Representation of facial muscles in human motor cortex
1 The Krembil Neuroscience Centre and Toronto Western Research Institute
2 Division of Neurology, Department of Medicine, University of Toronto, Ontario, Canada
Abstract
Whether there is a projection from the primary motor cortex (M1) to upper facial muscles and how the facial M1 area is modulated by intracortical inhibitory and facilitatory circuits remains controversial. To assess these issues, we applied transcranial magnetic stimulation (TMS) to the M1 and recorded from resting and active contralateral (C-OOc) and ipsilateral orbicularis oculi (I-OOc), and contralateral (C-Tr) and ipsilateral triangularis (I-Tr) muscles in 12 volunteers. In five subjects, the effects of stimulating at different scalp positions were assessed. Paired TMS at interstimulus intervals (ISIs) of 2 ms were used to elicit short interval intracortical inhibition (SICI) and ISI of 10 ms for intracortical facilitation (ICF). Long interval intracortical inhibition (LICI) was evaluated at ISIs between 50 and 200 ms, both at rest and during muscle activation. The silent period (SP) was also determined. C-OOc and I-OOc responses were recorded in all subjects. The optimal position for eliciting C-OOc responses was lateral to the hand representation in all subjects and MEP amplitude markedly diminished when the coil was placed 2 cm away from the optimal position. For the I-OOc, responses were present in more scalp sites and the latency decreased with more anterior placement of the coil. C-Tr response was recorded in 10 out of 12 subjects and the I-Tr muscle showed either no response or low amplitude response, probably due to volume conduction. SICI and ICF were present in the C-OOc and C-Tr, but not in the I-OOc muscle. Muscle activation attenuated SICI and ICF. LICI at rest showed facilitation at 50 ms ISI in all muscles, but there was no significant inhibition at other ISIs. There was no significant inhibition or facilitation with the LICI protocol during muscle contraction. The SP was present in the C-OOc, C-Tr and I-OOc muscles and the mean durations ranged from 92 to 104 ms. These findings suggest that the I-OOc muscle response is probably related to the first component (R1) of the blink reflex. There is M1 projection to the contralateral upper and lower facial muscles in humans and the facial M1 area is susceptible to cortical inhibition and facilitation, similar to limb muscles.
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Introduction
The facial motor system has several unique features. Facial muscles carry few or no muscle spindles (Voss, 1956; Lovell et al. 1977). The facial muscles are under both voluntary and emotional control (Lees, 1988). Dissociation between voluntary and emotional movements may occur in patients with supranuclear lesions, suggesting that they are under the control of different descending pathways (Hopf et al. 1992). Since the upper face is usually spared in patients with hemispheric lesion, the upper facial muscles are considered to have bilateral cortical innervation (Brodal, 1981). However, it is controversial whether there are projections from the primary motor cortex (M1) to the upper facial muscles in humans. While some authors reported responses in the upper and lower facial muscles with TMS of the facial M1 area, the latencies were similar to the first component (R1) of the blink reflex and the central delay is significantly longer for facial muscles compared to limb muscles or muscles innervated by other cranial nerves (Benecke et al. 1988; Cruccu et al. 1990b). A study using paired TMS at short interstimulus intervals found that the lower facial muscles followed the same cortical inhibitory and facilitatory pattern as in hand muscles, but the upper facial muscles showed no cortical inhibition and reduced facilitation. The authors suggested that the movements of the upper face are mainly modulated by brainstem projections (Kobayashi et al. 2001). Another study found no contralateral upper facial responses from stimulation of the facial M1 area but there were low amplitude responses from stimulation of the mesial frontal region, suggesting that the upper facial movements are controlled by the medial frontal cortex rather than by the M1 (Sohn et al. 2004).
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TMS can be used to evaluate cortical excitability (Hallett, 2000). A suprathreshold TMS pulse delivered during voluntary contraction of a target muscle results in a transient interruption of the muscle activity, known as the silent period (SP). The SP is due to activation of inhibitory circuits in the spinal cord and the cortex (Fuhr et al. 1991; Cantello et al. 1992; Inghilleri et al. 1993b). Inhibitory and facilitatory interactions in the motor cortex can also be assessed with paired-pulse TMS (Kujirai et al. 1993; Chen, 2000; Kobayashi & Pascual-Leone, 2003). Studies in limb muscles showed that a subthreshold conditioning stimulus (CS) followed by a suprathreshold test stimulus (TS) at interstimulus intervals (ISIs) between 1 and 4 ms resulted in intracortical inhibition (short interval intracortical inhibition, SICI) (Kujirai et al. 1993), whereas ISIs of 7–20 ms resulted in intracortical facilitation (ICF) (Kujirai et al. 1993; Ziemann et al. 1996c). When a suprathreshold TS is paired with a suprathreshold CS at longer ISIs (50–200 ms), the amplitude of the motor-evoked potential (MEP) is reduced compared to the amplitude of the MEP elicited by the TS alone, due to long interval intracortical inhibition (LICI) (Valls-Sole et al. 1992; Wassermann et al. 1996). SICI and LICI are mediated by different mechanisms (Sanger et al. 2001). SICI and ICF can be observed in proximal and distal muscles in both upper and lower limbs (Chen et al. 1998).
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The aim of this study is to determine whether there are projections from the M1 to facial muscles and to assess the intracortical inhibitory and excitatory circuits of the human facial M1.
Methods
We studied 12 healthy volunteers (8 males, 4 females; aged 47 ± 12 (S.D.) years, range 29–60 years). Subjects were recruited through advertisements in the community and hospital postings. All subjects gave their written informed consent and the University Health Network Research Ethics Board approved the protocol. All studies conformed to the standards set by the Declaration of Helsinki.
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EMG recording
The subjects were seated in a comfortable chair and surface EMG was recorded from the right and left frontalis (Fr), orbicularis oculi (OOc), triangularis (Tr, also known as depressor anguli oris) and masseter (Ma) muscles using disposable disc electrodes. For the Fr muscle, the recording electrode was placed 2.5 cm above the mid-point of the eyebrow and the reference electrode was located 2 cm laterally. For the OOc muscle, the recording electrode was placed in the middle of the lower lid, and the reference electrode was placed at the lateral angle of the eye. For the Tr muscle, a recording electrode was placed at the mid-point between the angle of the mouth and the lower border of the mandible, and the reference electrode was placed 3 cm laterally. Recordings from the Ma muscle were performed with the recording electrode over the muscle belly, at a mid-point between the zygomatic arch and the lower border of the mandible, and with the reference electrode positioned at the mandibular angle.
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EMG was monitored on a computer screen and through speakers set up at high gain. The signal was amplified (Intronix Technologies Corporation, model 2024F, Bolton, Ontario, Canada), filtered (band-pass: 2 Hz to 2.5 kHz), digitized at 5 kHz (Micro 1401, Cambridge Electronics Design, Cambridge, UK) and stored in a laboratory computer for offline analysis.
Transcranial magnetic stimulation
TMS was performed with a 7 cm figure-of-eight coil and two Magstim 200 stimulators (Magstim Company, Dyfed, UK) connected via a Bistim module. The coil was placed over the dominant motor cortex at the optimal site for eliciting motor-evoked potentials from the contralateral OOc (C-OOc). The location of this optimal site relative to the optimal site to evoke contraction in hand muscles was noted. The optimal site was marked on the scalp with a felt pen to ensure that the coil remained in the same place throughout the study. The handle of the coil pointed backwards and was perpendicular to the presumed direction of the central sulcus, approximately 45 deg to the midsagittal line. The direction of the induced current was from posterior to anterior.
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The resting motor threshold (MT) was determined by asking the subject to relax, maintain eyes open, and blink as little as possible. The active C-OOc MT was determined with the subject performing simultaneous sustained closure of the eyes and depression of the angles of the mouth, at about 50% of the maximum effort as determined through the sound of the EMG from the speaker and feedback from the investigators. The MT is expressed as a percentage of maximum stimulator output, measured to the nearest 1%. Resting MT was defined as the lowest intensity that elicited MEPs of > 50 μV in at least 5 out of 10 trials. For the active MT, the MEP threshold was >100 μV.
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Recordings from ipsilateral OOc (I-OOc) and C-OOc, as well as I-Tr and C-Tr, were performed in all experiments. The influence of coil position was studied in five subjects, and in three subjects the responses from I-Fr, C-Fr, I-Ma and C-Ma were also recorded. The blink reflex was assessed in all five subjects and the acoustic reflex in two subjects. The effect of coil position was evaluated with the stimulator output adjusted to elicit MEPs of about 0.3 mV with the coil at the optimal position for the C-OOc muscle. The mean stimulation intensity used in the five subjects studied was 80% (range 67–90%) of the maximum stimulator output. TMS was delivered at the optimal site, and at sites 2, 4 and 6 cm anterior, posterior, medial and lateral to the optimal site (Fig. 1). Blink reflex was elicited in the same subjects using magnetic stimulation of the supraorbital branch of the trigeminal nerve with the junction of the figure-of-eight coil placed over the supraorbital notch.
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The numbers in each position denote the distance (in cm) from the optimal position. The hand represents the optimal position for eliciting MEPs from the contralateral first dorsal interosseus muscle. In most subjects, it is about 2 cm medial and 1 cm posterior to the optimal position for the C-OOc muscle.
To evaluate whether the noise produced by the coil during TMS triggers the acoustic facial reflex, stimulation at maximum stimulator output was performed with the coil positioned about 3 cm above the vertex. Direct stimulation of the facial nerve was achieved with the coil placed behind the ear, in the temporal-occipital area (Benecke et al. 1988).
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SICI and ICF were studied in all subjects with a paired-pulse TMS protocol consisting of a subthreshold CS followed by a suprathreshold test stimulus (TS) delivered 2 ms (SICI) and 10 ms (ICF) later. The CS was set at 80% (SICI80 and ICF80) and 95% (SICI95 and ICF95) of the resting MT for the resting condition and at 95% of active MT for the active condition. The CS with a relatively high intensity of 95% of the resting MT was used because a previous paper showed no SICI and little ICF in the upper facial muscles using CS set at 90% of the MT (Kobayashi et al. 2001). TS intensity was set to elicit MEP amplitudes of about 0.3 mV in the C-OOc muscle for both resting and active conditions. Each run consisted of 10 trials of TS alone and 10 trials of each ISI delivered in random order 6 s apart.
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LICI was studied with a paired-pulse protocol with supra-threshold CS and TS at intensities adjusted to elicit 0.3 mV MEPs in the C-OOc muscle for both resting and active conditions in all subjects. ISIs of 50, 100, 150 and 200 ms were studied. Each run consisted of 20 trials of TS alone and 10 trials of each ISI delivered in random order 6 s apart.
