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Changes in the perioral muscle responses to cortical TMS induced by decrease of sensory input and electrical stimulation to lower facial region
Clinical Neurophysiology 115 (2004) 2343–2349 www.elsevier.com/locate/clinph
Changes in the perioral muscle responses to cortical TMS induced by decrease of sensory input and electrical stimulation to lower facial region N. Yıldıza,c,*, S. Yıldıza,c, C. Ertekina,b, I. Aydog˘dua,b, B. Uludaga,b a
Departments of Clinical Neurophysiology, Ege University, Medical School Hospital, Izmir, Turkey b Departments of Neurology, Ege University, Medical School Hospital, Izmir, Turkey c Department of Neurology, Medical School Hospital, Abant Izzet Baysal University, Golkoy, 14300 Bolu, Turkey Accepted 25 April 2004 Available online 7 June 2004
Abstract Objective: To determine the changes in the motor cortex due to repetitive electrical stimulation and cutaneous anesthesia in lower facial region. Methods: A total of 11 subjects participated in the study of repetitive electrical stimulation, and 10 other subjects in the study of lower facial anesthesia. Facial nerve root and face associated cortical MEPs by transcranial magnetic stimulation (eight-shaped coil) were recorded from perioral muscles pre- and post- electrical stimulation and lower facial anesthesia. Cheek near to the corner of the mouth was transcutaneously stimulated by bipolar surface electrode giving repetitive electrical shocks at 5 Hz. Five percent lidocain/prilocain local anesthetic cream was applied to left or right lip-cheek region. Results: There was no significant change in perioral MEP responses after 10 – 30 min of 5 Hz electrical stimulation. We found a significant increase of amplitude in cortical MEP recordings during lower facial anesthesia especially in cases of cortical magnetic stimulations ipsilateral and contralateral to the anaesthetized side and in perioral recordings contralateral to the anaesthetized side. Conclusions: The present study demonstrates that topical anesthesia to the lower facial region leads to cortical modulation and fast plastic changes in both hemispheres that are directed to the normal side. q 2004 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved. Keywords: Plasticity; Neuronal-motor cortex-face-evoked potentials; Motor-anesthesia; Local-electrical stimulation
1. Introduction It has been reported recently that there are relevant motor cortex excitability and MEP amplitude increases during and after the repetitive nerve stimulations at the periphery (Luft et al., 2002; Ridding et al., 2000). Similarly, following an ischemic nerve block, there occurs an expansion in the motor cortex representation area, an increase in the motor cortex excitability and in the MEP amplitudes of the same extremity proximal muscles as well as in the opposite homolog muscles (Brasil-Neto et al., 1992; Ridding et al., 1995; Werhahn et al., 2002; Ziemann et al., 1998). * Corresponding author. Address: Department of Neurology, School of Medicine, Abant Izzet Baysal University, Golkoy, 14300 Bolu, Turkey. Tel.: þ 90-374-217-85-05; fax: þ 90-253-45-59. E-mail addresses: [email protected] (N. Yıldız), erteker@ unimedya.net.tr (C. Ertekin).
While regional anesthesia and stimulation studies are conducted more on the extremity muscles and nerves, studies on the nerves and muscles of the face remained relatively less in number. Among these, a number of studies have demonstrated that there is an expansion in hand motor cortex area in cases with peripheral facial nerve paralysis (Rijntjes et al., 1997) and after application of botulinum toxin in the hemifacial spasms (Liepert et al., 1999). The purpose of the current study is to analyze the variations in facial motor cortex due to repetitive electrical stimulation and decrease of the sensory input on the lower facial region. We hypothesized that both hemispheres could have rapid rearrangements. This is particularly due to the importance of lower facial musculature and of the bilateral innervation of the corticonuclear fibers to lower facial muscles which also has been discussed previously (Benecke et al., 1988; Huang et al., 1988; Jenny and Saper, 1987;
1388-2457/$30.00 q 2004 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.clinph.2004.04.021
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Kuypers, 1958; Meyer et al., 1994; Morecraft et al., 2001; Penfield, 1958; Urban et al., 1997).
2. Materials and method Twenty-one healthy subjects participated in two separate experiments. Their written consents were obtained and the ethical committee of Ege University has approved the conduct of the study. 2.1. Standard conditions Perioral muscle responses were recorded unilaterally in electrical stimulation experiment (experiment 1), and bilaterally in topical anesthesia experiment (experiment 2). Nicolet Viking IV electromyography was used. The EMG recordings were made by Ag – AgCl electrodes which were placed 1 – 1.5 cm. upper and lower corners of the mouth. High and low pass filters were 150 Hz and 10 KHz. High pass filter was adjusted to the 150 Hz to prevent the head-neck movement artifact. The subjects were reminded to hold tightly the paper tissue placed between their lips during transcranial magnetic stimulation to avoid squeezing the teeth. Holding paper tissue helped to provide stable maximal contraction with very effective facilitation; volume conduction possibility from masticator muscle was lessened by avoiding the squeeze of the teeth. The level of contraction was controlled by auditory feedback of the EMG signal. Cortical and facial nerve root TMS studies were performed with eight-shaped coil connected to the Magstim 200 magnetic stimulator (Novametrix, Dyfed, Whales, UK). The center of the coil was placed 2– 4 cm lateral and 2 –3 cm frontal to Cz., posteromedial and tangential in cortical stimulation with about 450 angle to the vertex; in facial nerve root stimulation, a few centimeters behind the ear, in the parietooccipital region. These positions were marked on the scalp with a pen to ensure an identical coil placement throughout the experiment. Four to eight responses were recorded from each stimulation site. The amplitudes of the perioral muscle MEPs were peak to peak. The arithmetic mean values were considered for each set of experiments. 200 mV was the limit for the MEP amplitude to avoid interference of the volume conduction effect. This limit was concluded from another previously unpublished study of ours in patients with peripheral facial paralysis which demonstrated volume conduction effect (close to 200 mV) on the totally axonal degenerated side from the intact side.
