Clinical Neurophysiology
Volume 120, Issue 1 , Pages 174-180, January 2009

Effect of slow rTMS of motor cortex on the excitability of the Blink Reflex: A study in healthy humans☆

Department of Neurosciences, Section of Neurological Clinic, S. Anna University-Hospital, C.so Giovecca 203, 44100 Ferrara, Italy

Accepted 5 September 2008.

Article Outline

Abstract 

Objective

To evaluate the after-effects of low frequency, sub-threshold repetitive Transcranial Magnetic Stimulation (rTMS) of primary motor cortex, on the excitability of Blink Reflex (BR) in healthy subjects.

Methods

The BR recovery cycle was carried out in 10 healthy volunteers in basal conditions, immediately after rTMS (30s), 15 and 60min later. A paired electric supraorbital stimulus paradigm with inter-stimulus intervals (ISI) of 100–600–1000–1500ms was used. The “real” rTMS consisted of a 200 stimuli long train delivered at 1Hz and intensity 80% of rest Motor Threshold of the FDI muscle, using a focal coil applied over the primary motor cortex region. The basal BR recovery cycle was also compared with that obtained after a “sham” rTMS.

Results

The recovery of the R2 component of the BR was significantly suppressed 30s after rTMS. This effect was also observed at 15min, though of lower magnitude and only at long ISIs (1000-1500ms). No significant effect on R2 recovery was observed 60min after real rTMS as well as after sham rTMS.

Conclusions

rTMS of motor cortex modulates the excitability of BR through its action on cortical excitability and on the cortical facilitatory drive to the brainstem reflex pathways.

Significance

Slow (1Hz), sub-threshold rTMS of motor cortex determines a long-lasting reduction of excitability of BR.

Keywords: rTMS, Motor cortex, Blink Reflex

 

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1. Introduction 

Several studies in humans demonstrate that a train of transcranial magnetic pulses (rTMS) of the same intensity applied to a specific brain region can induce a modulation of cortical excitability which ranges from inhibition to facilitation depending on stimulation variables, particularly frequency: high (>5Hz) rTMS seems to lead to a temporary increase in cortical excitability; low (1Hz and below 1Hz) rTMS can suppress excitability of the motor cortex. While the former effect varies among individuals, the latter appears to be a more robust and longer lasting after-effect (Pascual Leone et al., 1994, Chen et al., 1997, Berardelli et al., 1998, Maeda et al., 2000, Touge et al., 2001, Romero et al., 2002).

The mechanisms of the modulation of cortical excitability beyond the duration of the rTMS train are still unclear, but there is a consistent experimental evidence that they take place at a cortical level (Di Lazzaro et al., 2002).

The Blink Reflex (BR) elicited by electric stimulation of supraorbital nerve consists of two main responses in orbicularis oculi muscles: the early response, R1, ipsilateral to the side of stimulation, and the late response, R2, bilaterally expressed and responsible for most of the eyelid closure of the blink. As studies in humans have shown (Snow and Frith, 1989, Evinger et al., 1991), R1 also lowers the eyelid. R1 has an oligosynaptic organisation with its central representation in the main trigeminal nucleus of the pons (Esteban, 1999, Trontelj and Trontelj, 1978). Other authors, in animal studies, highlighted the role of the rostral area of the spinal trigeminal complex in the origin of R1 response (Pellegrini et al., 1995). R2 circuit is multisynaptic and lies in the tractus and nucleus spinalis trigeminalis from which a long interneuronal ascending pathway, involving the lateral propriobulbar system of the reticular formation, connects to the ipsilateral and contralateral facial nuclei (Esteban, 1999, Cruccu and Deuschl, 2000, Aramideh and Ongerboer de Visser, 2002). In several subjects it is also possible to elicit a third late response (R3), probably related to the cranial pain pathways (Esteban, 1999, Kimura, 1989).

The modulation and basal excitability of the BR can be studied using the paired-stimulus paradigm. Both stimuli, delivered on the supraorbital notch, have similar characteristics and intensity. The first one is called conditioning and the second one is the test stimulus. The response to the test stimulus (test response) is modified by the conditioning one (conditioning response) in relation to the inter-stimulus interval (ISI) duration.

The multisynaptic R2 response is virtually suppressed with ISI around 100ms and then it gradually recovers, until 100% or more of the conditioning response size, beyond ISIs of 1s. The values of the test responses, expressed as the percentage of the conditioning responses at different ISIs, build up the recovery curve of the BR (Esteban, 1999, Cruccu and Deuschl, 2000, Aramideh and Ongerboer de Visser, 2002, Kimura et al., 1969, Powers et al., 1997).