Data analysis
The peak-to-peak MEP amplitude for each trial was measured offline. Inhibition or facilitation was expressed as a ratio of the MEP amplitude of the conditioned trials to the mean MEP amplitude produced by the TS alone. Ratios less than one indicate inhibition, and ratios greater than one indicate facilitation. Values are expressed as mean ± S.D.
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The trials with TS alone recorded in the active LICI were used for measurement of the SP. Twenty trials were recorded in each subject. The SP was measured using cursors on a computer screen from the onset of the stimulus artifact to the beginning of sustained voluntary EMG activity. The trial with the shortest SP duration was estimated by visual inspection of superimposed trials. In subjects with late responses interrupting the SP (e.g. late response of the blink reflex), these responses were easily identified since they appeared early after the MEP and were followed by SP. The SP was considered consistent and was included in the analysis when it was present in at least eight trials.
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Statistical analysis
Paired t tests were used to compare resting and active MT, MEP amplitudes and latencies between C-OOc and I-OOc. For each muscle, repeated measures analysis of variance (ANOVA) was performed to analyse the effects of ISIs. Repeated measures ANOVA was also used to examine the effect of muscle (C-OOc, C-TR and I-OOc) on SICI, ICF and SP. If F values were significant, post hoc testing was carried out with Fisher's PLSD. Paired t tests were performed in each muscle between TS alone and TS preceded by CS at ISIs of 2 and 10 ms to assess SICI and ICF. The significance level for the paired t test was set at 0.017 (0.05/3) to correct for multiple comparison.
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Results
Effects of coil position, blink reflex and acoustic reflex
In all subjects, the optimal position for eliciting MEPs in the OOc muscle was about 2 cm lateral and 1 cm anterior to the position that evokes the strongest contraction in hand muscles (Fig. 1). In three subjects, we recorded from bilateral Fr, OOc, Tr and Ma muscles with the coil placed at the optimal position for C-OOc muscle. At rest, two of the three subjects showed a small-amplitude response from the I-Ma muscle, which had a latency of 2.3 ms, and a response with inverted polarity on the contralateral side (Fig. 2), whereas the remaining subject showed no Ma response (Fig. 3). Activation of the OOc muscles resulted in facilitation of the C-OOc, but the Ma responses remained unchanged (Figs 2 and 3). Activation of the Tr muscle resulted in marked facilitation of the C-Tr MEP, with volume conduction to other lower facial muscles (I-Tr and both Ma), and the C-OOc muscle (Fig. 3).
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Stimulus intensity was 90% of the maximal stimulator output. Four trials from one subject were superimposed. All muscles were at rest in the left column, whereas the responses of the right column were recorded during bilateral OOc muscle contraction. The arrowheads and the numbers below the R and L OOc and the L Ma responses denote the onset latencies. OOc activation results in increased amplitude and decreased latency of the R OOc MEPs. There were no changes in the amplitude, shape or latency in the L OOc and L Ma responses, suggesting R1 of the blink reflex followed by R2 for L OOc and compound muscle action potential due to stimulation of the motor axons of the trigeminal nerve for L Ma.
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Four trials from one subject were superimposed. Stimulus intensity was 67% of the maximal stimulator output. All muscles were at rest in the left column, whereas the responses of the middle column were recorded during bilateral OOc muscle contraction and those of the right column during bilateral Tr muscle contraction. The arrowheads and the numbers below denote the onset latencies. OOc activation results in increased R OOc MEP amplitude. There is also a moderate amplitude increase in the R Fr and R Tr muscles. Tr muscle activation results in marked facilitation of the R Tr response, which may be transmitted via volume conduction to the other muscles recorded.
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The effects of different coil positions (Fig. 1) were studied in five subjects. Figure 4 shows the responses in both OOc muscles following stimulation at different scalp positions, and following stimulation of the supraorbital nerve in one subject. Stimulation over the supraorbital notch elicited a blink reflex with an ipsilateral early response (R1, onset latency about 10 ms, peak latency about 13 ms) and bilateral late responses (R2, onset latency about 32 ms) (Fig. 4A). For C-OOc, the maximum MEP amplitude occurred with stimulation at the optimal site with an onset latency of 12.0 ms. The MEP amplitude decreased markedly when the coil was moved to 2 cm anterior, posterior, medial or lateral to the optimal site, and there was no response with stimulation 4 and 6 cm away from the optimal site (Fig. 4B and C). For the I-OOc, stimulation at the optimal site produced responses with similar amplitude and latency to those of the C-OOc (Fig. 4B and C). However, the effects of stimulating at other positions were very different. Stimulation at 2, 4 and 6 cm anterior and 2 cm posterior to the optimal site elicited responses with similar amplitude. Stimulation 4 and 6 cm posterior to the optimal site produced no response (Fig. 4B). The I-OOc response showed a consistent reduction in onset latency with movement of the stimulating coil in the posterior to anterior direction, approaching the value of the R1 response at 4 and 6 cm anterior to the optimal position (Fig. 4B). In the coronal axis, responses were present following stimulation at 2 and 4 cm medial and 2 cm lateral to the optimal site. Stimulation at 4 and 6 cm below the optimal site induced high amplitude I-OOc compound muscle action potentials (CMAPs) with much shorter latencies (Fig. 4C), but there was no response in the range of the R1 latency. The onset and peak latencies showed a decrement from the medial to the lateral direction (Fig. 4C).
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For comparison, A shows the blink reflex elicited with the centre of the coil applied over the supraorbital notch (3 superimposed trials). The number below the trace of the I-OOc denotes the onset of the early response of the blink reflex (R1). There is no R1 in the contralateral OOc. The arrows indicate the onset of the late response of the blink reflex (R2) at 35.6 ms in the ipsilateral and 35.9 ms in the contralateral OOc. Responses in the anterior–posterior axis are shown in B, and with TMS at different scalp sites in the coronal plane in C. Each trace represents 5 superimposed trials in one subject. Stimulus intensity was 70% of the maximal stimulator output in all sites. The numbers preceding the traces denote the distance (in cm) with respect to the optimal stimulation site, with anterior being positive and posterior negative in B, and with medial being positive and lateral negative in C. Zero represents the optimal position for the contralateral OOc response. The numbers below the responses denote the onset latencies (in ms). TMS elicited a maximal response in the contralateral OOc muscle when the coil was placed in the optimal site. When the coil was displaced 2 cm in any direction, there was a pronounced reduction in amplitude and further displacement resulted in no response. In B, the ipsilateral OOc muscle showed responses of similar shape and amplitude between 2 cm posterior to the optimal site and 6 cm anterior to the optimal site. The onset latency decreased with progressively more anterior placement of the coil, eventually approaching the latency of the early response of the BR. In C, the ipsilateral OOc muscle showed a response with similar shape and amplitude with the coil placed 2 cm medial or lateral to optimal site. Stimulation at 4 and 6 cm lateral to the optimal site produced a large, short latency response due to direct facial nerve stimulation.
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Out of the three subjects in whom the Fr responses were recorded, two showed C-Fr MEPs at the optimal site for the C-OOc muscle at rest with latencies of about 11 ms (Figs 2 and 3), and at 2 cm away from this position in the anterior and lateral directions, but the response disappeared further away from the optimal position. Muscle activation resulted in MEP facilitation. This is similar to the observation for the C-OOc muscle. One subject had no C-Fr response. In all three subjects, the response from the I-Fr was a short latency CMAP with latencies of 2–3 ms, and the amplitude remained unchanged with muscle activation (Figs 2 and 3). However, in one subject there was a late response in the I-Fr muscle with similar latency to the C-Fr muscle (Fig. 2).
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The I-Ma muscle showed a response at about 2.5 ms in two of three subjects (Fig. 2), which did not change significantly with different coil positions in the anterior–posterior axis. However, there was a marked increase in amplitude when the coil was moved laterally. The C-Ma response was often a mirror image of the I-Ma (Fig. 2). One subject had no response.
Direct stimulation of the right and left facial nerves in the retroauricular area elicited ipsilateral short latency (about 4.0 ms) and high amplitude (>1 mV) CMAPs, and bilateral late responses with onset latency of about 34 ms (Fig. 5).
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Eyes were open and facial muscles were at rest. Each trace shows three superimposed trials. The vertical line shows the onset of late responses (LR), which occurred at latencies of about 35 ms in all traces. Both types of stimulation resulted in bilateral LR. The latency of the OOc M response was 3.0 ms on both sides and the amplitude was 1.2 mV on the right side and 1.5 mV on the left side. R, right; L, left; Ooc, orbicularis oculi; M, M wave; LR, late response.
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Response to single pulse TMS in facial muscles
TMS elicited consistent MEPs in the C- and I-OOc muscles of all 12 subjects, and in the contralateral Tr (C-Tr) muscle in 10 subjects. Resting MT in the C-OOc muscle was 65.4 ± 11.4% of stimulator output. The active MT was 46.7 ± 7.2% and was significantly lower than the resting MT (P < 0.0001). For comparison, the threshold for eliciting the R1 response of the blink reflex with the coil placed over the supraorbital notch was 39% (3 subjects, range 32–45%) of stimulator output. The response of the ipsilateral Tr (I-Tr) muscle was studied in nine subjects. MEPs were recorded in four subjects at rest and during muscle activation. The amplitudes (165 ± 93 μV at rest, 328 ± 124 μV during muscle activation) were significantly smaller (P = 0.030 at rest, P = 0.048 during muscle activation) than the amplitude of the C-Tr MEP (275 ± 196 μV at rest, 833 ± 645 μV during muscle activation). All I-Tr MEPs showed the same latency and similar shape to the C-Tr MEPs. These features suggested that the responses of the I-Tr muscle are mainly due to volume conduction from contralateral facial muscles. Therefore, the findings in the I-Tr muscle were not analysed further.
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The silent period
The SP was present in 10 subjects in the C-OOc (duration 100 ± 30 ms, range 67–163 ms) and the C-Tr (duration 104 ± 31 ms, range 69–169 ms), and in 9 subjects in the I-OO (duration 92 ± 15 ms, range 68–111 ms) muscle (Fig. 6). In most subjects, there was obvious decrement of EMG activity during the SP but there was no complete suppression. No consistent SP was obtained in one subject. There was no significant effect of muscle on SP duration.
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Twenty sweeps were superimposed. The horizontal bars indicate the duration of the silent period measured from the stimulus artifact to the first return of EMG activity. Both C- and I-OOC show a consistent SP following the motor-evoked potential (MEP) which is interrupted by a long latency reflex in the latency range of R2 of the blink reflex.