recorded ipsilateral to the stimulated site. TMS recordings and measurements were performed as mentioned above. Cheek near to the corner of the mouth was transcutaneously stimulated by bipolar surface electrodes with duration of 0.05– 0.1 ms, and in frequency of 5 Hz. The stimulus intensity was increased until the emergence of lower facial muscles twitching. Standardization was performed according to twitching emergence level, stimulus properties were arranged to achieve this level. In 6 cases 10 min, and in 5 cases 30 min continuous stimulations were applied. Perioral MEP responses to the face associated cortex were recorded before and after repetitive electrical stimulation (10 – 20– 30th min). Facial nerve root TMS were recorded at the beginning of the pre and post electrical stimulus period. 3.2. Experiment 2 Ten healthy subjects, aged between 19 and 59 (mean age 40.5) participated. Bilateral perioral recordings, TMS application, and measurements were recorded as mentioned above. Topical anesthesia was performed with 5% of lidocain/prilocain local anesthetic cream (EMLA). This has the known effect of blocking the free nerve endings and receptors in the skin (Arendt-Nielsen et al., 1989; Kundu and Achar, 2002). The cream was applied in the form of a thin layer to left or right cheek skin and to lip mucosa and both regions were plastered for a period of 60– 90 min (Arendt-Nielsen and Bjerring, 1989; Kundu and Achar, 2002). The level of anesthesia was carefully evaluated by pinprick and light touch examination. In cases where the level was decided to be insufficient, an additional 30 min period was added with plastered cream application. Before the application of the cream (0), and after (þ 15, þ 35, þ 60, þ 120 min), cortical MEPs were recorded. Facial nerve root MEPs were recorded at the beginning pre- and postanesthesia periods. Cheek-lip anesthesia level was scored over touch-andpain perception as below: normal (no anesthesia) ¼ 0; mild ¼ 1; mild-moderate ¼ 2; moderate ¼ 3; total ¼ 4. Both stimulation and recording places were labeled in relation to anesthetized side as described: ILIL, hemisphere stimulation and perioral recordings ipsilateral to the anaesthetized side; ILCL, hemisphere stimulation ipsilateral to anaesthetized side and perioral recordings contralateral to the anaesthetized side; CLCL, hemisphere stimulation and perioral recordings contralateral to the anaesthetized side; CLIL, hemisphere stimulation contralateral to anaesthetized side and perioral recordings ipsilateral to the anaesthetized side.
3. Experimental design 3.3. Data analysis 3.1. Experiment 1 11 healthy subjects, aged between 20 and 50 (mean age 33) participated. Perioral muscle responses were
Poststimulus and postanesthesia mean values for each time period were compared for baseline mean amplitude values of each experiment.
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Table 1 Pre- and post- stimulus mean amplitude (mV) values of the perioral MEP responses to the cortical TMS. (mean ^ SD, N ¼ 6 and N ¼ 5) Hemisphere
CL Ampl.* IL Ampl.
10 min repetitive stimulation
30 min repetitive stimulation
Prestim.
10 th min
20 th min
30 th min
Prestim.
10 th min
20 th min
30 th min
630 ^ 288 441 ^ 233
583 ^ 262 441 ^ 257
612 ^ 289 416 ^ 280
594 ^ 213 441 ^ 309
570 ^ 288 354 ^ 172
534 ^ 211 368 ^ 184
580 ^ 189 380 ^ 179
542 ^ 220 322 ^ 115
CL*, Contralateral; IL, Ipsilateral; Ampl, Amplitude; Lat., Latency; Dur., Duration.
The distribution properties were assessed with normal distribution curves and with Kolmogorov Smirnov/Shapiro Wilk tests. In normal distribution groups, noting the dependent variable, repeated measures ANOVA was performed and for post hoc pairwise comparisons, Bonferroni procedure was used. For nonparametric data, we used Friedmann and Wilcoxon tests with correction for multiple comparisons.
4. Results In both experiments, pre and post applications, the mean latency and duration values displayed no significant differences (Tables 1 and 2). Rest motor threshold for facial nerve root TMS was 44.5 ^ 5.8 (%). Active motor threshold for cortical TMS was 57.7 ^ 9.6 (%) (in rest, it was usually hard to elicit, in subjects that it was obtainable, rest motor threshold was about 85%). In experiment 1, due to low group sizes and some stimulation groups deviating from normal distribution, nonparametric Friedmann and Wilcoxon tests were administered. The mean amplitude of the perioral MEP calculated at the end of each time period (10, 20, 30th min) did not reveal any significant differences in comparison with the baseline values. Table 1 displays pre and post stimulus perioral MEP response mean amplitude values for each subgroup. Additionally, facial nerve root TMS perioral MEP responses also did not change significantly (Table 3). In the second experimental study, the perioral MEP responses were elicited bilaterally in all subjects. The distribution was normal for all subgroups (ILCL, CLIL, ILIL, CLCL conditions) and repeated measures ANOVA was preferred; Bonferroni test was administered for post hoc
comparisons. The application of 5% lidocain/prilocain local anesthetic cream to the lower facial region for 60 – 90 min period induced moderate anesthesia level which diminished gradually after 30 –40 min following the end of application. Generally, we have determined an increase in amplitude at 15th and 35th min after the maximal anesthesia in all stimulation and recording conditions except CLIL (Fig. 1). These increases were significant in ILCL condition at 35th and 60th min (dF ¼ 4; F ¼ 9:9; P , 0:001; Bonferroni, 35th min: P , 0:05 and 60th min: P , 0:05) and in CLCL condition at 35th min (dF ¼ 4; F ¼ 3:7; P , 0:05; Bonferroni, 35th min: P , 0:05). The latency and duration values of the cortical TMS-perioral MEP responses are given in Table 2, the mean amplitude values are presented in the graphs of the Fig. 1 (see also Fig. 2 for MEP recording samples). Facial nerve root TMS perioral MEP responses did not display significant differences (Table 3).
