TRIGEMINAL-HYPOGLOSSAL SILENT PERIOD: A PONTOMEDULLARY BRAINSTEM REFLEX PETER P. URBAN, MD, PhD Department of Neurology, Asklepios Klinik Barmbek, R€ ubenkamp 220, 22291 Hamburg, Germany Accepted 18 July 2014 ABSTRACT: Introduction: Animal studies have shown inhibitory connections between the sensory trigeminal nucleus and hypoglossal nucleus. I investigated whether these inhibitory projections are present in humans. Methods: I examined 18 healthy subjects, 2 patients with brainstem stroke, and 5 patients with multiple sclerosis using a specially designed oral stimulation and recording device. Results: In 16 of 18 subjects, a bilateral suppression period of tongue muscle activity after unilateral electrical stimulation of the mucosal V2 afferents was observed. The silent period started at 31.1 (SD 4.7) ms (ipsilateral) and 32.0 (SD 4.9) ms (contralateral). The mean duration of the silent period was 31.4 (SD 10.2) ms (ispilateral) and 32.5 (SD 9.8) ms (contralateral). Patients with dorsolateral pontomedullary lesions had ipsilateral absence of the silent period. Conclusions: This study confirms the existence of a bilateral trigeminal-hypoglossal silent period in humans. Muscle Nerve 51: 538–540, 2015
Clinical observations have shown that tongue movements are coordinated intimately with jaw movements during oromotor behaviors. Furthermore, nociceptive mucosal innervation of the mouth has a protective function for the tongue. Thus, afferent trigeminal input and tongue motor control must be coordinated within the neuronal brainstem network. Inhibitory connections between neurons of the sensory trigeminal nucleus and the hypoglossal nucleus have been described previously in both cats1 and rats.2–4 This study demonstrates a bilateral inhibitory pathway between the trigeminal afferents innervating the hard palate and hypoglossal motoneurons in healthy human subjects, based on a bilateral silent period in tongue muscle activity evoked by unilateral electrical stimulation of the hard palate. The findings confirm the presence of this pathway in humans. In selected patients with brainstem infarctions the potential diagnostic value is highlighted. METHODS
In a preliminary study, I examined 18 healthy subjects (10 men and 8 women, age 42 6 13 years), 2 patients with brainstem stroke, and 5 patients with multiple sclerosis. All subjects gave informed consent to the procedure that was approved by the local ethics committee. A specially designed oral stimulation and Abbreviation: SP, silent period Key words: brainstem; brainstem reflex; hypoglossal nerve; inhibitory reflex; trigeminal nerve; silent period Correspondence to: P.P. Urban; e-mail: [email protected] C 2014 Wiley Periodicals, Inc. V
Published online 25 July 2014 in Wiley Online Library (wileyonlinelibrary.com). DOI 10.1002/mus.24349
538
Trigeminal-Hypoglossal Silent Period
recording device was developed for the investigations (Fig. 1). The spoon-shaped methacrylate device is reusable after disinfection and gas-sterilization and can be fitted to the individual palate using adjustable stimulation steel electrodes. The trigeminal (V2) innervated palatal mucosa was stimulated unilaterally with a cathode placed on the anterior hard palate and an anode placed on the posterior hard palate. The electromyographic activity from both halves of the tongue was recorded simultaneously using pairs of Ag/AgCl surface electrodes with an interelectrode distance of about 18 mm. The stimulation intensity was at least 5 times the perception threshold and increased to a maximum of 20 mA. During stimulation the subject pressed the tongue with maximum possible force against the recording device, thus securing electrode placement. Filter settings were from 20 HZ to 2 kHZ. Five consecutive measurements were recorded, and an analysis was made using nonrectified raw recordings that were superimposed offline. The onset and end of the inhibition period were determined graphically and set at approximately 30% of the mean pre-stimulus activity. RESULTS Healthy Subjects.