SICI and ICF
Resting SICI80 and resting ICF80. Figure 7 shows the MEPs in one subject and the group results are shown in Fig. 8.
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The figure shows recordings from the contralateral orbicularis oculi (C-OOc), contralateral triangularis (C-Tr) and ipsilateral orbicularis oculi (I-OOc) in one subject, with the conditioning stimulation intensity set at 80% of the resting motor threshold. Ten sweeps have been superimposed in each trace. The left column shows responses with test stimulation alone (Test), the middle column with 2 ms and right column with 10 ms interstimulus interval (ISI). C-OOc and C-Tr show decreased amplitude at 2 ms ISI (SICI), and increased amplitude at 10 ms ISI (ICF) compared to test stimulation alone. There was no significant change in MEP amplitude in the I-OOc muscle.
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SICI and ICF for contralateral orbicularis oculi (C-OO), contralateral triangularis (C-Tr) and ipsilateral orbicularis oculi (I-OO) with conditioning stimulation intensities set at 80% (Rest 80, open columns) and 95% (Rest 95, filled columns) of the motor threshold, and during muscle activation (Active, hatched columns). The amplitude of the motor-evoked potential (MEP) is expressed as a ratio to the MEP of test stimulus alone (vertical axis). Values above one indicate or facilitation and values below one indicate inhibition. Error bars represent S.E.M. * Significant inhibition facilitation at P < 0.017. The C-OOc muscle showed SICI80, SICI95 and active SICI. The C-Tr muscle had SICI80 and SICI95, but muscle activation resulted in no SICI. There was no significant inhibition in the I-OOc muscle. At rest, there was significant ICF in C-OO and C-Tr.
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C-OOc. The MEP latency for TS alone was 10.8 ± 0.8 ms and MEP amplitude was 296 ± 94 μV (range: 188–460 μV). In some subjects, the MEP latency was slightly reduced for both ISIs of 2 and 10 ms. ANOVA showed a significant effect of ISI (P < 0.0001) on MEP amplitude and a paired t test showed significant SICI (P < 0.0001) and ICF (P = 0.0042).
C-Tr. The MEP latency for TS alone was 11.0 ± 1.5 ms and the MEP amplitude was 171 ± 69 μV (range: 72–310 μV). In some subjects, the MEP latency was slightly reduced for both ISIs of 2 and 10 ms. ANOVA showed a significant effect of ISI (P < 0.0001) on MEP amplitude and a paired t test showed significant SICI (P = 0.0004) and ICF (P < 0.0005).
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I-OOc. MEP latency for TS alone was 11.1 ± 0.7 ms and MEP amplitude was 333 ± 149 μV (range: 132–605 μV). There was no significant difference in MEP amplitudes and latencies between C-OOc and I-OOc for TS alone. The effect of ISI on MEP amplitude was not significant and there was no significant SICI and ICF.
Repeated measures ANOVA showed a significant effect of muscle on SICI (P = 0.005) and ICF (P = 0.005). The post hoc Fisher's PLSD test showed that there was greater SICI in C-OOc (P = 0.0041) and C-Tr (P = 0.0054) compared to I-OOc. There was no difference in SICI between C-OOc and C-Tr muscles. ICF was significantly higher in C-Tr compared to I-OOc (P = 0.0012), but there was no significant difference between C-OOc and I-OOc (P = 0.08) and between C-OOc and C-Tr.
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SICI95 and ICF95. SICI and ICF at rest were studied in eight subjects with CS set at 95% MT intensity. The C-OOc MT was 63.9 ± 13%. The results are shown in Fig. 8.
C-OOc. The MEP latency for TS alone was 10.9 ± 0.8 ms and the MEP amplitude was 265 ± 85 μV (range: 167–380 μV). ANOVA showed a significant effect for ISI on MEP amplitude (P = 0.002). The paired t test showed significant SICI (P = 0.013), whereas ICF did not reach significance (P = 0.078).
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C-Tr. The MEP latency for TS alone was 11.0 ± 1.5 ms and the amplitude was 260 ± 111 μV (range: 115–366 μV). ANOVA disclosed a significant effect of ISI on MEP amplitude (P = 0.006) and the paired t test showed significant SICI (P = 0.012), but ICF was not significant when corrected for multiple comparisons (P = 0.025).
I-OOc. The MEP latency for TS alone was 11.1 ± 0.7 ms and amplitude was 238 ± 135 μV (range: 100–464 μV). There was no significant effect of ISI on MEP amplitude (ANOVA, P = 0.06).
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SICI and ICF during muscle activation. SICI and ICF were studied during muscle activation in 11 subjects. Figure 8 summarizes the findings.
C-OOc. MEPs were elicited in all 11 subjects. MEP amplitude was 464 ± 214 μV (range: 100–963 μV) for TS alone. ANOVA showed a significant effect of ISI on MEP amplitude (P = 0.01). A paired t test showed that there was significant SICI (P = 0.0046) but no significant ICF (P = 0.36).
C-Tr. MEPs could be discriminated from the background EMG in 8 out of the 11 subjects. The MEP amplitude was 419 ± 233 μV (range: 105–712 μV) for TS alone. ANOVA showed no significant effect of ISI on MEP amplitude.
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I-OOc recordings. MEPs were recorded in 9 of the 11 subjects. MEP amplitude was 355 ± 114 μV (range: 168–513 μV) for TS alone. ANOVA showed no effects of ISI on MEP amplitude.
LICI
Figure 9 summarizes the findings in all subjects. For resting LICI, TS alone elicited an MEP amplitude of 245 ± 109 μV (range: 122–482 μV) for C-OOc, 178 ± 86 μV (range: 66–330 μV) for C-Tr, and 321 ± 166 μV (range: 100–548 μV) for I-OOc muscles. ANOVA showed a significant effect of ISI on MEP amplitude of C-OOc (P < 0.0001), C-Tr (P < 0.0001) and I-OOc (P = 0.0003) muscles. Post hoc Fisher's PLSD test showed significant facilitation at 50 ms ISI in all three muscles (C-OOc: P < 0.0002; C-Tr: P < 0.0001; I-OOc: P = 0.0030).
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The amplitude of the motor-evoked potential (MEP) was expressed as a ratio to that of the test stimulus alone (vertical axis) in the contralateral orbicularis oculi (C-OOc, open columns), in the contralateral triangularis (C-Tr, filled columns) and in the ipsilateral orbicularis oculi (I-OOc, hatched columns) muscles at ISIs of 50, 100, 150 and 200 ms. Values above one indicate facilitation and values below one indicate inhibition. Error bars represent S.E.M. * Significant inhibition or facilitation at P < 0.01. At rest there was significant facilitation at 50 ms ISI in all three muscles. There was no significant inhibition.
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For active LICI, the MEP amplitudes for TS alone were: C-Ooc, 516 ± 257 μV (range: 185–1107 μV); C-Tr, 344 ± 202 μV (range: 101–655 μV); and I-Ooc, 468 ± 109 μV (range: 286–639 μV). ANOVA showed a significant effect of ISI on MEP amplitude for C-OOc (P = 0.04) and C-TR (P = 0.03) muscles, but post hoc Fisher's PLSD showed no significant MEP amplitude difference at any ISI in either muscle. There was no effect of ISI on MEP amplitude in the I-OOc muscle.
Discussion
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TMS applied to the motor cortex lateral to the hand representation elicited MEPs in contralateral upper and lower facial muscles, suggesting that there are M1 projections to these muscles. Intracortical modulation of the upper and lower contralateral facial muscles follows a pattern analogous to that of the contralateral upper and lower limb muscles, showing SICI at 2 ms ISI and ICF at 10 ms ISI (Chen et al. 1998). Similar to limb muscles, SICI is attenuated by muscle activation (Ridding et al. 1995). The LICI protocol at rest showed MEP facilitation at 50 ms ISI in C-OOc, C-Tr and I-OOc muscles and no inhibition at longer ISIs.
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M1 projection to facial muscles
Studies of the corticofacial projections in monkeys suggested that the lower facial muscles receive direct inputs mainly from the contralateral M1, whereas the upper facial muscles receive scant direct M1 projections (Jenny & Saper, 1987; Morecraft et al. 2001). Cortical innervation of the upper face in monkeys appears to be mainly supplied by the supplementary motor and the rostral cingulate cortices bilaterally (Morecraft et al. 2001).
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In humans, the anatomy of corticofacial pathways has not been studied in detail and the cortical areas that control facial muscles remain controversial. Due to the complexity of the facial expression, the cortical projections to the facial nucleus in humans for both voluntary and spontaneous movements may differ from those of monkeys. A functional magnetic resonance imaging study showed that externally paced blinking activates the orbitofrontal cortex (Tsubota et al. 1999), but normal blinking or self-paced activity of the orbicularis oculi muscles were not studied. Similar to our findings, previous TMS studies using a figure-of-eight coil applied to M1 elicited responses with latencies of about 11 ms in the contralateral upper and lower facial muscles (Cruccu et al. 1997; Kobayashi et al. 2001). The authors suggested that the M1 projects to contralateral facial muscles. However, this latency is in the range of the early component of the blink reflex (R1) (Benecke et al. 1988; Kimura, 1989; Esteban, 1999) and it results in a central conduction time that is much longer than those obtained for other limb and cranial muscles. TMS applied to the midfrontal scalp position, aimed at stimulating the mesial frontal cortex while avoiding M1 activation, elicited a small response in the OOc muscles with latencies ranging from 6 to 8 ms which were interpreted as MEPs (Sohn et al. 2004). Therefore, Sohn et al. (2004) suggested that the mesial frontal cortex projects directly to facial muscles and the OOc MEPs obtained with TMS over the M1 can be explained by the R1 component of the blink reflex rather than cortical projection from the M1 (Sohn et al. 2004).
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Several findings in our study suggest that the M1 gives rise to contralateral upper facial innervation. First, stimulation of a restricted area of the scalp overlying M1 elicited MEPs in the C-OOc muscle. Stimulation more than 2 cm away from the optimal position in the horizontal or vertical axes elicited no response. Secondly, the R1 response is usually only present on the ipsilateral side. Thirdly, although the C-Tr muscle does not participate in the blink reflex in normal subjects, M1 stimulation led to MEPs in the C-Tr muscle with similar latencies to the C-OOc muscle. Moreover, paired-pulse TMS applied to M1 elicited SICI and ICF in the C-OOc and C-Tr muscles. SICI and ICF have been demonstrated to arise from the cortex (Kujirai et al. 1993; Nakamura et al. 1997; Di Lazzaro et al. 1998). Finally, the SP can be elicited in the C-OOc and C-Tr muscles. Because there is little or no muscle spindle in the facial muscles, the SP is probably related to cortical inhibition (Cruccu et al. 1997).