5. Discussion Following 10 and 30 min of duration of repetitive electrical stimulation (at 5 Hz) of the lower facial skin unilaterally; the amplitude of the perioral MEPs to cortical TMS did not alter significantly compared to pre-experiment values. This finding is not compatible with the similar studies applied on the extremities (Luft et al., 2002; McKay et al., 2002; Ridding et al., 2000) and on pharyngeal mucosa (Fraser et al., 2002; Hamdy et al., 1997). The repetitive sustained stimulation may be expected to provide two different effects by means of trigeminal afferents to sensorimotor cortex and by the prolonged sustained excitation of the perioral muscles. The indirect stimulation of the perioral muscle fibers beneath the stimulation
Table 2 Mean latency and duration values (ms) of the perioral MEP responses to the cortical TMS in pre-poststimulus and pre-postanesthesia groups (mean ^ SD) Prestimulus
CL Latency CL Duration IL Latency IL Duration
9.62 ^ 0.44 22 ^ 2.3 9.57 ^ 0.4 22.3 ^ 2.3
Poststimulus*
9.7 ^ 0.35 22 ^ 2 9.6 ^ 0.3 22 ^ 2
*Post stimulus 30th min and postanesthesia 35th min.
Preanesthesia
Postanesthesia*
Anesthetized side
Unanesthetized side
Anesthetized side
Unanesthetized side
9.63 ^ 0.7 22.4 ^ 2 9.7 ^ 0.56 22 ^ 2,1
9.7 ^ 0.64 22.7 ^ 2.3 9.74 ^ 0.52 23 ^ 2,9
9.5 ^ 0.62 23 ^ 2,9 9.7 ^ 0.62 22.7 ^ 2,6
9.6 ^ 0.4 22.8 ^ 2,4 9.8 ^ 0.6 23 ^ 2,9
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Table 3 Mean latency and amplitude values of the pre-post stimulus/anesthesia perioral MEP responses to the facial nerve root TMS (Mean ^ SD) Pre-poststimulus
Amplitude (mV) Latency (ms)
Preanesthesia
Postanesthesia
Prestimulus
Poststimulus
Unanesthetized side
Anesthetized side
Unanesthetized side
Anesthetized side
1417 ^ 431 4.2 ^ 0.4
1412 ^ 435 4.2 ^ 0.4
1366 ^ 513 4.1 ^ 0.3
1491 ^ 384 4.3 ^ 0.5
1398 ^ 516 4.1 ^ 0.3
1450 ^ 396 4.2 ^ 0.5
electrode would influence the changes in the amplitude of the perioral MEPs to cortical magnetic stimulation. However, the possibility of the effects of the perioral muscles should not be considered for two reasons. First, the facial muscles are completely different than limb muscles and even from masseter physiologically (Shahani and Young, 1973). They lack of marked silent period with muscle nerve or cutaneous nerve stimulation (Cruccu et al., 1997; Shahani and Young, 1973). The facial musculature are not tied to a bone and to a joint; they are almost completely devoid of deep sensory receptors (muscle spindle, tendon organs, joint receptors) and muscle afferent nerve fibers (Nordin and Hagdarth, 1989; Nordin et al., 1986; Popelle, 1993; Lin and Sessle, 1994; Cruccu et al.,
1997; Connor and Abbs, 1998; Trulsson and Johansson, 2002). Any kind of peripheral effect should have come from the trigeminal sensory afferents. It was also reported that the mechanoreceptors found within the facial skin and oral mucosa provide kinesthetic and proprioceptive information about orofacial movements (Connor and Abbs, 1998; Johansson et al., 1988; Lin and Sessle, 1994; Trulsson and Johansson, 2002). On the other hand, it has been reported that the cutaneous stimulation at the periphery does not produce significant cortical changes and muscle afferents play the prominent role in cortical modulation (Ridding et al., 2000). One additional possibility is that the site, duration, and frequency of the stimulation variables, might have not been adequate for this study, although
Fig. 1. The graphs display postanesthesia mean amplitude variations (mean mV ^ SD, black line) of the perioral MEPs in 4 different conditions (ILCL, ILIL, CLIL, CLCL) of a total 10 subjects. There occurs a noticeable amplitude increase at 15th and 35th min in all conditions except CLIL (*P , 0:05 at 35 and 60th min in ILCL condition and at 35th min in CLCL condition). In ILCL condition graph, the gray line that shows the changes of the anesthesia level (same for all conditions) was added (Anest: Anesthesia).
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Fig. 2. Time course of amplitude changes of the perioral MEPs in ILCL condition (each sweep is the average of 4 MEPs). In this case, increase of MEPs amplitude occurred 15 min after one and half hour local anesthesia application, continued at 35 and 60th min and returned to the baseline value at 120th min.