The examination was well tolerated by all subjects, and there were no adverse events. In 16 of 18 subjects there was a bilateral suppression period of tongue muscle activity after unilateral electrical stimulation of the mucosal V2 afferents (Fig. 2). The silent period (SP) started at 31.1 6 4.7 ms (ipsilateral) and 32.0 6 4.9 ms (contralateral). The interside latency difference was 4.3 6 3.6 ms (ipsilateral) and 4.0 6 4.1 ms (contralateral). The mean SP duration was 31.4 6 10.2 ms (ispilateral) and 32.5 6 9.8 ms (contralateral). In 1 patient we investigated the effect of stimulation intensity and tongue muscle activity on SP latency and duration parameters. With increasing stimulation intensity we observed an earlier onset of the SP (Fig. 3A). Increasing tongue pressure led to shortening of the SP (Fig. 3B), and therefore nearmaximum tongue pressure was used in all subjects. In 2 subjects, however, no suppression of tongue muscle activity was observed, although electrical stimulation was perceived as slightly painful on both halves of the palate. Case Reports. Patient 1. In patient 1, dorsolateral medullary infarction on the right side had occurred 5 days earlier (Fig. 4). Clinical testing MUSCLE & NERVE
April 2015
FIGURE 1. Stimulation and recording device for unilateral electrical stimulation of the hard palate with adjustable steel electrodes. Ag/AgCl electrodes embedded in the methacrylate device are used for recording tongue muscle activity. (A) View from above. (B) View from below.
FIGURE 2. Trigeminal-hypoglossal silent period in a healthy subject, demonstrating bilateral suppression of tongue muscle activity following unilateral electrical stimulation of the hard palate. Superimposition of 5 trials [V2 r/l: stimulation of the right/left side of the trigeminal innervated (V2) palatal mucosa; tongue r/l: recording muscle activity from the right/left half of the tongue].
showed normal sensation of the palate, although the SP was absent bilaterally on electrical stimulation of the right palate, whereas stimulation of the left side led to bilateral suppression of tongue muscle activity. Patient 2. Patient 2 had a left pontine tegmental hemorrhage due to a cavernous angioma that occurred 1 year previously. Clinical testing also showed normal sensation of the palate, although,
on electrical stimulation of the left palate, the SP was absent on both halves of the tongue. Patients 3–7. Five additional patients with clinically definite relapsing-remitting multiple sclerosis, clinically normal sensation of the mouth, and normal brainstem functions were also investigated. In 1 patient the SP was absent bilaterally on stimulation of the right palate, although MRI (performed with a slice thickness of 3 mm without gap) disclosed no tegmental brainstem lesion. DISCUSSION
Trigeminal-hypoglossal connections between neurons of the sensory trigeminal and hypoglossal nucleus have been demonstrated in the cat and the rat using anterograde and retrograde neuronal tracers.1–3 The central projections of primary sensory neurons innervating the hard palate in the cat were located in all subdivisions of the sensory trigeminal nuclear complex,5 whereas, in other studies, a termination in the dorsomedial part of the trigeminal subnucleus oralis was described.6 Recent retrograde tracer studies showed that nociceptive afferents from the caudal spinal trigeminal nucleus are connected to pre-motor neurons that send axons simultaneously to the facial and hypoglossal motoneurons by axon collaterals.4 In humans, however, only a trigeminal-facial inhibitory reflex was shown on mentalis nerve stimulation with electromyographic recordings from lower face muscles.7,8 Trigeminalhypoglossal inhibitory reflexes in humans have not been described. However, in this study I have shown inhibitory pontomedullary projections between sensory neurons of the enoral endings of the second trigeminal nerve and hypoglossal neurons in the majority of healthy subjects studied. The trigeminalhypoglossal SP may therefore serve as an indication of a nociceptive protection reflex. From a clinical point of view, the existence of a nociceptive
FIGURE 3. Trigeminal-hypoglossal silent period in a healthy subject. (A) Increasing stimulation intensity (from 2 to 12 mA) leads to an earlier onset of the silent period. (B) Increasing tongue pressure (10–100% of maximum force) leads to shortening of the silent period. Trigeminal-Hypoglossal Silent Period
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FIGURE 4. (A) MRI of a patient with a dorsolateral infarction of the right medulla oblongata. (B) On electrical stimulation of the right palate, the silent period was absent bilaterally, whereas stimulation of the left side led to bilateral suppression of tongue muscle activity. This finding indicates an afferent lesion of the trigeminal input.