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We did not observe any MEPs in the Ma muscle, probably because Ma MEPs are best elicited with a current direction that is different from the one we used (Guggisberg et al. 2001). Therefore, our findings are unlikely to be related to volume conduction from muscles innervated from the trigeminal nerve. In two subjects, there was a short latency response in the I-Ma muscle indicating direct activation of the trigeminal root (Fig. 2) but this was absent in one subject (Fig. 3). Since subjects with or without trigeminal root activation showed similar responses in the facial muscles, a reflex related to activation of the trigeminal nerve root is unlikely to explain our findings although a contribution to the late responses in some subjects cannot be ruled out.
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In contrast to C-OOc muscle, the I-OOc showed responses with similar amplitude and decreasing onset latency in the 13–10 ms range, as the coil was moved in the anterior direction. Since the supraorbital nerve provides cutaneous sensation to the frontal scalp up to the vertex, this finding suggests that the I-OOc response may be mainly due to the R1 component of the blink reflex, where reduction in MEP latency with more anterior stimulation reflects the shift of the stimulation site from distal to more proximal locations along the scalp branches of the supraorbital nerve (Fig. 4). The absent I-OOc response with the coil placed more than 4 cm posterior to the optimal position may be explained by the stimulation site being posterior to the cutaneous supply of the supraorbital nerve.
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The absence of SICI and ICF in the I-OOc support the assumption that the response is contaminated with the R1 component of the blink reflex which does not depend on cortical mechanisms. Identical paired electrical stimulation with a short interval (less than 10 ms) applied to the supraorbital notch results in facilitation of the R1 with little or no influence on the R2 (Esteban, 1999), or produce responses in subjects with no R1 response to a single stimulus (Kimura, 1989). The lack of facilitation in I-OOc in the SICI and ICF studies may be because we used a weaker conditioning stimulus followed by stronger test stimulation.
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Because of the presence of the R1 response, we cannot determine whether there is an ipsilateral projection to OOc muscle from the M1 and the presence of ipsilateral SICI or ICF. The presence of SP in the I-OOc muscle in our experiments favours ipsilateral projections. However, it is not possible to rule out the possibility that the silent period is related to cutaneous stimulation, which has the same characteristics (Sanes & Ison, 1980; Ishikawa et al. 2001). We also found possible MEPs in the I-Fr muscle in one out of three subjects (Fig. 2). Previous TMS studies recording from upper facial muscles have found ipsilateral responses not only in the OOc muscle, which may have been contaminated with an R1 response, but also in the frontalis and lower face muscles, which do not participate in the blink reflex (Meyer et al. 1989; Rodel et al. 2001).
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MEPs from the I-Tr were absent in most of the subjects studied. When recorded, the I-Tr MEPs were of lower amplitude, and had a similar shape and latency compared to the C-Tr MEPs, suggesting that the ipsilateral responses were mainly due to volume conduction from the C-Tr muscle. Our findings suggest that the M1 projection to lower facial muscles is mainly contralateral, although we cannot rule out a small ipsilateral projection in some subjects. TMS studies using needle recording electrodes to avoid electrical cross-talk have reported ipsilateral MEPs in the lower facial muscles (Benecke et al. 1988; Werhahn et al. 1995; Rodel et al. 1999). Furthermore, SP was elicited in the ipsilateral mentalis muscle (Werhahn et al. 1995). However, electrical stimulation of the exposed human motor cortex resulted in bilateral contraction of the upper facial muscles and only contralateral twitching of the lower facial muscles (Penfield & Rasmussen, 1950) and a TMS study found no response in the ipsilateral lower face muscles (Cruccu et al. 1990a). Therefore, the presence of significant ipsilateral M1 projection to the lower facial muscles remains controversial.
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We found that TMS elicited MEPs from contralateral lower facial muscles at rest, and that the MEP amplitudes were significantly increased with muscle activation. This is similar to other cranial and limb muscles, and is consistent with the findings of several previous studies (Benecke et al. 1988; Kobayashi et al. 2001). Other studies on the central pathways to the lower facial muscles were performed with single pulse TMS during muscle activation (Cruccu et al. 1990a; Meyer et al. 1994; Liscic et al. 1998; Fischer et al. 2005), and some studies did not find consistent MEPs at rest in lower facial muscles. Possible reasons for the difference include differences in TMS parameters such as type of TMS coil, current direction, stimulus intensities as well as the selection of the target muscle.
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Intracortical inhibition and facilitation in the facial M1 area
A previous report found SICI and ICF in the contralateral mentalis muscle but not in C-OOc or I-OOc muscles (Kobayashi et al. 2001). The discrepancy with our results for the C-OOc muscle may be due to two reasons. First, the authors applied TS with a stimulus intensity less than 120% of MT to elicit MEPs of approximately 0.2 mV. Although the TS intensity and MEP amplitude were not reported, their values were probably considerably lower than the values of our study (mean TS intensity 126% of MT and mean MEP amplitude 0.3 mV for C-OOc). Second, their patients kept their eyes closed and therefore the OOc muscles were active. Both low TS intensity and muscle activation may result in less inhibition. In hand muscles, low TS amplitude reduces or abolishes SICI (Sanger et al. 2001; Daskalakis et al. 2002; Roshan et al. 2003). In addition, even minimal levels of voluntary activation significantly reduce SICI (Ridding et al. 1995; Hanajima et al. 1998).
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In order to obtain a reliable MEP, we used TS at intensities that resulted in a late response in many subjects. These late responses occurred at latencies of around 50 ms and did not interfere with the measurement of MEP with peak latencies of about 15 ms. Late responses were also obtained when the coil was placed 3 cm above the scalp (Fig. 3), suggesting that the noise of the stimulating coil elicited either an acoustic blink reflex (Rushworth, 1962; Tackmann et al. 1982) or a startle response (Brown et al. 1991; Chokroverty et al. 1992). Persistence of the response throughout the trials with no habituation favours the acoustic blink reflex, but definite differentiation between these possibilities cannot be achieved without further studies (Meincke et al. 2002). Moreover, direct magnetic stimulation of the facial nerve also elicited a late response bilaterally (Fig. 3) that may represent either an acoustic blink reflex or a facio-facial reflex (Willer & Lamour, 1977; Csecsei, 1979). The acoustic blink reflex, the startle response and the facio-facial reflexes are all bilateral and have similar latencies in the OOc muscle, which is in the range of the R2 response of the blink reflex elicited by supraorbital nerve stimulation. However, none of these facial reflexes is preceded by an earlier response in the latency range of the MEP and the R1 of the electrical blink reflex. Therefore, the presence of a late response with higher TMS intensity did not indicate contamination with the R1 in the C-OOc muscle.
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Paired TMS in the facial representation of the M1 with CS at 80% of the TS intensity produced SICI and ICF similar to the limb muscles, both in the C-OOc and C-Tr muscles. Several studies indicate that SICI is mediated through cortical interneurones (Kujirai et al. 1993; Nakamura et al. 1997; Chen et al. 1998; Di Lazzaro et al. 1998). The slightly shorter latency for the inhibited response seen in some subjects is consistent with SICI as this has been reported for SICI in hand muscles (Kujirai et al. 1993), but we cannot rule out a small contribution from changes in brainstem excitability. Pharmacological investigations suggest that it involves GABAA mechanisms (Ziemann et al. 1996a,b; Di Lazzaro et al. 2000; Ilic et al. 2002). ICF also occurs in the cortex (Ziemann et al. 1996c; Nakamura et al. 1997) and is probably mediated by glutamate (Ziemann et al. 1998).
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The LICI protocol has not previously been studied in facial muscles. There was facilitation at 50 ms, which occurred at a similar latency to the long latency responses and therefore may be due to increased excitability of the facial motoneurones mediated by subcortical circuits such as the facio-facial, acoustic blink or startle reflexes (Willer & Lamour, 1977; Meincke et al. 2002). We found no significant LICI at ISIs between 100 and 200 ms. The inhibitory mechanisms mediating LICI are different from those mediating SICI (Sanger et al. 2001). In contrast to SICI, LICI in limb muscles is not significantly influenced by muscle activation (Wassermann et al. 1996; Chen et al. 1997). In limb muscles, LICI at ISIs longer than about 50 ms occurs in the cortex (Fuhr et al. 1991; Inghilleri et al. 1993a; Nakamura et al. 1997; Chen et al. 1999) and is probably mediated by GABAB receptors (Roick et al. 1993; Siebner et al. 1998; Werhahn et al. 1999). LICI and the silent period elicited with TMS may be mediated by similar mechanisms, since the period of paired-pulse inhibition coincided with the silent period (Wassermann et al. 1996). TMS over the facial representation of M1 elicited SP in all three muscles in our subjects, with a mean duration of about 100 ms. This may explain the absence of LICI at ISIs of 100 ms or longer as these times may fall outside the activation period of the inhibitory interneurones responsible for LICI and SP. Previous reports found longer SPs (140–215 ms) and complete absence of EMG in the facial muscles using a large circular coil centred at the vertex and high stimulus intensities (Werhahn et al. 1995; Cruccu et al. 1997). This is consistent with the finding that SP increases with higher stimulus intensity (Valls-Sole et al. 1992; Wassermann et al. 1996).
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Potential roles of different facial motor areas
Our results do not exclude projection of the medial frontal cortex to facial muscles (Sohn et al. 2004). Dissociation of emotional and voluntary movement is frequently observed in facial paralysis resulting from supranuclear lesions (Monrad-Krohn, 1924; Taverner, 1969; Topper et al. 1995). Although the pathways responsible for these two types of facial activity are not well understood, it has been suggested that volitional activity may be mediated by the M1 and the descending pyramidal tract whereas emotional movements may be mediated by the anterior frontal-thalamo-pontine connection that descends in the anterior limb of the internal capsule (Hopf et al. 1992). Since the cingulate cortex is part of the limbic system associated with emotional expression, the mesial frontal cortex may be responsible for emotional facial expressions (Morecraft et al. 2001). It is not known why the central conduction time from M1 to facial muscles is long compared to limb muscles. Possible reasons include the involvement of a polysynaptic pathway or that the corticobulbar fibres may be of smaller diameter and therefore have a slower conduction speed compared to the corticospinal fibres.
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In conclusion, our findings suggest that there are M1 projections to contralateral upper and lower facial muscles in humans. The facial M1 representation is under the influence of short interval intracortical inhibitory and intracortical facilitatory circuits, similar to the arm and leg areas of the M1.