the stimulation conditions performed were similar to some other studies (Fraser et al., 2002; Hamdy et al., 1997; McKay et al., 2002). The local application of %5 lidocain/prilocain anesthetic cream to the cheek-lip skin in the lower facial region transiently diminished tactile and pain sensation (Arendt-Nielsen and Bjerring, 1989; Kundu and Achar, 2002). During the moderate anesthesia of the lower facial skin area, at the 35 and 60 th min, the amplitude of the perioral MEP responses contralateral to anaesthetized side were significantly increased with the hemisphere TMS ipsilateral to anaesthetized side. The hemisphere TMS contralateral to the anaesthetized side also provided significant increase in amplitude at 35th min in the perioral muscle MEP responses contralateral to the anesthetized side. All these electrophysiological changes are partly similar to that of the previous ischemic nerve block studies, which demonstrated that the related motor cortical representation areas expand, and the motor cortex excitability increases, including the amplitude enhancement of the proximal muscles of same extremity as well as in the opposite homolog muscles (Brasil-Neto et al., 1992; Ridding and Rothwell, 1995; Werhahn et al., 2002; Ziemann et al., 1998). Although we have mean amplitude increases at the opposite homolog
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muscles with both hemisphere stimulations (especially with the hemisphere stimulation ipsilateral to the anaesthetized side), they are less than those obtained in ischemic nerve block studies (INB), probably due to the topical anesthesia that we have used created only a moderate cutaneous anesthesia while superficial and deep anesthesia with the complete sensory-motor block was provided in the INB studies (Brasil-Neto et al., 1992; Ridding and Rothwell, 1995; Werhahn et al., 2002; Ziemann et al., 1998). The hand motor cortex area enlarges in patients with peripheral facial nerve involvement (Luft et al., 2002; Rijntjes et al., 1997). After facial nerve transsection, a forearm motor cortex expansion and after forearm amputation, an expansion in the representation of facial and shoulder motor cortex is demonstrated in rats (Sanes et al., 1988). In monkeys, 10 years after forearm amputation, it has been observed that some facial afferents direct themselves to cuneate nucleus instead of trigeminal nucleus (Jain et al., 2000); in another study with monkeys, it was suggested that the expansion of the lower jaw and face representation, in chronic deafferentation of the upper limb, would have had to occur at trigeminal relay centers within brainstem and/or thalamus and/or within the cortex itself (Manger et al., 1997). Therefore, the perioral muscles are open to modulations in the representation of the motor cortex, and are effected by any kind of changes coming from the periphery. It has been argued in the previous studies with transient loss of sensory input that changes do not occur at spinal or brainstem level but prominently in the cortical level, and this has been explained by the nonexistence of changes in responses to the transcranial, cervical, and brainstem electrical stimulation responses contrary to those changes elicited by TMS (Werhahn et al., 2002; Ziemann et al., 1998; ). The regional anesthesia of the lower facial skin unilaterally must have reduced inputs mainly to the contralateral thalamus and to the sensorimotor cortex. Such reduction in the tonic sensory flow from the face area should have triggered some of the disinhibition phenomena in the cortex. Disinhibition might have also occurred in the ipsilateral hemisphere. It has been reported that the cortical disinhibition takes place in reduced sensory input from the extremities (Werhahn et al., 2002; Ziemann et al., 1998). Contralateral cortical disinhibition must have been carried to the other hemisphere via callosal pathways. Therefore both hemispheres are expected to send down more descending impulses to both perioral muscles, especially to the unanesthetized side. The perioral or lower facial muscles are represented mainly in the contralateral primary motor cortex (M1) as well as in the ventral-lateral premotor cortex (LPMCV) in non human primate (Morecraft et al., 2001) where the bilateral perioral MEPs are evoked by the unilateral TMS in human subjects (Meyer et al., 1994). Probably the perioral muscles are innervated bilaterally due to the different tasks with different cortical-subcortical foci (Morecraft et al.,
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2001). Therefore unilateral anesthesia should first be effective in the contralateral motor cortex, and the disinhibition seems to be among the causes of the motor response enhancement to TMS. At the present study, it seems that the mechanisms that initiate the disinhibition in the contralateral hemisphere are directed from the ipsilateral volleys to the unanesthetized side and are transferred by callosal fibers to ipsilateral hemisphere again directed to the unanesthetized side. There were not evident amplitude changes in the CLIL condition while the amplitude increases in the ILIL condition remained insignificant. It is not an easy task to account for the nonexistence of clear amplitude increase in the MEP of the perioral muscle ipsilateral to the anaesthetized side with hemispheral stimulation contralateral to anaesthetized side (CLIL); however, we may suppose that brain perceives a problem in this area, and initiates an adaptation activity in the neighboring cortical area and in the same cortical area in the other hemisphere directed to the unanesthetized side. This result is partially similar to Rossini et al.’s study (1996a,1996b) which showed that the motor map of FDI reduces in size during radial and median nerve anesthetic block at the wrist in which the FDI muscle maintains its usual proprioceptive feedback and strength through the ulnar nerve even when deprived of cutaneous sensory information. However, at the present study, mean amplitude of the MEP of the perioral muscle ipsilateral to the anaesthetized side with hemispheral stimulation contralateral to anaesthetized side (CLIL) remained unchanged probably because of lower anesthesia level compared to the level with mepivacaine injection they have provided. Another difference was that in Rossini et al.’s study, there was also partly a phalangeal joint anesthesia. This study supports the conclusion that cortical plastic changes develop in minutes and in hours, as indicated in many other previous studies (Merzenich et al., 1983; Sanes and Donoghue, 2000; Sanes et al., 1988; Wall et al., 2002). We know that following 2 h stimulation of median nerve, pinch strength increases (Conforto et al., 2002). Moreover, following anesthesia limited to the arm, an improvement is observed in the functions of the hand in a patient with a chronical stroke who has lost his muscle strength and lacks manual skills (Muellbacher et al., 2002). For the moment, we cannot claim that the methods noted in this study can be adapted in rehabilitation studies; we need additional studies which will validate our conclusion. In conclusion, repetitive facial nerve stimulation does not produce any change in the facial motor cortex and thus may not be identified as an appropriate method for the rehabilitation of related muscle weakness. On the other hand, topical anesthesia to the lower facial region leads to cortical modulation. Both hemispheres seem to be effective in developing rapid plastic changes that are directed to
the normal side. We consider that this hemispheral coordination even at the moderate cutaneous anesthesia conditions, arises from the importance of lower facial musculature and bilateral innervation of the corticonuclear fibers to lower facial muscles. We suggest that this peculiarity and local anesthesia methods to induce more plastic changes will be helpful in prospective rehabilitation procedures.