protection reflex may be assumed to include the trigeminal innervated intraoral area as an afferent and the tongue as an efferent part, leading to retraction of the tongue muscle, such as what occurs after consuming extremely hot food (“hot potato reflex”). Although the exact course of the trigeminalhypoglossal projections responsible for the SP cannot be delineated based on these results, this preliminary study demonstrates that, in contrast to animal studies, the SP in humans is organized bilaterally, indicating bilateral projections from 1 trigeminal nucleus to both hypoglossal nuclei. Consideration of the mean latency of the trigeminal-hypoglossal SP gives rise to the assumption of a polysynaptic pathway. After trigeminal nerve stimulation (mentalis nerve, V3), inhibitory reflexes of the masticatory9 and certain facial muscles,7 1 or 2 inhibitory periods (SP1 and SP2) have been observed. Trigeminal nerve (V2) stimulation of the palate, however, resulted in only 1 suppression period of the tongue. I have demonstrated in selected patients a potential topodiagnostic value of the trigeminal-hypoglossal SP. In 2 patients with unilateral tegmental brainstem lesions there was bilateral absent suppression of tongue muscle activity on palatal stimulation ipsilateral to the lesion side, indicating an ipsilateral afferent lesion. Because clinical testing of oral sensation showed normal results in both patients, the abnormal findings of the trigeminal-hypoglossal reflex serve as an indication of subclinical lesions. The brainstem lesions were found to affect the pontomedullary tegmentum, indicating that the trigeminal-hypoglossal pathway travels through this area. Further studies will need to clarify whether the trigeminal-hypoglossal reflex pathway is associated with an additional topodiagnostic benefit, as compared with the R2 component of the blink reflex10 and the second suppression period of the masseter SP. Furthermore, a subclinical and MRI-negative lesion can be assumed in 1 patient with multiple sclerosis and normal brainstem function based on abnormal findings of the trigeminal-hypoglossal SP. 540
Trigeminal-Hypoglossal Silent Period
Two healthy subjects lacked trigeminalhypoglossal SPs on bilateral palatal stimulation, which may be due to the insufficient stimulation intensity restricted to 20 mA. Bilaterally absent SPs can therefore not be regarded as abnormal. However, a unilateral absent SP was never observed in the control subjects, indicating a pathological result. Only the presence or absence of the SP was assessed in the patients described here. The diagnostic relevance of latency parameters requires further investigation in a larger sample of patients with clinically definite brainstem lesions. Furthermore, the influence of stimulus intensity and tongue muscle pressure on latency and duration of the SP should be evaluated in a larger number of subjects. Such findings may contribute to the development of a quantitative assessment of the inhibitory reflex. The author thanks I. Kirchhoff (Department of Neurology, University of Mainz) for technical assistance and U. Wahlmann (Department of Maxillofacial Surgery, University of Mainz) for providing the stimulation and recording device. REFERENCES 1. Tomioka S, Nakajo N, Takata M. Inhibition of styloglossus motoneurons during the palatally induced jaw-closing reflex. Neuroscience 1999;92:353–360. 2. Zhang J, Pendlebury W, Luo P. Synaptic organization of monosynaptic connections from mesencephalic trigeminal nucleus neurons to hypoglossal motoneurons in the rat. Synapse 2003;49:157–169. 3. Luo P, Zhang J, Yang R, Pendlebury W. Neuronal circuitry and synaptic organization of trigeminal proprioceptive afferents mediating tongue movement and jaw-tongue coordination via hypoglossal premotor neuron. Eur J Neurosci 2006;23:3269–3283. 4. Dong Y, Li J, Zhang F, Li Y. Nociceptive afferents to the premotor neurons that send axons simultaneously to the facial and hypoglossal motoneurons by means of axon collaterals. PloS One 2011;6:e25615. 5. Arvidsson J, Hellstrand E. A horseradish peroxidase study of the central projections of primary trigeminal neurons innervating the hard palate in the cat. Brain Res 1988;451:197–204. 6. Takemura M, Sugimoto T, Shigenaga Y. Difference in central projection of primary afferents innervating facial and intraoral structures in the rat. Exp Neurol 1991;111:324–331. 7. Pavesi G, Macaluso GM, Marchetti P, Cattaneo L, Tinchelli S, de Laat A, et al. Trigemino-facial reflex inhibitory responses in some lower facial muscles. Muscle Nerve 2000;23:939–945. 8. Cattaneo L, Pavesi G. Recording the trigemino-facial inhibitory reflex: technique and normal findings. J Clin Neurophysiol 2010;27:126–129. 9. Ongerboer de Visser BW, Cruccu G, Manfredi M, Koelman JHTM. Effects of brainstem lesions on the masseter inhibitory reflex. Brain 1989;113:781–792. 10. Fitzek S, Fitzek C, Marx J, Speckter H, Urban PP, Th€ omke F, et al. Blink reflex R2 changes and localization of lesions in lower brainstem. An electrophysiological and MRI study. J Neurol Neurosurg Psychiatry 1999;67:630–636.