The BR is influenced by many suprasegmental structures that usually affect its basal excitability and its response to modulation factors (Esteban, 1999). The R1 response appeared to be stable and not influenced by suprasegmental inputs, both in single stimulus studies (Cruccu and Deuschl, 2000), and in double stimulation paradigm (Kimura, 1989).

The only studies demonstrating how the basal ganglia modulate trigeminal reflex blink excitability are in rodents (Basso et al., 1993, Basso et al., 1996, Basso and Evinger, 1996). A strong influence comes from the central dopamine level (Penders and Delwaide, 1971, Esteban and Giménez-Roldán, 1975).

Moreover, anatomo-physiological and clinical studies have demonstrated that cortex is responsible for a crossed facilitation on the brainstem reticular networks of BR (Kuypers, 1958, Kimura, 1974, Fisher et al., 1979, Dengler et al., 1982, Catz et al., 1988, Berardelli et al., 1983, Kimura et al., 1985), but there is no study, to our knowledge, in which rTMS has been used to investigate the cortical modulation of the excitability of these brainstem systems. For instance, the suppression of cortical excitability provoked by slow rTMS could lead to a reduction of this cortical drive and consequently of the excitability of BR, thus reproducing, in a transient way, the effect of hemispheric lesions (virtual lesion mode).

So, the aim of the present study was to assess, in healthy humans, the after-effects of slow, sub-threshold rTMS of primary motor cortex, on the excitability of these reflexes, tested by using the BR recovery cycle.

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2. Methods 

2.1. Subjects 

Ten healthy volunteers (six women and four men, mean age 31 years old, range 24–36 years old, all right-handed) were recruited. All subjects, in accordance with the Declaration of Helsinki, gave their written informed consent to the study, which was approved by the local ethical committee. None of them was a smoker and all reported a restful sleep in the night before the experiment. No subject was using drugs that could alter neuro-muscular excitability, stimulants (like caffeine or teofilline) or substances related to dopaminergic, serotoninergic and adrenergic systems either during the evaluation or 48h prior to it. During the study subjects laid down supine, with the eyes gently closed, on a comfortable examination bed, in a quiet and dimly lit room.

2.2. Blink Reflex recovery cycle 

Ag–AgCl surface recording electrodes were applied over the orbicularis oculi (OO) muscle of both sides (mid-lower eyelid and temple). In all volunteers, the cathode of the stimulating electrode was placed over the right supraorbital (SO) notch and the anode 3cm away over the skin of the frontal bone. In five subjects, the SO stimulation was performed on the left side too. Skin impedance was lower than 5kΩ. Ground electrode was placed over the nasion. The stimulus intensity was adjusted to obtain a well-defined and reproducible ipsi and contralateral R2 in five consecutive trials. This was reached at painless intensities, usually 2–3 times the sensory threshold level. This stimulus intensity was kept constant during the whole experiment.

EMG signal was amplified (2000–5000 times) using a conventional electromyograph (Keypoint, Dantec Medical Inc., Copenhagen, Denmark), filtered (100–2000Hz; −3dB), digitized with a sampling rate of 5kHz and stored on a PC for off-line analysis.

The recovery cycle of the R2 component of the reflex was obtained using the paired-stimulus paradigm (conditioning and test electric pulse of equal intensity), at ISI of 100, 600, 1000 and 1500ms. Trials of five consecutive responses at each ISI have been full-wave rectified and averaged. The ISI order varied randomly and the interval between each stimulus of a trial varied between 15 and 30s to avoid habituation. The area of the R2 of both sides was calculated off-line through the integrated values of the averaged EMG signals between the onset and end (return to the baseline) pointing markers of the response, using a Dantec software. The area of the test R2 was expressed as a percentage of the conditioning one (considered to be 100%) at each ISI (Esteban, 1999, Cruccu and Deuschl, 2000, Aramideh and Ongerboer de Visser, 2002).