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2 Division of Neurology, Department of Medicine, University of Toronto, Ontario, Canada
Abstract
Whether there is a projection from the primary motor cortex (M1) to upper facial muscles and how the facial M1 area is modulated by intracortical inhibitory and facilitatory circuits remains controversial. To assess these issues, we applied transcranial magnetic stimulation (TMS) to the M1 and recorded from resting and active contralateral (C-OOc) and ipsilateral orbicularis oculi (I-OOc), and contralateral (C-Tr) and ipsilateral triangularis (I-Tr) muscles in 12 volunteers. In five subjects, the effects of stimulating at different scalp positions were assessed. Paired TMS at interstimulus intervals (ISIs) of 2 ms were used to elicit short interval intracortical inhibition (SICI) and ISI of 10 ms for intracortical facilitation (ICF). Long interval intracortical inhibition (LICI) was evaluated at ISIs between 50 and 200 ms, both at rest and during muscle activation. The silent period (SP) was also determined. C-OOc and I-OOc responses were recorded in all subjects. The optimal position for eliciting C-OOc responses was lateral to the hand representation in all subjects and MEP amplitude markedly diminished when the coil was placed 2 cm away from the optimal position. For the I-OOc, responses were present in more scalp sites and the latency decreased with more anterior placement of the coil. C-Tr response was recorded in 10 out of 12 subjects and the I-Tr muscle showed either no response or low amplitude response, probably due to volume conduction. SICI and ICF were present in the C-OOc and C-Tr, but not in the I-OOc muscle. Muscle activation attenuated SICI and ICF. LICI at rest showed facilitation at 50 ms ISI in all muscles, but there was no significant inhibition at other ISIs. There was no significant inhibition or facilitation with the LICI protocol during muscle contraction. The SP was present in the C-OOc, C-Tr and I-OOc muscles and the mean durations ranged from 92 to 104 ms. These findings suggest that the I-OOc muscle response is probably related to the first component (R1) of the blink reflex. There is M1 projection to the contralateral upper and lower facial muscles in humans and the facial M1 area is susceptible to cortical inhibition and facilitation, similar to limb muscles.
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Introduction
The facial motor system has several unique features. Facial muscles carry few or no muscle spindles (Voss, 1956; Lovell et al. 1977). The facial muscles are under both voluntary and emotional control (Lees, 1988). Dissociation between voluntary and emotional movements may occur in patients with supranuclear lesions, suggesting that they are under the control of different descending pathways (Hopf et al. 1992). Since the upper face is usually spared in patients with hemispheric lesion, the upper facial muscles are considered to have bilateral cortical innervation (Brodal, 1981). However, it is controversial whether there are projections from the primary motor cortex (M1) to the upper facial muscles in humans. While some authors reported responses in the upper and lower facial muscles with TMS of the facial M1 area, the latencies were similar to the first component (R1) of the blink reflex and the central delay is significantly longer for facial muscles compared to limb muscles or muscles innervated by other cranial nerves (Benecke et al. 1988; Cruccu et al. 1990b). A study using paired TMS at short interstimulus intervals found that the lower facial muscles followed the same cortical inhibitory and facilitatory pattern as in hand muscles, but the upper facial muscles showed no cortical inhibition and reduced facilitation. The authors suggested that the movements of the upper face are mainly modulated by brainstem projections (Kobayashi et al. 2001). Another study found no contralateral upper facial responses from stimulation of the facial M1 area but there were low amplitude responses from stimulation of the mesial frontal region, suggesting that the upper facial movements are controlled by the medial frontal cortex rather than by the M1 (Sohn et al. 2004).
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TMS can be used to evaluate cortical excitability (Hallett, 2000). A suprathreshold TMS pulse delivered during voluntary contraction of a target muscle results in a transient interruption of the muscle activity, known as the silent period (SP). The SP is due to activation of inhibitory circuits in the spinal cord and the cortex (Fuhr et al. 1991; Cantello et al. 1992; Inghilleri et al. 1993b). Inhibitory and facilitatory interactions in the motor cortex can also be assessed with paired-pulse TMS (Kujirai et al. 1993; Chen, 2000; Kobayashi & Pascual-Leone, 2003). Studies in limb muscles showed that a subthreshold conditioning stimulus (CS) followed by a suprathreshold test stimulus (TS) at interstimulus intervals (ISIs) between 1 and 4 ms resulted in intracortical inhibition (short interval intracortical inhibition, SICI) (Kujirai et al. 1993), whereas ISIs of 7–20 ms resulted in intracortical facilitation (ICF) (Kujirai et al. 1993; Ziemann et al. 1996c). When a suprathreshold TS is paired with a suprathreshold CS at longer ISIs (50–200 ms), the amplitude of the motor-evoked potential (MEP) is reduced compared to the amplitude of the MEP elicited by the TS alone, due to long interval intracortical inhibition (LICI) (Valls-Sole et al. 1992; Wassermann et al. 1996). SICI and LICI are mediated by different mechanisms (Sanger et al. 2001). SICI and ICF can be observed in proximal and distal muscles in both upper and lower limbs (Chen et al. 1998).
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The aim of this study is to determine whether there are projections from the M1 to facial muscles and to assess the intracortical inhibitory and excitatory circuits of the human facial M1.
Methods
We studied 12 healthy volunteers (8 males, 4 females; aged 47 ± 12 (S.D.) years, range 29–60 years). Subjects were recruited through advertisements in the community and hospital postings. All subjects gave their written informed consent and the University Health Network Research Ethics Board approved the protocol. All studies conformed to the standards set by the Declaration of Helsinki.
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EMG recording
The subjects were seated in a comfortable chair and surface EMG was recorded from the right and left frontalis (Fr), orbicularis oculi (OOc), triangularis (Tr, also known as depressor anguli oris) and masseter (Ma) muscles using disposable disc electrodes. For the Fr muscle, the recording electrode was placed 2.5 cm above the mid-point of the eyebrow and the reference electrode was located 2 cm laterally. For the OOc muscle, the recording electrode was placed in the middle of the lower lid, and the reference electrode was placed at the lateral angle of the eye. For the Tr muscle, a recording electrode was placed at the mid-point between the angle of the mouth and the lower border of the mandible, and the reference electrode was placed 3 cm laterally. Recordings from the Ma muscle were performed with the recording electrode over the muscle belly, at a mid-point between the zygomatic arch and the lower border of the mandible, and with the reference electrode positioned at the mandibular angle.
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EMG was monitored on a computer screen and through speakers set up at high gain. The signal was amplified (Intronix Technologies Corporation, model 2024F, Bolton, Ontario, Canada), filtered (band-pass: 2 Hz to 2.5 kHz), digitized at 5 kHz (Micro 1401, Cambridge Electronics Design, Cambridge, UK) and stored in a laboratory computer for offline analysis.
Transcranial magnetic stimulation
TMS was performed with a 7 cm figure-of-eight coil and two Magstim 200 stimulators (Magstim Company, Dyfed, UK) connected via a Bistim module. The coil was placed over the dominant motor cortex at the optimal site for eliciting motor-evoked potentials from the contralateral OOc (C-OOc). The location of this optimal site relative to the optimal site to evoke contraction in hand muscles was noted. The optimal site was marked on the scalp with a felt pen to ensure that the coil remained in the same place throughout the study. The handle of the coil pointed backwards and was perpendicular to the presumed direction of the central sulcus, approximately 45 deg to the midsagittal line. The direction of the induced current was from posterior to anterior.
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The resting motor threshold (MT) was determined by asking the subject to relax, maintain eyes open, and blink as little as possible. The active C-OOc MT was determined with the subject performing simultaneous sustained closure of the eyes and depression of the angles of the mouth, at about 50% of the maximum effort as determined through the sound of the EMG from the speaker and feedback from the investigators. The MT is expressed as a percentage of maximum stimulator output, measured to the nearest 1%. Resting MT was defined as the lowest intensity that elicited MEPs of > 50 μV in at least 5 out of 10 trials. For the active MT, the MEP threshold was >100 μV.
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Recordings from ipsilateral OOc (I-OOc) and C-OOc, as well as I-Tr and C-Tr, were performed in all experiments. The influence of coil position was studied in five subjects, and in three subjects the responses from I-Fr, C-Fr, I-Ma and C-Ma were also recorded. The blink reflex was assessed in all five subjects and the acoustic reflex in two subjects. The effect of coil position was evaluated with the stimulator output adjusted to elicit MEPs of about 0.3 mV with the coil at the optimal position for the C-OOc muscle. The mean stimulation intensity used in the five subjects studied was 80% (range 67–90%) of the maximum stimulator output. TMS was delivered at the optimal site, and at sites 2, 4 and 6 cm anterior, posterior, medial and lateral to the optimal site (Fig. 1). Blink reflex was elicited in the same subjects using magnetic stimulation of the supraorbital branch of the trigeminal nerve with the junction of the figure-of-eight coil placed over the supraorbital notch.
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The numbers in each position denote the distance (in cm) from the optimal position. The hand represents the optimal position for eliciting MEPs from the contralateral first dorsal interosseus muscle. In most subjects, it is about 2 cm medial and 1 cm posterior to the optimal position for the C-OOc muscle.
To evaluate whether the noise produced by the coil during TMS triggers the acoustic facial reflex, stimulation at maximum stimulator output was performed with the coil positioned about 3 cm above the vertex. Direct stimulation of the facial nerve was achieved with the coil placed behind the ear, in the temporal-occipital area (Benecke et al. 1988).
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SICI and ICF were studied in all subjects with a paired-pulse TMS protocol consisting of a subthreshold CS followed by a suprathreshold test stimulus (TS) delivered 2 ms (SICI) and 10 ms (ICF) later. The CS was set at 80% (SICI80 and ICF80) and 95% (SICI95 and ICF95) of the resting MT for the resting condition and at 95% of active MT for the active condition. The CS with a relatively high intensity of 95% of the resting MT was used because a previous paper showed no SICI and little ICF in the upper facial muscles using CS set at 90% of the MT (Kobayashi et al. 2001). TS intensity was set to elicit MEP amplitudes of about 0.3 mV in the C-OOc muscle for both resting and active conditions. Each run consisted of 10 trials of TS alone and 10 trials of each ISI delivered in random order 6 s apart.
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LICI was studied with a paired-pulse protocol with supra-threshold CS and TS at intensities adjusted to elicit 0.3 mV MEPs in the C-OOc muscle for both resting and active conditions in all subjects. ISIs of 50, 100, 150 and 200 ms were studied. Each run consisted of 20 trials of TS alone and 10 trials of each ISI delivered in random order 6 s apart.