MUSCLE & NERVE
April 2015
Clinical observations have shown that tongue movements are coordinated intimately with jaw movements during oromotor behaviors. Furthermore, nociceptive mucosal innervation of the mouth has a protective function for the tongue. Thus, afferent trigeminal input and tongue motor control must be coordinated within the neuronal brainstem network. Inhibitory connections between neurons of the sensory trigeminal nucleus and the hypoglossal nucleus have been described previously in both cats1 and rats.2–4 This study demonstrates a bilateral inhibitory pathway between the trigeminal afferents innervating the hard palate and hypoglossal motoneurons in healthy human subjects, based on a bilateral silent period in tongue muscle activity evoked by unilateral electrical stimulation of the hard palate. The findings confirm the presence of this pathway in humans. In selected patients with brainstem infarctions the potential diagnostic value is highlighted. METHODS
In a preliminary study, I examined 18 healthy subjects (10 men and 8 women, age 42 6 13 years), 2 patients with brainstem stroke, and 5 patients with multiple sclerosis. All subjects gave informed consent to the procedure that was approved by the local ethics committee. A specially designed oral stimulation and Abbreviation: SP, silent period Key words: brainstem; brainstem reflex; hypoglossal nerve; inhibitory reflex; trigeminal nerve; silent period Correspondence to: P.P. Urban; e-mail: [email protected] C 2014 Wiley Periodicals, Inc. V
Published online 25 July 2014 in Wiley Online Library (wileyonlinelibrary.com). DOI 10.1002/mus.24349
538
Trigeminal-Hypoglossal Silent Period
recording device was developed for the investigations (Fig. 1). The spoon-shaped methacrylate device is reusable after disinfection and gas-sterilization and can be fitted to the individual palate using adjustable stimulation steel electrodes. The trigeminal (V2) innervated palatal mucosa was stimulated unilaterally with a cathode placed on the anterior hard palate and an anode placed on the posterior hard palate. The electromyographic activity from both halves of the tongue was recorded simultaneously using pairs of Ag/AgCl surface electrodes with an interelectrode distance of about 18 mm. The stimulation intensity was at least 5 times the perception threshold and increased to a maximum of 20 mA. During stimulation the subject pressed the tongue with maximum possible force against the recording device, thus securing electrode placement. Filter settings were from 20 HZ to 2 kHZ. Five consecutive measurements were recorded, and an analysis was made using nonrectified raw recordings that were superimposed offline. The onset and end of the inhibition period were determined graphically and set at approximately 30% of the mean pre-stimulus activity. RESULTS Healthy Subjects.
The examination was well tolerated by all subjects, and there were no adverse events. In 16 of 18 subjects there was a bilateral suppression period of tongue muscle activity after unilateral electrical stimulation of the mucosal V2 afferents (Fig. 2). The silent period (SP) started at 31.1 6 4.7 ms (ipsilateral) and 32.0 6 4.9 ms (contralateral). The interside latency difference was 4.3 6 3.6 ms (ipsilateral) and 4.0 6 4.1 ms (contralateral). The mean SP duration was 31.4 6 10.2 ms (ispilateral) and 32.5 6 9.8 ms (contralateral). In 1 patient we investigated the effect of stimulation intensity and tongue muscle activity on SP latency and duration parameters. With increasing stimulation intensity we observed an earlier onset of the SP (Fig. 3A). Increasing tongue pressure led to shortening of the SP (Fig. 3B), and therefore nearmaximum tongue pressure was used in all subjects. In 2 subjects, however, no suppression of tongue muscle activity was observed, although electrical stimulation was perceived as slightly painful on both halves of the palate. Case Reports. Patient 1. In patient 1, dorsolateral medullary infarction on the right side had occurred 5 days earlier (Fig. 4). Clinical testing MUSCLE & NERVE
April 2015
FIGURE 1. Stimulation and recording device for unilateral electrical stimulation of the hard palate with adjustable steel electrodes. Ag/AgCl electrodes embedded in the methacrylate device are used for recording tongue muscle activity. (A) View from above. (B) View from below.