Acknowledgements This work has been supported in part by the Turkish Academy of Sciences (TUBA).
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Changes in the perioral muscle responses to cortical TMS induced by decrease of sensory input and electrical stimulation to lower facial region N. Yıldıza,c,*, S. Yıldıza,c, C. Ertekina,b, I. Aydog˘dua,b, B. Uludaga,b a
Departments of Clinical Neurophysiology, Ege University, Medical School Hospital, Izmir, Turkey b Departments of Neurology, Ege University, Medical School Hospital, Izmir, Turkey c Department of Neurology, Medical School Hospital, Abant Izzet Baysal University, Golkoy, 14300 Bolu, Turkey Accepted 25 April 2004 Available online 7 June 2004
Abstract Objective: To determine the changes in the motor cortex due to repetitive electrical stimulation and cutaneous anesthesia in lower facial region. Methods: A total of 11 subjects participated in the study of repetitive electrical stimulation, and 10 other subjects in the study of lower facial anesthesia. Facial nerve root and face associated cortical MEPs by transcranial magnetic stimulation (eight-shaped coil) were recorded from perioral muscles pre- and post- electrical stimulation and lower facial anesthesia. Cheek near to the corner of the mouth was transcutaneously stimulated by bipolar surface electrode giving repetitive electrical shocks at 5 Hz. Five percent lidocain/prilocain local anesthetic cream was applied to left or right lip-cheek region. Results: There was no significant change in perioral MEP responses after 10 – 30 min of 5 Hz electrical stimulation. We found a significant increase of amplitude in cortical MEP recordings during lower facial anesthesia especially in cases of cortical magnetic stimulations ipsilateral and contralateral to the anaesthetized side and in perioral recordings contralateral to the anaesthetized side. Conclusions: The present study demonstrates that topical anesthesia to the lower facial region leads to cortical modulation and fast plastic changes in both hemispheres that are directed to the normal side. q 2004 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved. Keywords: Plasticity; Neuronal-motor cortex-face-evoked potentials; Motor-anesthesia; Local-electrical stimulation
1. Introduction It has been reported recently that there are relevant motor cortex excitability and MEP amplitude increases during and after the repetitive nerve stimulations at the periphery (Luft et al., 2002; Ridding et al., 2000). Similarly, following an ischemic nerve block, there occurs an expansion in the motor cortex representation area, an increase in the motor cortex excitability and in the MEP amplitudes of the same extremity proximal muscles as well as in the opposite homolog muscles (Brasil-Neto et al., 1992; Ridding et al., 1995; Werhahn et al., 2002; Ziemann et al., 1998). * Corresponding author. Address: Department of Neurology, School of Medicine, Abant Izzet Baysal University, Golkoy, 14300 Bolu, Turkey. Tel.: þ 90-374-217-85-05; fax: þ 90-253-45-59. E-mail addresses: [email protected] (N. Yıldız), erteker@ unimedya.net.tr (C. Ertekin).
While regional anesthesia and stimulation studies are conducted more on the extremity muscles and nerves, studies on the nerves and muscles of the face remained relatively less in number. Among these, a number of studies have demonstrated that there is an expansion in hand motor cortex area in cases with peripheral facial nerve paralysis (Rijntjes et al., 1997) and after application of botulinum toxin in the hemifacial spasms (Liepert et al., 1999). The purpose of the current study is to analyze the variations in facial motor cortex due to repetitive electrical stimulation and decrease of the sensory input on the lower facial region. We hypothesized that both hemispheres could have rapid rearrangements. This is particularly due to the importance of lower facial musculature and of the bilateral innervation of the corticonuclear fibers to lower facial muscles which also has been discussed previously (Benecke et al., 1988; Huang et al., 1988; Jenny and Saper, 1987;
1388-2457/$30.00 q 2004 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.clinph.2004.04.021
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Kuypers, 1958; Meyer et al., 1994; Morecraft et al., 2001; Penfield, 1958; Urban et al., 1997).
2. Materials and method Twenty-one healthy subjects participated in two separate experiments. Their written consents were obtained and the ethical committee of Ege University has approved the conduct of the study. 2.1. Standard conditions Perioral muscle responses were recorded unilaterally in electrical stimulation experiment (experiment 1), and bilaterally in topical anesthesia experiment (experiment 2). Nicolet Viking IV electromyography was used. The EMG recordings were made by Ag – AgCl electrodes which were placed 1 – 1.5 cm. upper and lower corners of the mouth. High and low pass filters were 150 Hz and 10 KHz. High pass filter was adjusted to the 150 Hz to prevent the head-neck movement artifact. The subjects were reminded to hold tightly the paper tissue placed between their lips during transcranial magnetic stimulation to avoid squeezing the teeth. Holding paper tissue helped to provide stable maximal contraction with very effective facilitation; volume conduction possibility from masticator muscle was lessened by avoiding the squeeze of the teeth. The level of contraction was controlled by auditory feedback of the EMG signal. Cortical and facial nerve root TMS studies were performed with eight-shaped coil connected to the Magstim 200 magnetic stimulator (Novametrix, Dyfed, Whales, UK). The center of the coil was placed 2– 4 cm lateral and 2 –3 cm frontal to Cz., posteromedial and tangential in cortical stimulation with about 450 angle to the vertex; in facial nerve root stimulation, a few centimeters behind the ear, in the parietooccipital region. These positions were marked on the scalp with a pen to ensure an identical coil placement throughout the experiment. Four to eight responses were recorded from each stimulation site. The amplitudes of the perioral muscle MEPs were peak to peak. The arithmetic mean values were considered for each set of experiments. 200 mV was the limit for the MEP amplitude to avoid interference of the volume conduction effect. This limit was concluded from another previously unpublished study of ours in patients with peripheral facial paralysis which demonstrated volume conduction effect (close to 200 mV) on the totally axonal degenerated side from the intact side.