Data analysis
The peak-to-peak MEP amplitude for each trial was measured offline. Inhibition or facilitation was expressed as a ratio of the MEP amplitude of the conditioned trials to the mean MEP amplitude produced by the TS alone. Ratios less than one indicate inhibition, and ratios greater than one indicate facilitation. Values are expressed as mean ± S.D.
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The trials with TS alone recorded in the active LICI were used for measurement of the SP. Twenty trials were recorded in each subject. The SP was measured using cursors on a computer screen from the onset of the stimulus artifact to the beginning of sustained voluntary EMG activity. The trial with the shortest SP duration was estimated by visual inspection of superimposed trials. In subjects with late responses interrupting the SP (e.g. late response of the blink reflex), these responses were easily identified since they appeared early after the MEP and were followed by SP. The SP was considered consistent and was included in the analysis when it was present in at least eight trials.
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Statistical analysis
Paired t tests were used to compare resting and active MT, MEP amplitudes and latencies between C-OOc and I-OOc. For each muscle, repeated measures analysis of variance (ANOVA) was performed to analyse the effects of ISIs. Repeated measures ANOVA was also used to examine the effect of muscle (C-OOc, C-TR and I-OOc) on SICI, ICF and SP. If F values were significant, post hoc testing was carried out with Fisher's PLSD. Paired t tests were performed in each muscle between TS alone and TS preceded by CS at ISIs of 2 and 10 ms to assess SICI and ICF. The significance level for the paired t test was set at 0.017 (0.05/3) to correct for multiple comparison.
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Results
Effects of coil position, blink reflex and acoustic reflex
In all subjects, the optimal position for eliciting MEPs in the OOc muscle was about 2 cm lateral and 1 cm anterior to the position that evokes the strongest contraction in hand muscles (Fig. 1). In three subjects, we recorded from bilateral Fr, OOc, Tr and Ma muscles with the coil placed at the optimal position for C-OOc muscle. At rest, two of the three subjects showed a small-amplitude response from the I-Ma muscle, which had a latency of 2.3 ms, and a response with inverted polarity on the contralateral side (Fig. 2), whereas the remaining subject showed no Ma response (Fig. 3). Activation of the OOc muscles resulted in facilitation of the C-OOc, but the Ma responses remained unchanged (Figs 2 and 3). Activation of the Tr muscle resulted in marked facilitation of the C-Tr MEP, with volume conduction to other lower facial muscles (I-Tr and both Ma), and the C-OOc muscle (Fig. 3).
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Stimulus intensity was 90% of the maximal stimulator output. Four trials from one subject were superimposed. All muscles were at rest in the left column, whereas the responses of the right column were recorded during bilateral OOc muscle contraction. The arrowheads and the numbers below the R and L OOc and the L Ma responses denote the onset latencies. OOc activation results in increased amplitude and decreased latency of the R OOc MEPs. There were no changes in the amplitude, shape or latency in the L OOc and L Ma responses, suggesting R1 of the blink reflex followed by R2 for L OOc and compound muscle action potential due to stimulation of the motor axons of the trigeminal nerve for L Ma.
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Four trials from one subject were superimposed. Stimulus intensity was 67% of the maximal stimulator output. All muscles were at rest in the left column, whereas the responses of the middle column were recorded during bilateral OOc muscle contraction and those of the right column during bilateral Tr muscle contraction. The arrowheads and the numbers below denote the onset latencies. OOc activation results in increased R OOc MEP amplitude. There is also a moderate amplitude increase in the R Fr and R Tr muscles. Tr muscle activation results in marked facilitation of the R Tr response, which may be transmitted via volume conduction to the other muscles recorded.
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The effects of different coil positions (Fig. 1) were studied in five subjects. Figure 4 shows the responses in both OOc muscles following stimulation at different scalp positions, and following stimulation of the supraorbital nerve in one subject. Stimulation over the supraorbital notch elicited a blink reflex with an ipsilateral early response (R1, onset latency about 10 ms, peak latency about 13 ms) and bilateral late responses (R2, onset latency about 32 ms) (Fig. 4A). For C-OOc, the maximum MEP amplitude occurred with stimulation at the optimal site with an onset latency of 12.0 ms. The MEP amplitude decreased markedly when the coil was moved to 2 cm anterior, posterior, medial or lateral to the optimal site, and there was no response with stimulation 4 and 6 cm away from the optimal site (Fig. 4B and C). For the I-OOc, stimulation at the optimal site produced responses with similar amplitude and latency to those of the C-OOc (Fig. 4B and C). However, the effects of stimulating at other positions were very different. Stimulation at 2, 4 and 6 cm anterior and 2 cm posterior to the optimal site elicited responses with similar amplitude. Stimulation 4 and 6 cm posterior to the optimal site produced no response (Fig. 4B). The I-OOc response showed a consistent reduction in onset latency with movement of the stimulating coil in the posterior to anterior direction, approaching the value of the R1 response at 4 and 6 cm anterior to the optimal position (Fig. 4B). In the coronal axis, responses were present following stimulation at 2 and 4 cm medial and 2 cm lateral to the optimal site. Stimulation at 4 and 6 cm below the optimal site induced high amplitude I-OOc compound muscle action potentials (CMAPs) with much shorter latencies (Fig. 4C), but there was no response in the range of the R1 latency. The onset and peak latencies showed a decrement from the medial to the lateral direction (Fig. 4C).
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For comparison, A shows the blink reflex elicited with the centre of the coil applied over the supraorbital notch (3 superimposed trials). The number below the trace of the I-OOc denotes the onset of the early response of the blink reflex (R1). There is no R1 in the contralateral OOc. The arrows indicate the onset of the late response of the blink reflex (R2) at 35.6 ms in the ipsilateral and 35.9 ms in the contralateral OOc. Responses in the anterior–posterior axis are shown in B, and with TMS at different scalp sites in the coronal plane in C. Each trace represents 5 superimposed trials in one subject. Stimulus intensity was 70% of the maximal stimulator output in all sites. The numbers preceding the traces denote the distance (in cm) with respect to the optimal stimulation site, with anterior being positive and posterior negative in B, and with medial being positive and lateral negative in C. Zero represents the optimal position for the contralateral OOc response. The numbers below the responses denote the onset latencies (in ms). TMS elicited a maximal response in the contralateral OOc muscle when the coil was placed in the optimal site. When the coil was displaced 2 cm in any direction, there was a pronounced reduction in amplitude and further displacement resulted in no response. In B, the ipsilateral OOc muscle showed responses of similar shape and amplitude between 2 cm posterior to the optimal site and 6 cm anterior to the optimal site. The onset latency decreased with progressively more anterior placement of the coil, eventually approaching the latency of the early response of the BR. In C, the ipsilateral OOc muscle showed a response with similar shape and amplitude with the coil placed 2 cm medial or lateral to optimal site. Stimulation at 4 and 6 cm lateral to the optimal site produced a large, short latency response due to direct facial nerve stimulation.
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Out of the three subjects in whom the Fr responses were recorded, two showed C-Fr MEPs at the optimal site for the C-OOc muscle at rest with latencies of about 11 ms (Figs 2 and 3), and at 2 cm away from this position in the anterior and lateral directions, but the response disappeared further away from the optimal position. Muscle activation resulted in MEP facilitation. This is similar to the observation for the C-OOc muscle. One subject had no C-Fr response. In all three subjects, the response from the I-Fr was a short latency CMAP with latencies of 2–3 ms, and the amplitude remained unchanged with muscle activation (Figs 2 and 3). However, in one subject there was a late response in the I-Fr muscle with similar latency to the C-Fr muscle (Fig. 2).
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The I-Ma muscle showed a response at about 2.5 ms in two of three subjects (Fig. 2), which did not change significantly with different coil positions in the anterior–posterior axis. However, there was a marked increase in amplitude when the coil was moved laterally. The C-Ma response was often a mirror image of the I-Ma (Fig. 2). One subject had no response.
Direct stimulation of the right and left facial nerves in the retroauricular area elicited ipsilateral short latency (about 4.0 ms) and high amplitude (>1 mV) CMAPs, and bilateral late responses with onset latency of about 34 ms (Fig. 5).
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Eyes were open and facial muscles were at rest. Each trace shows three superimposed trials. The vertical line shows the onset of late responses (LR), which occurred at latencies of about 35 ms in all traces. Both types of stimulation resulted in bilateral LR. The latency of the OOc M response was 3.0 ms on both sides and the amplitude was 1.2 mV on the right side and 1.5 mV on the left side. R, right; L, left; Ooc, orbicularis oculi; M, M wave; LR, late response.
, 百拇医药 Stimulation at maximum stimulator output with the coil positioned 3 cm above the vertex elicited bilateral responses in the OOc muscles with latency onset of about 35 ms (Fig. 5).
Response to single pulse TMS in facial muscles
TMS elicited consistent MEPs in the C- and I-OOc muscles of all 12 subjects, and in the contralateral Tr (C-Tr) muscle in 10 subjects. Resting MT in the C-OOc muscle was 65.4 ± 11.4% of stimulator output. The active MT was 46.7 ± 7.2% and was significantly lower than the resting MT (P < 0.0001). For comparison, the threshold for eliciting the R1 response of the blink reflex with the coil placed over the supraorbital notch was 39% (3 subjects, range 32–45%) of stimulator output. The response of the ipsilateral Tr (I-Tr) muscle was studied in nine subjects. MEPs were recorded in four subjects at rest and during muscle activation. The amplitudes (165 ± 93 μV at rest, 328 ± 124 μV during muscle activation) were significantly smaller (P = 0.030 at rest, P = 0.048 during muscle activation) than the amplitude of the C-Tr MEP (275 ± 196 μV at rest, 833 ± 645 μV during muscle activation). All I-Tr MEPs showed the same latency and similar shape to the C-Tr MEPs. These features suggested that the responses of the I-Tr muscle are mainly due to volume conduction from contralateral facial muscles. Therefore, the findings in the I-Tr muscle were not analysed further.
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The silent period
The SP was present in 10 subjects in the C-OOc (duration 100 ± 30 ms, range 67–163 ms) and the C-Tr (duration 104 ± 31 ms, range 69–169 ms), and in 9 subjects in the I-OO (duration 92 ± 15 ms, range 68–111 ms) muscle (Fig. 6). In most subjects, there was obvious decrement of EMG activity during the SP but there was no complete suppression. No consistent SP was obtained in one subject. There was no significant effect of muscle on SP duration.
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Twenty sweeps were superimposed. The horizontal bars indicate the duration of the silent period measured from the stimulus artifact to the first return of EMG activity. Both C- and I-OOC show a consistent SP following the motor-evoked potential (MEP) which is interrupted by a long latency reflex in the latency range of R2 of the blink reflex.
