetric following unilateral stimulation, the VEMP is predominantly ipsilateral (Colebatch et al., 1994). This is likely due to the different functional role played by these muscles, the
(i) The unrectified EMG is a complex signal formed of many partially overlapping positive/negative action potentials. The average of a set of unrectified traces is flat since on average all the positive phases of the potentials are balanced by the negative phase (see Fig. 6). Imagine now that motor unit inhibition occurs at the same time ‘‘t” in every sweep, and that the inhibition only lasts for a short period of time, as in all the reflexes described above. Thus, while action potentials occur at random times over most of each sweep, no action potentials ever begin over this time ‘‘t” in every sweep. The fact that these action potentials are missing, means that there is no cancellation of the positive tails of action potentials that start before time ‘‘t”. Similarly, there is nothing to cancel the negative peaks of action potentials
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t
Sweep 1
Sweep 2
Average
Fig. 6. Single motor unit inhibition and surface unrectified EMG average. The middle two traces are separate single sweeps (sweep 1 and sweep 2) of unrectified surface EMG activity. They show the discharge of a number of identical motor units. Imagine that no units can ever fire for time ‘‘t” delineated by the two vertical lines. When the average is made of the two sweeps, there is a probability that the upgoing phases of the discharge of a unit in one sweep will be cancelled out by the downgoing phases of another unit in the second sweep (and vice versa). Some examples of this are outlined by the shaded boxes. However, the downgoing phases of units that start just before the period of inhibition, and the upgoing phases of units that start just after the end of the period of inhibition (like units outlined in bold in sweep 1), can never be cancelled out because no units ever start to discharge over time ‘‘t”. What will remain, after averaging a much larger number of sweeps than illustrated, is that most of the grand average will be flat apart from a downgoing/upgoing potential that starts at the time of motor unit inhibition (like the thick unit illustrated in the average). This potential is effectively the inverse of all the motor unit activity that would have appeared in time ‘‘t” (see top trace). (By courtesy of Prof. John C. Rothwell.)
that start just after time ‘‘t”. There is thus a ‘‘failure of cancellation” because action potentials are always missing at the same time in every sweep. Effectively what is seen in the average unrectified EMG (Fig. 3) is a ‘‘missing action potential” that has the opposite polarity (positive–negative) to the normal motor unit potential (M wave, negative– positive). (ii) In the rectified EMG average there is no sign of inhibition. Going back to the model (Fig. 6), we can see that although no motor units begin to fire during time ‘‘t”, there is still activity in that period, due to the tails of motor units that begin to discharge before time ‘‘t”. As we have seen, because no motor units start to fire during time ‘‘t”, these tails are not cancelled out by the upgoing peaks in other sweeps of the average, and hence they ‘‘fill” in activity during time ‘‘t” in the rectified average. Inhibition in the average rectified EMG only becomes evident when the duration of motor unit inhibition exceeds approximately half the duration of a motor unit action potential. When the period of inhibition is shorter than half the duration of the action potentials, there is no sign of any response in the rectified average, although the failure of cancellation produces a clear positive–negative potential in the unrectified average. As the period of inhibition is lengthened, the lack of activity becomes evident in the rectified average. So, the reason why the short period of unit inhibition (2–3 ms), corresponding to the p11/n15 wave in the unrectified EMG, gives no obvious deflections in the rectified EMG average is because the period of inhibition ‘‘t” is much shorter than the duration of a typical action potential in the surface EMG. However, as noted by Widmer and Lund (1989), a sudden onset of motor unit inhibition can sometimes lead to a paradoxical early increase in rectified EMG activity arising
from failure of cancellation of the tails of unit action potentials that had begun to discharge before the inhibition began. Indeed, very short periods of inhibition, such as the VEMP and the VMR, may appear as an increase of the rectified average (see Colebatch (2009) for a complete formulation of this argument). 3.3. Possible functional consequences of sound-induced vestibular and cochlear masseter reflexes At this stage there is no definitive conclusion as to the role of the reflexes we describe here. Both produce EMG inhibition at approximately the same latency. A local protective function was attributed to the acoustic jaw reflex by Meier-Ewert et al. (1974). Indeed, the fact that it is inhibitory may allow it to play a role in preventing the subject biting his/her tongue and/or cheek when startled. The brief vestibular inhibition preceding the cochlear inhibition may have some role in adjusting or prepare masseter muscle tone to sustain the acoustic response following immediately after.