recorded ipsilateral to the stimulated site. TMS recordings and measurements were performed as mentioned above. Cheek near to the corner of the mouth was transcutaneously stimulated by bipolar surface electrodes with duration of 0.05– 0.1 ms, and in frequency of 5 Hz. The stimulus intensity was increased until the emergence of lower facial muscles twitching. Standardization was performed according to twitching emergence level, stimulus properties were arranged to achieve this level. In 6 cases 10 min, and in 5 cases 30 min continuous stimulations were applied. Perioral MEP responses to the face associated cortex were recorded before and after repetitive electrical stimulation (10 – 20– 30th min). Facial nerve root TMS were recorded at the beginning of the pre and post electrical stimulus period. 3.2. Experiment 2 Ten healthy subjects, aged between 19 and 59 (mean age 40.5) participated. Bilateral perioral recordings, TMS application, and measurements were recorded as mentioned above. Topical anesthesia was performed with 5% of lidocain/prilocain local anesthetic cream (EMLA). This has the known effect of blocking the free nerve endings and receptors in the skin (Arendt-Nielsen et al., 1989; Kundu and Achar, 2002). The cream was applied in the form of a thin layer to left or right cheek skin and to lip mucosa and both regions were plastered for a period of 60– 90 min (Arendt-Nielsen and Bjerring, 1989; Kundu and Achar, 2002). The level of anesthesia was carefully evaluated by pinprick and light touch examination. In cases where the level was decided to be insufficient, an additional 30 min period was added with plastered cream application. Before the application of the cream (0), and after (þ 15, þ 35, þ 60, þ 120 min), cortical MEPs were recorded. Facial nerve root MEPs were recorded at the beginning pre- and postanesthesia periods. Cheek-lip anesthesia level was scored over touch-andpain perception as below: normal (no anesthesia) ¼ 0; mild ¼ 1; mild-moderate ¼ 2; moderate ¼ 3; total ¼ 4. Both stimulation and recording places were labeled in relation to anesthetized side as described: ILIL, hemisphere stimulation and perioral recordings ipsilateral to the anaesthetized side; ILCL, hemisphere stimulation ipsilateral to anaesthetized side and perioral recordings contralateral to the anaesthetized side; CLCL, hemisphere stimulation and perioral recordings contralateral to the anaesthetized side; CLIL, hemisphere stimulation contralateral to anaesthetized side and perioral recordings ipsilateral to the anaesthetized side.
3. Experimental design 3.3. Data analysis 3.1. Experiment 1 11 healthy subjects, aged between 20 and 50 (mean age 33) participated. Perioral muscle responses were
Poststimulus and postanesthesia mean values for each time period were compared for baseline mean amplitude values of each experiment.
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Table 1 Pre- and post- stimulus mean amplitude (mV) values of the perioral MEP responses to the cortical TMS. (mean ^ SD, N ¼ 6 and N ¼ 5) Hemisphere
CL Ampl.* IL Ampl.
10 min repetitive stimulation
30 min repetitive stimulation
Prestim.
10 th min
20 th min
30 th min
Prestim.
10 th min
20 th min
30 th min
630 ^ 288 441 ^ 233
583 ^ 262 441 ^ 257
612 ^ 289 416 ^ 280
594 ^ 213 441 ^ 309
570 ^ 288 354 ^ 172
534 ^ 211 368 ^ 184
580 ^ 189 380 ^ 179
542 ^ 220 322 ^ 115
CL*, Contralateral; IL, Ipsilateral; Ampl, Amplitude; Lat., Latency; Dur., Duration.
The distribution properties were assessed with normal distribution curves and with Kolmogorov Smirnov/Shapiro Wilk tests. In normal distribution groups, noting the dependent variable, repeated measures ANOVA was performed and for post hoc pairwise comparisons, Bonferroni procedure was used. For nonparametric data, we used Friedmann and Wilcoxon tests with correction for multiple comparisons.
4. Results In both experiments, pre and post applications, the mean latency and duration values displayed no significant differences (Tables 1 and 2). Rest motor threshold for facial nerve root TMS was 44.5 ^ 5.8 (%). Active motor threshold for cortical TMS was 57.7 ^ 9.6 (%) (in rest, it was usually hard to elicit, in subjects that it was obtainable, rest motor threshold was about 85%). In experiment 1, due to low group sizes and some stimulation groups deviating from normal distribution, nonparametric Friedmann and Wilcoxon tests were administered. The mean amplitude of the perioral MEP calculated at the end of each time period (10, 20, 30th min) did not reveal any significant differences in comparison with the baseline values. Table 1 displays pre and post stimulus perioral MEP response mean amplitude values for each subgroup. Additionally, facial nerve root TMS perioral MEP responses also did not change significantly (Table 3). In the second experimental study, the perioral MEP responses were elicited bilaterally in all subjects. The distribution was normal for all subgroups (ILCL, CLIL, ILIL, CLCL conditions) and repeated measures ANOVA was preferred; Bonferroni test was administered for post hoc
comparisons. The application of 5% lidocain/prilocain local anesthetic cream to the lower facial region for 60 – 90 min period induced moderate anesthesia level which diminished gradually after 30 –40 min following the end of application. Generally, we have determined an increase in amplitude at 15th and 35th min after the maximal anesthesia in all stimulation and recording conditions except CLIL (Fig. 1). These increases were significant in ILCL condition at 35th and 60th min (dF ¼ 4; F ¼ 9:9; P , 0:001; Bonferroni, 35th min: P , 0:05 and 60th min: P , 0:05) and in CLCL condition at 35th min (dF ¼ 4; F ¼ 3:7; P , 0:05; Bonferroni, 35th min: P , 0:05). The latency and duration values of the cortical TMS-perioral MEP responses are given in Table 2, the mean amplitude values are presented in the graphs of the Fig. 1 (see also Fig. 2 for MEP recording samples). Facial nerve root TMS perioral MEP responses did not display significant differences (Table 3).