2.3. Transcranial Magnetic Stimulation (TMS) 

Subjects were instructed to keep their hands as relaxed as possible. A tightly fitting latex swimming cap was placed on their head to mark the site of stimulation. Stimulation was delivered to the “optimal scalp position” for the right first dorsal interosseus (FDI) muscle, that is the scalp position where TMS induced, with the lowest intensity, motor evoked potentials (MEPs) of maximal amplitude in the target muscle. Two Ag–AgCl surface recording electrodes were placed over the belly and tendon of the right FDI. A round ground electrode was placed on the wrist. MEPs were amplified (2000–5000 times) with a band pass of 50–2000Hz (−3dB) using a conventional electromyograph (Keypoint, Dantec Medical Inc., Copenhagen, Denmark), digitized with a sampling rate of 5kHz and stored on a PC for off-line analysis. TMS was performed using a 90mm “figure of eight” coil connected to a Dantec Maglite-r 25 Magnetic Stimulator (Dantec Medical Inc., Copenhagen, Denmark). The coil was positioned tangentially over the “optimal scalp position” of the left motor cortical area, with the handle 135 degrees from the midsagittal axis of the subject’s head and the coil pointing in anterior position. This orientation induces a posterior-to-anterior directed current flow in the cortex, which is known to recruit the greatest proportion of I waves that are highly sensitive to the level of cortical excitability at the time the stimulus is given (Brasil-Neto et al., 1992, Di Lazzaro et al., 2001).

The following two TMS parameters were determined in each subject in order to establish, respectively, the intensity of the rTMS and the level of cortico-spinal excitability:

•rest Motor Threshold (rMTh) of the right FDI muscle, defined as the minimal intensity of stimulation, expressed as a percentage of the maximum power output of the magnetic stimulator, that can elicit MEPs greater than 50μV peak-to-peak amplitude in the fully relaxed target muscle in at least 5 of 10 successive trials (Rossini et al., 1994). Stimulation was started at suprathreshold intensities and decreased by steps of 2% of the stimulator output. Complete muscle relaxation was monitored with audio-visual EMG feedback during the threshold determination.

•MEP maximal amplitude (determined peak-to-peak) recorded from the right FDI muscle at rest, obtained with a single magnetic stimulus of appropriate intensity and measured in five consecutive trials.

2.4. Repetitive Transcranial Magnetic Stimulation (rTMS) 

A single conditioning train of 200 stimuli was delivered at 1Hz and intensity 80% of rMTh over the optimal scalp position previously determined, using the same magnetic stimulator, coil and coil orientation used for the determination of TMS parameters.

The “sham” rTMS consisted of a train of stimuli having the same duration, frequency and intensity characteristics as the real one, delivered holding the coil perpendicularly to the plane tangential to the optimal scalp position.

2.5. Study design 

The BR recovery cycle by right SO stimulation, optimal scalp position for TMS, rMTh and maximal MEP amplitude in the right FDI muscle were determined in basal conditions in each subject.

The absence of recordable BR responses to threshold single-pulse TMS applied over the optimal scalp position was verified before delivering rTMS train.

BR recovery cycle and MEP maximal amplitude were assessed again immediately (30s: short term), 15min (medium term) and 60min (long term) after the end of the conditioning rTMS.

The BR recovery obtained by left SO stimulation at ISI 1500 ms was also evaluated in five subjects of our study population in order to clarify the anatomical site where motor cortex stimulation exerted its influence.

In a further experimental session, performed one week later in the same subjects, the BR recovery cycle was assessed, as described above, in basal conditions and immediately (30s) after the “sham” rTMS.

2.6. Statistical analysis 

The baseline values of MEP maximal amplitude and of ipsi and contralateral test R2 (iR2 and cR2) area (percentage of the respective conditioning R2 area) at each ISI were compared to the homologous values obtained after the real rTMS at short, medium and long term.

In the “sham” session, baseline test iR2 and cR2 area percentage values at each ISI were compared to those obtained after the “sham” rTMS.

In order to check for the modifications of conditioning R2 after the rTMS, which could consequently influence the amount of recovery of test R2, we also compared the baseline area of the R2 responses elicited by the first electrical (conditioning) stimulation at ISI 1500ms to the corresponding values obtained after the conditioning procedures (real and sham rTMS).

Finally, we compared the values of the test R2 area obtained from the two sides (ipsi and contralateral) at the different ISIs, in each experimental condition.

Differences between conditions were evaluated using the non-parametric two-tailed Wilcoxon test for paired data.

Statistical significance was set at p value <0.05. Results are all expressed as mean±SE.

SYSTAT packages (Systat, Inc. Evanstone, IL USA) were employed for statistical processing.

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3. Results 

3.1. Effects of rTMS on the hand MEP 

Mean rMTh of right FDI muscle was 30.8% (±2.2), so the mean intensity used for rTMS was 24.6% of the maximum power output of our magnetic stimulator.