FIGURE 2. Trigeminal-hypoglossal silent period in a healthy subject, demonstrating bilateral suppression of tongue muscle activity following unilateral electrical stimulation of the hard palate. Superimposition of 5 trials [V2 r/l: stimulation of the right/left side of the trigeminal innervated (V2) palatal mucosa; tongue r/l: recording muscle activity from the right/left half of the tongue].
showed normal sensation of the palate, although the SP was absent bilaterally on electrical stimulation of the right palate, whereas stimulation of the left side led to bilateral suppression of tongue muscle activity. Patient 2. Patient 2 had a left pontine tegmental hemorrhage due to a cavernous angioma that occurred 1 year previously. Clinical testing also showed normal sensation of the palate, although,
on electrical stimulation of the left palate, the SP was absent on both halves of the tongue. Patients 3–7. Five additional patients with clinically definite relapsing-remitting multiple sclerosis, clinically normal sensation of the mouth, and normal brainstem functions were also investigated. In 1 patient the SP was absent bilaterally on stimulation of the right palate, although MRI (performed with a slice thickness of 3 mm without gap) disclosed no tegmental brainstem lesion. DISCUSSION
Trigeminal-hypoglossal connections between neurons of the sensory trigeminal and hypoglossal nucleus have been demonstrated in the cat and the rat using anterograde and retrograde neuronal tracers.1–3 The central projections of primary sensory neurons innervating the hard palate in the cat were located in all subdivisions of the sensory trigeminal nuclear complex,5 whereas, in other studies, a termination in the dorsomedial part of the trigeminal subnucleus oralis was described.6 Recent retrograde tracer studies showed that nociceptive afferents from the caudal spinal trigeminal nucleus are connected to pre-motor neurons that send axons simultaneously to the facial and hypoglossal motoneurons by axon collaterals.4 In humans, however, only a trigeminal-facial inhibitory reflex was shown on mentalis nerve stimulation with electromyographic recordings from lower face muscles.7,8 Trigeminalhypoglossal inhibitory reflexes in humans have not been described. However, in this study I have shown inhibitory pontomedullary projections between sensory neurons of the enoral endings of the second trigeminal nerve and hypoglossal neurons in the majority of healthy subjects studied. The trigeminalhypoglossal SP may therefore serve as an indication of a nociceptive protection reflex. From a clinical point of view, the existence of a nociceptive
FIGURE 3. Trigeminal-hypoglossal silent period in a healthy subject. (A) Increasing stimulation intensity (from 2 to 12 mA) leads to an earlier onset of the silent period. (B) Increasing tongue pressure (10–100% of maximum force) leads to shortening of the silent period. Trigeminal-Hypoglossal Silent Period
MUSCLE & NERVE
April 2015
539
FIGURE 4. (A) MRI of a patient with a dorsolateral infarction of the right medulla oblongata. (B) On electrical stimulation of the right palate, the silent period was absent bilaterally, whereas stimulation of the left side led to bilateral suppression of tongue muscle activity. This finding indicates an afferent lesion of the trigeminal input.