5. Discussion Following 10 and 30 min of duration of repetitive electrical stimulation (at 5 Hz) of the lower facial skin unilaterally; the amplitude of the perioral MEPs to cortical TMS did not alter significantly compared to pre-experiment values. This finding is not compatible with the similar studies applied on the extremities (Luft et al., 2002; McKay et al., 2002; Ridding et al., 2000) and on pharyngeal mucosa (Fraser et al., 2002; Hamdy et al., 1997). The repetitive sustained stimulation may be expected to provide two different effects by means of trigeminal afferents to sensorimotor cortex and by the prolonged sustained excitation of the perioral muscles. The indirect stimulation of the perioral muscle fibers beneath the stimulation
Table 2 Mean latency and duration values (ms) of the perioral MEP responses to the cortical TMS in pre-poststimulus and pre-postanesthesia groups (mean ^ SD) Prestimulus
CL Latency CL Duration IL Latency IL Duration
9.62 ^ 0.44 22 ^ 2.3 9.57 ^ 0.4 22.3 ^ 2.3
Poststimulus*
9.7 ^ 0.35 22 ^ 2 9.6 ^ 0.3 22 ^ 2
*Post stimulus 30th min and postanesthesia 35th min.
Preanesthesia
Postanesthesia*
Anesthetized side
Unanesthetized side
Anesthetized side
Unanesthetized side
9.63 ^ 0.7 22.4 ^ 2 9.7 ^ 0.56 22 ^ 2,1
9.7 ^ 0.64 22.7 ^ 2.3 9.74 ^ 0.52 23 ^ 2,9
9.5 ^ 0.62 23 ^ 2,9 9.7 ^ 0.62 22.7 ^ 2,6
9.6 ^ 0.4 22.8 ^ 2,4 9.8 ^ 0.6 23 ^ 2,9
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Table 3 Mean latency and amplitude values of the pre-post stimulus/anesthesia perioral MEP responses to the facial nerve root TMS (Mean ^ SD) Pre-poststimulus
Amplitude (mV) Latency (ms)
Preanesthesia
Postanesthesia
Prestimulus
Poststimulus
Unanesthetized side
Anesthetized side
Unanesthetized side
Anesthetized side
1417 ^ 431 4.2 ^ 0.4
1412 ^ 435 4.2 ^ 0.4
1366 ^ 513 4.1 ^ 0.3
1491 ^ 384 4.3 ^ 0.5
1398 ^ 516 4.1 ^ 0.3
1450 ^ 396 4.2 ^ 0.5
electrode would influence the changes in the amplitude of the perioral MEPs to cortical magnetic stimulation. However, the possibility of the effects of the perioral muscles should not be considered for two reasons. First, the facial muscles are completely different than limb muscles and even from masseter physiologically (Shahani and Young, 1973). They lack of marked silent period with muscle nerve or cutaneous nerve stimulation (Cruccu et al., 1997; Shahani and Young, 1973). The facial musculature are not tied to a bone and to a joint; they are almost completely devoid of deep sensory receptors (muscle spindle, tendon organs, joint receptors) and muscle afferent nerve fibers (Nordin and Hagdarth, 1989; Nordin et al., 1986; Popelle, 1993; Lin and Sessle, 1994; Cruccu et al.,
1997; Connor and Abbs, 1998; Trulsson and Johansson, 2002). Any kind of peripheral effect should have come from the trigeminal sensory afferents. It was also reported that the mechanoreceptors found within the facial skin and oral mucosa provide kinesthetic and proprioceptive information about orofacial movements (Connor and Abbs, 1998; Johansson et al., 1988; Lin and Sessle, 1994; Trulsson and Johansson, 2002). On the other hand, it has been reported that the cutaneous stimulation at the periphery does not produce significant cortical changes and muscle afferents play the prominent role in cortical modulation (Ridding et al., 2000). One additional possibility is that the site, duration, and frequency of the stimulation variables, might have not been adequate for this study, although
Fig. 1. The graphs display postanesthesia mean amplitude variations (mean mV ^ SD, black line) of the perioral MEPs in 4 different conditions (ILCL, ILIL, CLIL, CLCL) of a total 10 subjects. There occurs a noticeable amplitude increase at 15th and 35th min in all conditions except CLIL (*P , 0:05 at 35 and 60th min in ILCL condition and at 35th min in CLCL condition). In ILCL condition graph, the gray line that shows the changes of the anesthesia level (same for all conditions) was added (Anest: Anesthesia).
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Fig. 2. Time course of amplitude changes of the perioral MEPs in ILCL condition (each sweep is the average of 4 MEPs). In this case, increase of MEPs amplitude occurred 15 min after one and half hour local anesthesia application, continued at 35 and 60th min and returned to the baseline value at 120th min.