SICI and ICF
Resting SICI80 and resting ICF80. Figure 7 shows the MEPs in one subject and the group results are shown in Fig. 8.
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The figure shows recordings from the contralateral orbicularis oculi (C-OOc), contralateral triangularis (C-Tr) and ipsilateral orbicularis oculi (I-OOc) in one subject, with the conditioning stimulation intensity set at 80% of the resting motor threshold. Ten sweeps have been superimposed in each trace. The left column shows responses with test stimulation alone (Test), the middle column with 2 ms and right column with 10 ms interstimulus interval (ISI). C-OOc and C-Tr show decreased amplitude at 2 ms ISI (SICI), and increased amplitude at 10 ms ISI (ICF) compared to test stimulation alone. There was no significant change in MEP amplitude in the I-OOc muscle.
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SICI and ICF for contralateral orbicularis oculi (C-OO), contralateral triangularis (C-Tr) and ipsilateral orbicularis oculi (I-OO) with conditioning stimulation intensities set at 80% (Rest 80, open columns) and 95% (Rest 95, filled columns) of the motor threshold, and during muscle activation (Active, hatched columns). The amplitude of the motor-evoked potential (MEP) is expressed as a ratio to the MEP of test stimulus alone (vertical axis). Values above one indicate or facilitation and values below one indicate inhibition. Error bars represent S.E.M. * Significant inhibition facilitation at P < 0.017. The C-OOc muscle showed SICI80, SICI95 and active SICI. The C-Tr muscle had SICI80 and SICI95, but muscle activation resulted in no SICI. There was no significant inhibition in the I-OOc muscle. At rest, there was significant ICF in C-OO and C-Tr.
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C-OOc. The MEP latency for TS alone was 10.8 ± 0.8 ms and MEP amplitude was 296 ± 94 μV (range: 188–460 μV). In some subjects, the MEP latency was slightly reduced for both ISIs of 2 and 10 ms. ANOVA showed a significant effect of ISI (P < 0.0001) on MEP amplitude and a paired t test showed significant SICI (P < 0.0001) and ICF (P = 0.0042).
C-Tr. The MEP latency for TS alone was 11.0 ± 1.5 ms and the MEP amplitude was 171 ± 69 μV (range: 72–310 μV). In some subjects, the MEP latency was slightly reduced for both ISIs of 2 and 10 ms. ANOVA showed a significant effect of ISI (P < 0.0001) on MEP amplitude and a paired t test showed significant SICI (P = 0.0004) and ICF (P < 0.0005).
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I-OOc. MEP latency for TS alone was 11.1 ± 0.7 ms and MEP amplitude was 333 ± 149 μV (range: 132–605 μV). There was no significant difference in MEP amplitudes and latencies between C-OOc and I-OOc for TS alone. The effect of ISI on MEP amplitude was not significant and there was no significant SICI and ICF.
Repeated measures ANOVA showed a significant effect of muscle on SICI (P = 0.005) and ICF (P = 0.005). The post hoc Fisher's PLSD test showed that there was greater SICI in C-OOc (P = 0.0041) and C-Tr (P = 0.0054) compared to I-OOc. There was no difference in SICI between C-OOc and C-Tr muscles. ICF was significantly higher in C-Tr compared to I-OOc (P = 0.0012), but there was no significant difference between C-OOc and I-OOc (P = 0.08) and between C-OOc and C-Tr.
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SICI95 and ICF95. SICI and ICF at rest were studied in eight subjects with CS set at 95% MT intensity. The C-OOc MT was 63.9 ± 13%. The results are shown in Fig. 8.
C-OOc. The MEP latency for TS alone was 10.9 ± 0.8 ms and the MEP amplitude was 265 ± 85 μV (range: 167–380 μV). ANOVA showed a significant effect for ISI on MEP amplitude (P = 0.002). The paired t test showed significant SICI (P = 0.013), whereas ICF did not reach significance (P = 0.078).
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C-Tr. The MEP latency for TS alone was 11.0 ± 1.5 ms and the amplitude was 260 ± 111 μV (range: 115–366 μV). ANOVA disclosed a significant effect of ISI on MEP amplitude (P = 0.006) and the paired t test showed significant SICI (P = 0.012), but ICF was not significant when corrected for multiple comparisons (P = 0.025).
I-OOc. The MEP latency for TS alone was 11.1 ± 0.7 ms and amplitude was 238 ± 135 μV (range: 100–464 μV). There was no significant effect of ISI on MEP amplitude (ANOVA, P = 0.06).
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SICI and ICF during muscle activation. SICI and ICF were studied during muscle activation in 11 subjects. Figure 8 summarizes the findings.
C-OOc. MEPs were elicited in all 11 subjects. MEP amplitude was 464 ± 214 μV (range: 100–963 μV) for TS alone. ANOVA showed a significant effect of ISI on MEP amplitude (P = 0.01). A paired t test showed that there was significant SICI (P = 0.0046) but no significant ICF (P = 0.36).
C-Tr. MEPs could be discriminated from the background EMG in 8 out of the 11 subjects. The MEP amplitude was 419 ± 233 μV (range: 105–712 μV) for TS alone. ANOVA showed no significant effect of ISI on MEP amplitude.
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I-OOc recordings. MEPs were recorded in 9 of the 11 subjects. MEP amplitude was 355 ± 114 μV (range: 168–513 μV) for TS alone. ANOVA showed no effects of ISI on MEP amplitude.
LICI
Figure 9 summarizes the findings in all subjects. For resting LICI, TS alone elicited an MEP amplitude of 245 ± 109 μV (range: 122–482 μV) for C-OOc, 178 ± 86 μV (range: 66–330 μV) for C-Tr, and 321 ± 166 μV (range: 100–548 μV) for I-OOc muscles. ANOVA showed a significant effect of ISI on MEP amplitude of C-OOc (P < 0.0001), C-Tr (P < 0.0001) and I-OOc (P = 0.0003) muscles. Post hoc Fisher's PLSD test showed significant facilitation at 50 ms ISI in all three muscles (C-OOc: P < 0.0002; C-Tr: P < 0.0001; I-OOc: P = 0.0030).
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The amplitude of the motor-evoked potential (MEP) was expressed as a ratio to that of the test stimulus alone (vertical axis) in the contralateral orbicularis oculi (C-OOc, open columns), in the contralateral triangularis (C-Tr, filled columns) and in the ipsilateral orbicularis oculi (I-OOc, hatched columns) muscles at ISIs of 50, 100, 150 and 200 ms. Values above one indicate facilitation and values below one indicate inhibition. Error bars represent S.E.M. * Significant inhibition or facilitation at P < 0.01. At rest there was significant facilitation at 50 ms ISI in all three muscles. There was no significant inhibition.
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For active LICI, the MEP amplitudes for TS alone were: C-Ooc, 516 ± 257 μV (range: 185–1107 μV); C-Tr, 344 ± 202 μV (range: 101–655 μV); and I-Ooc, 468 ± 109 μV (range: 286–639 μV). ANOVA showed a significant effect of ISI on MEP amplitude for C-OOc (P = 0.04) and C-TR (P = 0.03) muscles, but post hoc Fisher's PLSD showed no significant MEP amplitude difference at any ISI in either muscle. There was no effect of ISI on MEP amplitude in the I-OOc muscle.
Discussion
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TMS applied to the motor cortex lateral to the hand representation elicited MEPs in contralateral upper and lower facial muscles, suggesting that there are M1 projections to these muscles. Intracortical modulation of the upper and lower contralateral facial muscles follows a pattern analogous to that of the contralateral upper and lower limb muscles, showing SICI at 2 ms ISI and ICF at 10 ms ISI (Chen et al. 1998). Similar to limb muscles, SICI is attenuated by muscle activation (Ridding et al. 1995). The LICI protocol at rest showed MEP facilitation at 50 ms ISI in C-OOc, C-Tr and I-OOc muscles and no inhibition at longer ISIs.
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M1 projection to facial muscles
Studies of the corticofacial projections in monkeys suggested that the lower facial muscles receive direct inputs mainly from the contralateral M1, whereas the upper facial muscles receive scant direct M1 projections (Jenny & Saper, 1987; Morecraft et al. 2001). Cortical innervation of the upper face in monkeys appears to be mainly supplied by the supplementary motor and the rostral cingulate cortices bilaterally (Morecraft et al. 2001).
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In humans, the anatomy of corticofacial pathways has not been studied in detail and the cortical areas that control facial muscles remain controversial. Due to the complexity of the facial expression, the cortical projections to the facial nucleus in humans for both voluntary and spontaneous movements may differ from those of monkeys. A functional magnetic resonance imaging study showed that externally paced blinking activates the orbitofrontal cortex (Tsubota et al. 1999), but normal blinking or self-paced activity of the orbicularis oculi muscles were not studied. Similar to our findings, previous TMS studies using a figure-of-eight coil applied to M1 elicited responses with latencies of about 11 ms in the contralateral upper and lower facial muscles (Cruccu et al. 1997; Kobayashi et al. 2001). The authors suggested that the M1 projects to contralateral facial muscles. However, this latency is in the range of the early component of the blink reflex (R1) (Benecke et al. 1988; Kimura, 1989; Esteban, 1999) and it results in a central conduction time that is much longer than those obtained for other limb and cranial muscles. TMS applied to the midfrontal scalp position, aimed at stimulating the mesial frontal cortex while avoiding M1 activation, elicited a small response in the OOc muscles with latencies ranging from 6 to 8 ms which were interpreted as MEPs (Sohn et al. 2004). Therefore, Sohn et al. (2004) suggested that the mesial frontal cortex projects directly to facial muscles and the OOc MEPs obtained with TMS over the M1 can be explained by the R1 component of the blink reflex rather than cortical projection from the M1 (Sohn et al. 2004).
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Several findings in our study suggest that the M1 gives rise to contralateral upper facial innervation. First, stimulation of a restricted area of the scalp overlying M1 elicited MEPs in the C-OOc muscle. Stimulation more than 2 cm away from the optimal position in the horizontal or vertical axes elicited no response. Secondly, the R1 response is usually only present on the ipsilateral side. Thirdly, although the C-Tr muscle does not participate in the blink reflex in normal subjects, M1 stimulation led to MEPs in the C-Tr muscle with similar latencies to the C-OOc muscle. Moreover, paired-pulse TMS applied to M1 elicited SICI and ICF in the C-OOc and C-Tr muscles. SICI and ICF have been demonstrated to arise from the cortex (Kujirai et al. 1993; Nakamura et al. 1997; Di Lazzaro et al. 1998). Finally, the SP can be elicited in the C-OOc and C-Tr muscles. Because there is little or no muscle spindle in the facial muscles, the SP is probably related to cortical inhibition (Cruccu et al. 1997).