protection reflex may be assumed to include the trigeminal innervated intraoral area as an afferent and the tongue as an efferent part, leading to retraction of the tongue muscle, such as what occurs after consuming extremely hot food (“hot potato reflex”). Although the exact course of the trigeminalhypoglossal projections responsible for the SP cannot be delineated based on these results, this preliminary study demonstrates that, in contrast to animal studies, the SP in humans is organized bilaterally, indicating bilateral projections from 1 trigeminal nucleus to both hypoglossal nuclei. Consideration of the mean latency of the trigeminal-hypoglossal SP gives rise to the assumption of a polysynaptic pathway. After trigeminal nerve stimulation (mentalis nerve, V3), inhibitory reflexes of the masticatory9 and certain facial muscles,7 1 or 2 inhibitory periods (SP1 and SP2) have been observed. Trigeminal nerve (V2) stimulation of the palate, however, resulted in only 1 suppression period of the tongue. I have demonstrated in selected patients a potential topodiagnostic value of the trigeminal-hypoglossal SP. In 2 patients with unilateral tegmental brainstem lesions there was bilateral absent suppression of tongue muscle activity on palatal stimulation ipsilateral to the lesion side, indicating an ipsilateral afferent lesion. Because clinical testing of oral sensation showed normal results in both patients, the abnormal findings of the trigeminal-hypoglossal reflex serve as an indication of subclinical lesions. The brainstem lesions were found to affect the pontomedullary tegmentum, indicating that the trigeminal-hypoglossal pathway travels through this area. Further studies will need to clarify whether the trigeminal-hypoglossal reflex pathway is associated with an additional topodiagnostic benefit, as compared with the R2 component of the blink reflex10 and the second suppression period of the masseter SP. Furthermore, a subclinical and MRI-negative lesion can be assumed in 1 patient with multiple sclerosis and normal brainstem function based on abnormal findings of the trigeminal-hypoglossal SP. 540
Trigeminal-Hypoglossal Silent Period
Two healthy subjects lacked trigeminalhypoglossal SPs on bilateral palatal stimulation, which may be due to the insufficient stimulation intensity restricted to 20 mA. Bilaterally absent SPs can therefore not be regarded as abnormal. However, a unilateral absent SP was never observed in the control subjects, indicating a pathological result. Only the presence or absence of the SP was assessed in the patients described here. The diagnostic relevance of latency parameters requires further investigation in a larger sample of patients with clinically definite brainstem lesions. Furthermore, the influence of stimulus intensity and tongue muscle pressure on latency and duration of the SP should be evaluated in a larger number of subjects. Such findings may contribute to the development of a quantitative assessment of the inhibitory reflex. The author thanks I. Kirchhoff (Department of Neurology, University of Mainz) for technical assistance and U. Wahlmann (Department of Maxillofacial Surgery, University of Mainz) for providing the stimulation and recording device. REFERENCES 1. Tomioka S, Nakajo N, Takata M. Inhibition of styloglossus motoneurons during the palatally induced jaw-closing reflex. Neuroscience 1999;92:353–360. 2. Zhang J, Pendlebury W, Luo P. Synaptic organization of monosynaptic connections from mesencephalic trigeminal nucleus neurons to hypoglossal motoneurons in the rat. Synapse 2003;49:157–169. 3. Luo P, Zhang J, Yang R, Pendlebury W. Neuronal circuitry and synaptic organization of trigeminal proprioceptive afferents mediating tongue movement and jaw-tongue coordination via hypoglossal premotor neuron. Eur J Neurosci 2006;23:3269–3283. 4. Dong Y, Li J, Zhang F, Li Y. Nociceptive afferents to the premotor neurons that send axons simultaneously to the facial and hypoglossal motoneurons by means of axon collaterals. PloS One 2011;6:e25615. 5. Arvidsson J, Hellstrand E. A horseradish peroxidase study of the central projections of primary trigeminal neurons innervating the hard palate in the cat. Brain Res 1988;451:197–204. 6. Takemura M, Sugimoto T, Shigenaga Y. Difference in central projection of primary afferents innervating facial and intraoral structures in the rat. Exp Neurol 1991;111:324–331. 7. Pavesi G, Macaluso GM, Marchetti P, Cattaneo L, Tinchelli S, de Laat A, et al. Trigemino-facial reflex inhibitory responses in some lower facial muscles. Muscle Nerve 2000;23:939–945. 8. Cattaneo L, Pavesi G. Recording the trigemino-facial inhibitory reflex: technique and normal findings. J Clin Neurophysiol 2010;27:126–129. 9. Ongerboer de Visser BW, Cruccu G, Manfredi M, Koelman JHTM. Effects of brainstem lesions on the masseter inhibitory reflex. Brain 1989;113:781–792. 10. Fitzek S, Fitzek C, Marx J, Speckter H, Urban PP, Th€ omke F, et al. Blink reflex R2 changes and localization of lesions in lower brainstem. An electrophysiological and MRI study. J Neurol Neurosurg Psychiatry 1999;67:630–636.
MUSCLE & NERVE
April 2015