We found a significant reduction of MEP maximal amplitude after rTMS at short (30s) and medium (15min) term: the mean value was 6.8 (±0.44)mV at baseline, 5.2 (±0.53)mV at short term and 5.8 (±0.58)mV at medium term after the end of the train, with a mean reduction of 23% (p=0.002) and 15% (p=0.008), respectively, (Fig. 1). MEP maximal amplitude was 6.5 (±0.64)mV at long term after the end of the train (p>0.05), with no significant difference compared to the basal value (Fig. 1).

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  • Fig. 1. 

    Effect of sub-threshold 1Hz rTMS over left M1 on corticospinal excitability as indexed by the MEP maximal amplitude recorded from the contralateral relaxed FDI muscle. Each column represents mean maximal amplitude of MEPs of subjects at the baseline (black column) and after rTMS at short (30s, dark grey column), medium (15min, light grey column) and long term (60min, white column). Error bars equal one fold SE.

The focal single-pulse TMS delivered at threshold intensity over the optimal scalp position for the right FDI muscle never elicited recordable EMG activity in the OO muscles.

3.2. Basal BR recovery cycle 

The mean basal BR recovery cycle in our study population is represented in Fig. 2A and B (real and sham rTMS sessions, respectively).

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  • Fig. 2. 

    (A) Mean (±SE) Blink Reflex recovery curve in basal condition, at short (30s), medium (15min) and long (60min) terms after real rTMS. The percentage area of the test iR2 (vertical axis) is represented as a function of the ISI (horizontal axis). Basal curve is represented with diamonds, short-term curve is represented with triangles, medium-term curve is represented with squares and long-term curve with circles. (B) Mean (±SE) Blink Reflex recovery curve in basal condition and at short term (30s) after sham rTMS. The percentage area of the test iR2 (vertical axis) is represented as a function of the ISI (horizontal axis). Basal curve is represented with diamonds and short-term curve is represented with triangles.

3.3. Effects of rTMS on BR 

The mean area value of the conditioning R2 response was 5,18±1,03mV/ms at the baseline and 4,15±0,91mV/ms after the real rTMS. In the sham session, it was 3,92±0,89mV/ms at the baseline and 4,02±0,91mV/ms after the sham rTMS. In both the experimental conditions there was no statistically significant difference between the baseline and conditioned (real and sham) results (p=0.23 and 0.86, respectively).

3.4. Effects of rTMS on BR recovery cycle 

Both iR2 and cR2 recoveries were significantly suppressed at the ISIs examined, at short and, to a lesser extent, at medium term after real rTMS compared to the corresponding basal values, with the only exception of the recovery values (iR2 and cR2) obtained at ISI 600ms at medium term after rTMS, whose suppression did not reach the statistical significance. In addition, the amount of suppression of R2 recovery after rTMS increased along with ISI duration (Fig. 2A). No significant modification of R2 recovery cycle was found at long term after the end of the conditioning train (Fig. 2A).

Particularly, test R2 was completely suppressed at ISI 100ms both at baseline and after the conditioning procedure. At ISI 600ms, mean basal test iR2 area was reduced by about 32% at short term (p=0.01), and 18% at medium term after rTMS (p>0.05). Test cR2 at ISI 600ms showed a reduction of 35% at short term after rTMS (p=0.03) and of 25% at medium term (p>0.05). At ISI 1000ms, the percentage reduction of mean basal test iR2 area after rTMS was of 40% and 32% (p=0.004) at short and medium terms, respectively. Test cR2 at ISI 1000ms was reduced of 42% (p=0.004) and 34% (p=0.008) at short and medium terms. At ISI 1500ms, the reduction of test iR2 area after rTMS was of 43% (p=0.002) and 38% (p=0.004), respectively at short (Fig. 3B) and medium terms, while test cR2 was reduced of 46% (p=0.004) and 35% (p=0.01) at short and medium terms after rTMS. Finally, by stimulating left SO nerve at ISI 1500ms, the mean reduction of test iR2 area was of 34% (p=0.004) and 32% (p=0.01) and that of test cR2 was of 40% (p=0.004) and 37% (p=0.005), respectively at short and medium terms after rTMS (Fig. 3C).

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  • Fig. 3. 