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We did not observe any MEPs in the Ma muscle, probably because Ma MEPs are best elicited with a current direction that is different from the one we used (Guggisberg et al. 2001). Therefore, our findings are unlikely to be related to volume conduction from muscles innervated from the trigeminal nerve. In two subjects, there was a short latency response in the I-Ma muscle indicating direct activation of the trigeminal root (Fig. 2) but this was absent in one subject (Fig. 3). Since subjects with or without trigeminal root activation showed similar responses in the facial muscles, a reflex related to activation of the trigeminal nerve root is unlikely to explain our findings although a contribution to the late responses in some subjects cannot be ruled out.
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In contrast to C-OOc muscle, the I-OOc showed responses with similar amplitude and decreasing onset latency in the 13–10 ms range, as the coil was moved in the anterior direction. Since the supraorbital nerve provides cutaneous sensation to the frontal scalp up to the vertex, this finding suggests that the I-OOc response may be mainly due to the R1 component of the blink reflex, where reduction in MEP latency with more anterior stimulation reflects the shift of the stimulation site from distal to more proximal locations along the scalp branches of the supraorbital nerve (Fig. 4). The absent I-OOc response with the coil placed more than 4 cm posterior to the optimal position may be explained by the stimulation site being posterior to the cutaneous supply of the supraorbital nerve.
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The absence of SICI and ICF in the I-OOc support the assumption that the response is contaminated with the R1 component of the blink reflex which does not depend on cortical mechanisms. Identical paired electrical stimulation with a short interval (less than 10 ms) applied to the supraorbital notch results in facilitation of the R1 with little or no influence on the R2 (Esteban, 1999), or produce responses in subjects with no R1 response to a single stimulus (Kimura, 1989). The lack of facilitation in I-OOc in the SICI and ICF studies may be because we used a weaker conditioning stimulus followed by stronger test stimulation.
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Because of the presence of the R1 response, we cannot determine whether there is an ipsilateral projection to OOc muscle from the M1 and the presence of ipsilateral SICI or ICF. The presence of SP in the I-OOc muscle in our experiments favours ipsilateral projections. However, it is not possible to rule out the possibility that the silent period is related to cutaneous stimulation, which has the same characteristics (Sanes & Ison, 1980; Ishikawa et al. 2001). We also found possible MEPs in the I-Fr muscle in one out of three subjects (Fig. 2). Previous TMS studies recording from upper facial muscles have found ipsilateral responses not only in the OOc muscle, which may have been contaminated with an R1 response, but also in the frontalis and lower face muscles, which do not participate in the blink reflex (Meyer et al. 1989; Rodel et al. 2001).
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MEPs from the I-Tr were absent in most of the subjects studied. When recorded, the I-Tr MEPs were of lower amplitude, and had a similar shape and latency compared to the C-Tr MEPs, suggesting that the ipsilateral responses were mainly due to volume conduction from the C-Tr muscle. Our findings suggest that the M1 projection to lower facial muscles is mainly contralateral, although we cannot rule out a small ipsilateral projection in some subjects. TMS studies using needle recording electrodes to avoid electrical cross-talk have reported ipsilateral MEPs in the lower facial muscles (Benecke et al. 1988; Werhahn et al. 1995; Rodel et al. 1999). Furthermore, SP was elicited in the ipsilateral mentalis muscle (Werhahn et al. 1995). However, electrical stimulation of the exposed human motor cortex resulted in bilateral contraction of the upper facial muscles and only contralateral twitching of the lower facial muscles (Penfield & Rasmussen, 1950) and a TMS study found no response in the ipsilateral lower face muscles (Cruccu et al. 1990a). Therefore, the presence of significant ipsilateral M1 projection to the lower facial muscles remains controversial.
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We found that TMS elicited MEPs from contralateral lower facial muscles at rest, and that the MEP amplitudes were significantly increased with muscle activation. This is similar to other cranial and limb muscles, and is consistent with the findings of several previous studies (Benecke et al. 1988; Kobayashi et al. 2001). Other studies on the central pathways to the lower facial muscles were performed with single pulse TMS during muscle activation (Cruccu et al. 1990a; Meyer et al. 1994; Liscic et al. 1998; Fischer et al. 2005), and some studies did not find consistent MEPs at rest in lower facial muscles. Possible reasons for the difference include differences in TMS parameters such as type of TMS coil, current direction, stimulus intensities as well as the selection of the target muscle.
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Intracortical inhibition and facilitation in the facial M1 area
A previous report found SICI and ICF in the contralateral mentalis muscle but not in C-OOc or I-OOc muscles (Kobayashi et al. 2001). The discrepancy with our results for the C-OOc muscle may be due to two reasons. First, the authors applied TS with a stimulus intensity less than 120% of MT to elicit MEPs of approximately 0.2 mV. Although the TS intensity and MEP amplitude were not reported, their values were probably considerably lower than the values of our study (mean TS intensity 126% of MT and mean MEP amplitude 0.3 mV for C-OOc). Second, their patients kept their eyes closed and therefore the OOc muscles were active. Both low TS intensity and muscle activation may result in less inhibition. In hand muscles, low TS amplitude reduces or abolishes SICI (Sanger et al. 2001; Daskalakis et al. 2002; Roshan et al. 2003). In addition, even minimal levels of voluntary activation significantly reduce SICI (Ridding et al. 1995; Hanajima et al. 1998).
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In order to obtain a reliable MEP, we used TS at intensities that resulted in a late response in many subjects. These late responses occurred at latencies of around 50 ms and did not interfere with the measurement of MEP with peak latencies of about 15 ms. Late responses were also obtained when the coil was placed 3 cm above the scalp (Fig. 3), suggesting that the noise of the stimulating coil elicited either an acoustic blink reflex (Rushworth, 1962; Tackmann et al. 1982) or a startle response (Brown et al. 1991; Chokroverty et al. 1992). Persistence of the response throughout the trials with no habituation favours the acoustic blink reflex, but definite differentiation between these possibilities cannot be achieved without further studies (Meincke et al. 2002). Moreover, direct magnetic stimulation of the facial nerve also elicited a late response bilaterally (Fig. 3) that may represent either an acoustic blink reflex or a facio-facial reflex (Willer & Lamour, 1977; Csecsei, 1979). The acoustic blink reflex, the startle response and the facio-facial reflexes are all bilateral and have similar latencies in the OOc muscle, which is in the range of the R2 response of the blink reflex elicited by supraorbital nerve stimulation. However, none of these facial reflexes is preceded by an earlier response in the latency range of the MEP and the R1 of the electrical blink reflex. Therefore, the presence of a late response with higher TMS intensity did not indicate contamination with the R1 in the C-OOc muscle.
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Paired TMS in the facial representation of the M1 with CS at 80% of the TS intensity produced SICI and ICF similar to the limb muscles, both in the C-OOc and C-Tr muscles. Several studies indicate that SICI is mediated through cortical interneurones (Kujirai et al. 1993; Nakamura et al. 1997; Chen et al. 1998; Di Lazzaro et al. 1998). The slightly shorter latency for the inhibited response seen in some subjects is consistent with SICI as this has been reported for SICI in hand muscles (Kujirai et al. 1993), but we cannot rule out a small contribution from changes in brainstem excitability. Pharmacological investigations suggest that it involves GABAA mechanisms (Ziemann et al. 1996a,b; Di Lazzaro et al. 2000; Ilic et al. 2002). ICF also occurs in the cortex (Ziemann et al. 1996c; Nakamura et al. 1997) and is probably mediated by glutamate (Ziemann et al. 1998).
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The LICI protocol has not previously been studied in facial muscles. There was facilitation at 50 ms, which occurred at a similar latency to the long latency responses and therefore may be due to increased excitability of the facial motoneurones mediated by subcortical circuits such as the facio-facial, acoustic blink or startle reflexes (Willer & Lamour, 1977; Meincke et al. 2002). We found no significant LICI at ISIs between 100 and 200 ms. The inhibitory mechanisms mediating LICI are different from those mediating SICI (Sanger et al. 2001). In contrast to SICI, LICI in limb muscles is not significantly influenced by muscle activation (Wassermann et al. 1996; Chen et al. 1997). In limb muscles, LICI at ISIs longer than about 50 ms occurs in the cortex (Fuhr et al. 1991; Inghilleri et al. 1993a; Nakamura et al. 1997; Chen et al. 1999) and is probably mediated by GABAB receptors (Roick et al. 1993; Siebner et al. 1998; Werhahn et al. 1999). LICI and the silent period elicited with TMS may be mediated by similar mechanisms, since the period of paired-pulse inhibition coincided with the silent period (Wassermann et al. 1996). TMS over the facial representation of M1 elicited SP in all three muscles in our subjects, with a mean duration of about 100 ms. This may explain the absence of LICI at ISIs of 100 ms or longer as these times may fall outside the activation period of the inhibitory interneurones responsible for LICI and SP. Previous reports found longer SPs (140–215 ms) and complete absence of EMG in the facial muscles using a large circular coil centred at the vertex and high stimulus intensities (Werhahn et al. 1995; Cruccu et al. 1997). This is consistent with the finding that SP increases with higher stimulus intensity (Valls-Sole et al. 1992; Wassermann et al. 1996).
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Potential roles of different facial motor areas
Our results do not exclude projection of the medial frontal cortex to facial muscles (Sohn et al. 2004). Dissociation of emotional and voluntary movement is frequently observed in facial paralysis resulting from supranuclear lesions (Monrad-Krohn, 1924; Taverner, 1969; Topper et al. 1995). Although the pathways responsible for these two types of facial activity are not well understood, it has been suggested that volitional activity may be mediated by the M1 and the descending pyramidal tract whereas emotional movements may be mediated by the anterior frontal-thalamo-pontine connection that descends in the anterior limb of the internal capsule (Hopf et al. 1992). Since the cingulate cortex is part of the limbic system associated with emotional expression, the mesial frontal cortex may be responsible for emotional facial expressions (Morecraft et al. 2001). It is not known why the central conduction time from M1 to facial muscles is long compared to limb muscles. Possible reasons include the involvement of a polysynaptic pathway or that the corticobulbar fibres may be of smaller diameter and therefore have a slower conduction speed compared to the corticospinal fibres.
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In conclusion, our findings suggest that there are M1 projections to contralateral upper and lower facial muscles in humans. The facial M1 representation is under the influence of short interval intracortical inhibitory and intracortical facilitatory circuits, similar to the arm and leg areas of the M1.
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