4. Possible role for the vestibulo-masseteric reflex pathways in trigeminal motor control In addition to mastication, the masseter muscle is involved in speech, swallowing, respiration and maintenance of the position of the mandible, by bringing it back to its physiological axis. Each of these functions require jaw muscles to perform motor tasks that differ in force produced, as well as rapidity, shape and precision of mouth movements. Furthermore, they are often required to perform these multiple and very different actions simultaneously, so that we are able, for instance to speak and laugh while chewing. To be able to achieve its many complex functions jaw muscle
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motor command is modulated by volition and by peripheral afferent feedback. So what role could there be for vestibular inputs? One possibility is that they may play a role in the adjustment of masticatory muscle tone during angular acceleration of the head in spatial planes, and also in postural adjustment of the mandible during changes in head position with respect to the gravity, such as when chewing with the head tilted or during extreme laterotrusion and protrusion/retrusion of the jaw (Goto et al., 2001). It seems plausible that this ‘‘postural” function is a prerogative for the multisynaptic, asymmetric, tonic, excitatory vestibular projection, which may control masseter muscle tone the same way as it does with all the other antigravity muscles of the body. The role of the monosynaptic, symmetric, phasic, inhibitory vestibulo-masseteric projection is more difficult to understand. One possibility is that it is involved in responding to sudden head tilt upwards or downwards. For instance, if the head is suddenly dropped, it may be of value to inhibit the masseters, and vice versa if the head is suddenly pitched upwards. However, the reflex appears to be weak, requiring the average of many trials to become evident (Deriu et al., 2003, 2005, 2007), so that whether the reflex does have a true functional relevance is unclear. A last perhaps unsatisfactory possibility is that the neural pathway is an evolutionary leftover that has no role in normal human activities.
5. Clinical prospects The study of the vestibulo-masseteric reflex and of the acoustic masseteric reflex in people with selective lesion of vestibular or cochlear receptors definitely demonstrated that these end organs originate the p11/n15 and the p16/n21 waves, respectively (Deriu et al., 2007). This study also shows that masseter responses to sound can be used as additional tools to test saccular and cochlear function in human otological investigations. However, it seems unlikely that these responses will replace the click-induced VEMPs which are commonly used in the clinical practice to study vestibular function. The advantage of the VEMPs, respect to the VMR is that they need a smaller number of trials to become evident (300 vs 500 sweeps) and are larger in magnitude (around 30% bigger). However, a possible application for the VMR is its assessment as an alternative to the SCM in patients who are unable to hold their neck up or who have had surgery to or congenital abnormalities of the SCM. The lack of normative data for latency, amplitudes and symmetry does limit this at present. In addition, if the clinical purpose is testing brainstem function, the investigation of masseter responses to sound, can be of some value. The partial knowledge available on the anatomical substrate for these reflexes is based on animal studies, so they cannot be applied to humans until anatomical–functional correlation studies, aided by neuroimaging, are done, similarly to those performed for trigeminal reflexes (Ongerboer de Visser et al., 1990; Cruccu et al., 2005). Nevertheless, both the vestibulo-masseteric and the acoustic masseteric reflex can be considered as new additional neurophysiological tools in the exploration of brainstem circuits in physiological as well as pathological conditions. Their evaluation may add useful information especially if it is combined with other neurophysiological methods already standardized in this field (Ref. in Aramideh and Ongerboer de Visser (2002)) and with neuroimaging data. Acknowledgements This work was supported by grants from the Ministero dell’Istruzione, dell’Università e della Ricerca (MIUR) and from Fondazione Italiana Sclerosi Multipla (FISM 2008/R/9). Dr. Elena Giaconi was supported by a grant from MIUR (PRIN).
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