    (A) Recovery of the R2 response of the Blink Reflex in a representative subject at short term (30s) after sham rTMS. Conditioning and test R2 at ISI 1500ms are represented. The averaged results are in the upper trace and the rectified superimposed responses are in the lower traces. (B) Recovery of the R2 response of the Blink Reflex (SO stimulus contralateral to rTMS) in a representative subject at short term (30s) after real rTMS. Conditioning and test R2 at ISI 1500ms are represented. The averaged results are in the upper trace and the rectified superimposed responses are in the lower traces. (C) Recovery of the R2 response of the Blink Reflex (SO stimulus ipsilateral to rTMS) in a representative subject at short term (30s) after real rTMS. Conditioning and test R2 at ISI 1500ms are represented. The averaged results are in the upper trace and the rectified superimposed responses are in the lower traces.

3.5. Effects of sham stimulation on BR recovery cycle 

The differences between the basal BR recovery curves obtained in the sham and real rTMS sessions were not statistically significant (p>0.05). In the sham session, we did not observe any significant modification of R2 recovery values at each ISI after the sham rTMS (Fig. 2, Fig. 3A).

Finally, we did not find any significant difference between ipsi and contralateral R2 recovery at each ISI, in both baseline and conditioned curves.

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4. Discussion 

The results of the present study confirm the inhibitory after-effect of slow (1Hz), sub-threshold rTMS of motor cortex on its basal excitability. Moreover, they show that this conditioning procedure can also influence the excitability of brainstem reflexes.

The basal BR recovery cycle in our study population showed a behaviour similar to that reported in the literature (Esteban, 1999, Cruccu and Deuschl, 2000, Aramideh and Ongerboer de Visser, 2002).

The BR late response (R2) did not change significantly after rTMS, this meaning that rTMS and the associated modification of cortical excitability do not modify the simple BR.

The recovery of the R2 component of the BR in the paired-stimulus paradigm was significantly depressed at short and medium terms after the conditioning rTMS (Fig. 2, Fig. 3B–C). This indicates a long-lasting reduction of excitability of the reflex. Conversely, the sham rTMS was completely ineffective on the R2 recovery cycle (Fig. 2, Fig. 3A) and this suggests both that the modulation of the excitability of BR takes place at a suprasegmental level and that the effect of the real rTMS cannot derive from a technical bias: for instance, we can exclude the influence of the repetitive acoustic stimulation due to the “click” of the coil during the conditioning train on the inhibition of R2 recovery, since it has the same characteristics both in the real and in the sham rTMS. We can also exclude the role of both intensity of electric SO stimuli, which was kept constant in the different experimental conditions, and frequency of SO stimulation, which was variable just to avoid habituation of the responses (Esteban, 1999, Sommer and Ferbert, 2001).

The TMS intensity used was not able to elicit a BR in the study subjects, nevertheless it could have caused a transient blink suppression (Pellegrini et al., 1995), and 1Hz rTMS could have produced a long-term depression of the trigeminal system (Ellrich and Schorr, 2004). To exclude this interaction, we previously examined the effect of rTMS delivered on the contralateral side respect to the electrical stimulation of the peripheral trigeminal branch. Nevertheless, this procedure could not exclude an interference with the cR2 circuit, but we did not observe a different behaviour between iR2 and cR2 in the different experimental conditions.

The inhibitory effect of rTMS on R2 recovery was bilaterally observed by stimulating the SO nerve contralateral to the side where rTMS was delivered. This inhibitory effect, tested at ISI 1500ms (maximal inhibition), was similarly observed in those subjects undergoing SO stimulation ipsilateral to rTMS. This, together with the observation that rTMS suppresses test R2 recovery while leaving conditioning R2 unmodified, suggests that whatever the mechanism responsible, this probably occurred at the level of the brainstem interneuronal network of the R2 component of the reflex (Catz et al., 1988).

Moreover, a direct effect of rTMS on the facial motoneurons is unlikely because they do not seem to modify, at rest, their excitability during the cortical silent period post-TMS of the orbicularis oculi muscle (Leis et al., 1993).

The observed decreased excitability of the BR after slow rTMS could be explained by the reduction of the cortical basal excitability that in turn could have caused a reduction of the cortical facilitation at the level of the interneuronal bulbar reticular network of the reflex.