the stimulation conditions performed were similar to some other studies (Fraser et al., 2002; Hamdy et al., 1997; McKay et al., 2002). The local application of %5 lidocain/prilocain anesthetic cream to the cheek-lip skin in the lower facial region transiently diminished tactile and pain sensation (Arendt-Nielsen and Bjerring, 1989; Kundu and Achar, 2002). During the moderate anesthesia of the lower facial skin area, at the 35 and 60 th min, the amplitude of the perioral MEP responses contralateral to anaesthetized side were significantly increased with the hemisphere TMS ipsilateral to anaesthetized side. The hemisphere TMS contralateral to the anaesthetized side also provided significant increase in amplitude at 35th min in the perioral muscle MEP responses contralateral to the anesthetized side. All these electrophysiological changes are partly similar to that of the previous ischemic nerve block studies, which demonstrated that the related motor cortical representation areas expand, and the motor cortex excitability increases, including the amplitude enhancement of the proximal muscles of same extremity as well as in the opposite homolog muscles (Brasil-Neto et al., 1992; Ridding and Rothwell, 1995; Werhahn et al., 2002; Ziemann et al., 1998). Although we have mean amplitude increases at the opposite homolog
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muscles with both hemisphere stimulations (especially with the hemisphere stimulation ipsilateral to the anaesthetized side), they are less than those obtained in ischemic nerve block studies (INB), probably due to the topical anesthesia that we have used created only a moderate cutaneous anesthesia while superficial and deep anesthesia with the complete sensory-motor block was provided in the INB studies (Brasil-Neto et al., 1992; Ridding and Rothwell, 1995; Werhahn et al., 2002; Ziemann et al., 1998). The hand motor cortex area enlarges in patients with peripheral facial nerve involvement (Luft et al., 2002; Rijntjes et al., 1997). After facial nerve transsection, a forearm motor cortex expansion and after forearm amputation, an expansion in the representation of facial and shoulder motor cortex is demonstrated in rats (Sanes et al., 1988). In monkeys, 10 years after forearm amputation, it has been observed that some facial afferents direct themselves to cuneate nucleus instead of trigeminal nucleus (Jain et al., 2000); in another study with monkeys, it was suggested that the expansion of the lower jaw and face representation, in chronic deafferentation of the upper limb, would have had to occur at trigeminal relay centers within brainstem and/or thalamus and/or within the cortex itself (Manger et al., 1997). Therefore, the perioral muscles are open to modulations in the representation of the motor cortex, and are effected by any kind of changes coming from the periphery. It has been argued in the previous studies with transient loss of sensory input that changes do not occur at spinal or brainstem level but prominently in the cortical level, and this has been explained by the nonexistence of changes in responses to the transcranial, cervical, and brainstem electrical stimulation responses contrary to those changes elicited by TMS (Werhahn et al., 2002; Ziemann et al., 1998; ). The regional anesthesia of the lower facial skin unilaterally must have reduced inputs mainly to the contralateral thalamus and to the sensorimotor cortex. Such reduction in the tonic sensory flow from the face area should have triggered some of the disinhibition phenomena in the cortex. Disinhibition might have also occurred in the ipsilateral hemisphere. It has been reported that the cortical disinhibition takes place in reduced sensory input from the extremities (Werhahn et al., 2002; Ziemann et al., 1998). Contralateral cortical disinhibition must have been carried to the other hemisphere via callosal pathways. Therefore both hemispheres are expected to send down more descending impulses to both perioral muscles, especially to the unanesthetized side. The perioral or lower facial muscles are represented mainly in the contralateral primary motor cortex (M1) as well as in the ventral-lateral premotor cortex (LPMCV) in non human primate (Morecraft et al., 2001) where the bilateral perioral MEPs are evoked by the unilateral TMS in human subjects (Meyer et al., 1994). Probably the perioral muscles are innervated bilaterally due to the different tasks with different cortical-subcortical foci (Morecraft et al.,
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2001). Therefore unilateral anesthesia should first be effective in the contralateral motor cortex, and the disinhibition seems to be among the causes of the motor response enhancement to TMS. At the present study, it seems that the mechanisms that initiate the disinhibition in the contralateral hemisphere are directed from the ipsilateral volleys to the unanesthetized side and are transferred by callosal fibers to ipsilateral hemisphere again directed to the unanesthetized side. There were not evident amplitude changes in the CLIL condition while the amplitude increases in the ILIL condition remained insignificant. It is not an easy task to account for the nonexistence of clear amplitude increase in the MEP of the perioral muscle ipsilateral to the anaesthetized side with hemispheral stimulation contralateral to anaesthetized side (CLIL); however, we may suppose that brain perceives a problem in this area, and initiates an adaptation activity in the neighboring cortical area and in the same cortical area in the other hemisphere directed to the unanesthetized side. This result is partially similar to Rossini et al.’s study (1996a,1996b) which showed that the motor map of FDI reduces in size during radial and median nerve anesthetic block at the wrist in which the FDI muscle maintains its usual proprioceptive feedback and strength through the ulnar nerve even when deprived of cutaneous sensory information. However, at the present study, mean amplitude of the MEP of the perioral muscle ipsilateral to the anaesthetized side with hemispheral stimulation contralateral to anaesthetized side (CLIL) remained unchanged probably because of lower anesthesia level compared to the level with mepivacaine injection they have provided. Another difference was that in Rossini et al.’s study, there was also partly a phalangeal joint anesthesia. This study supports the conclusion that cortical plastic changes develop in minutes and in hours, as indicated in many other previous studies (Merzenich et al., 1983; Sanes and Donoghue, 2000; Sanes et al., 1988; Wall et al., 2002). We know that following 2 h stimulation of median nerve, pinch strength increases (Conforto et al., 2002). Moreover, following anesthesia limited to the arm, an improvement is observed in the functions of the hand in a patient with a chronical stroke who has lost his muscle strength and lacks manual skills (Muellbacher et al., 2002). For the moment, we cannot claim that the methods noted in this study can be adapted in rehabilitation studies; we need additional studies which will validate our conclusion. In conclusion, repetitive facial nerve stimulation does not produce any change in the facial motor cortex and thus may not be identified as an appropriate method for the rehabilitation of related muscle weakness. On the other hand, topical anesthesia to the lower facial region leads to cortical modulation. Both hemispheres seem to be effective in developing rapid plastic changes that are directed to
the normal side. We consider that this hemispheral coordination even at the moderate cutaneous anesthesia conditions, arises from the importance of lower facial musculature and bilateral innervation of the corticonuclear fibers to lower facial muscles. We suggest that this peculiarity and local anesthesia methods to induce more plastic changes will be helpful in prospective rehabilitation procedures.
Acknowledgements This work has been supported in part by the Turkish Academy of Sciences (TUBA).
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