This hypothesis is sustained by the description of the existence in humans of direct projections of motor cortical areas to the lateral medullary reticular formation (Kuypers, 1958). In addition, there are several arguments about the cortical modulation of the R2: corneal reflex (whose circuit partially overlaps that of the R2 response of the BR) is reduced or abolished in patients with supratentorial lesions and this may occur even in patients with pure motor deficit and no demonstrable sensory loss (Fisher et al., 1979, Berardelli et al., 1985). Hemispheric lesions alter the responses of BR, particularly late ones, which can be absent or markedly depressed when BR is elicited in the affected side of the face, even after long periods from the onset of lesion (Esteban, 1999). BR excitability studies in patients with hemispheric cerebrovascular damage showed a greater disfacilitation at the level of brainstem interneurons than at the motoneurons, with a diffuse loss of excitability contralateral to the lesion. In these studies, CT scans of patients with and without BR abnormalities showed differences only in the size of cerebral lesion, which was larger in the former group of patients, but not in its location. Overall, these findings suggest the existence of a crossed facilitation to this reflex from wide areas of cortex (Kimura, 1974, Fisher et al., 1979, Dengler et al., 1982, Berardelli et al., 1983, Kimura et al., 1985, Catz et al., 1988). Loss of similar suprasegmental influences is likely to be implicated in the depression of late BR responses that occurs during the coma of supratentorial origin, as well as after the therapeutic doses of diazepam (Lyon et al., 1972, Kimura, 1989). Even the state of arousal profoundly modifies the excitability of R2 (Boelhouwer and Brunia, 1977).

Furthermore, R2 responses show a clear suppression during the post-TMS silent period of the orbicularis oculi muscle (Leis et al., 1993).

Finally, on the basis of the experimental observations by Strafella and coll., coming from their PET studies in humans after rTMS of motor and prefrontal cortex, we can at least speculate about a possible increase of striatal dopamine release induced by rTMS in our subjects (Strafella et al., 2001, Strafella et al., 2003). The BR excitability has a direct and strong relation to the dopamine levels in the central nervous system: an increased reflex excitability occurs with the lower levels, such as in Parkinsonisms, and is reversed by dopaminergic drugs (Penders and Delwaide, 1971). Conversely, Huntington’s disease, in which a loss of medium spiny neurons in the direct pathway or a reduction in D1 receptors in the striatum lead to a relative dopaminergic hyperfunction, shows a hypoexcitable BR (Esteban and Giménez-Roldán, 1975).

The temporal course of MEP inhibition after rTMS observed in our experiment also needs a brief discussion. We used a 200 stimuli long single train for the conditioning rTMS, which significantly inhibited MEP at short (30s) and, to a lesser extent, medium terms (15min). Train duration (number of stimuli) is known to correlate to the duration of MEP suppression: trains of 150 stimuli at 1Hz frequency determine a MEP suppression about 5min long (Touge et al., 2001). On the other hand, Maeda et al. found a greater inhibitory effect on the second day of rTMS administration than that on the first (Maeda et al., 2000), according to the LTD-like effect showed by Wang et al. with 240 pulses of rTMS at 8Hz, lasting occasionally up to the observed 24h (Wang et al., 1996).

Finally, we applied rTMS over the hand motor cortical region instead of the face one which would appear more appropriate for our experimental purpose. This choice has several reasons. First, MEPs from the hand muscles are more stable and have the lowest rMTh (to which the intensity of rTMS is tightly linked) compared to other muscles. Second, CT scans in patients with cerebrovascular accidents and BR abnormalities revealed widely scattered lesions, failing to demonstrate a topographic specificity (Catz et al., 1988, Berardelli et al., 1983, Kimura et al., 1985). Third, testing the cortical silent period duration of the orbicularis oculi muscles after TMS applied over the different electrode locations of the International 10–20 system, Leis et al. obtained the longest one when the coil was placed over the vertex (Cz) (Leis et al., 1993). Fourth, Siebner et al. demonstrated that the stimulation of trigeminal afferents interferes with the motor output to the intrinsic hand muscles, inducing a bilateral inhibition (Siebner et al., 1999). Lastly, Sohn et al. have recently provided evidence that the cortical control for the upper facial movements, including blinking, does not principally derive from the facial area of primary motor cortex, but rather from the mesial frontal region (Sohn et al., 2004).

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5. Conclusions 

Slow (1Hz), sub-threshold rTMS of motor cortex determines a long lasting reduction of BR excitability, probably related to the depression of cortical excitability and to the consequent reduction of cortical facilitation to the brainstem interneuronal network of the BR. It is also possible that an increased striatal dopamine release is induced by rTMS with the consequent inhibition of BR excitability.

These results should be confirmed in larger populations and by other methods of BR excitability evaluation, such as the acoustic BR recovery cycle, which would allow to avoid the interferences coming from the peripheral trigeminal stimulation. The comparison of the effect of rTMS applied over different cortical regions, such as the facial motor area, supplementary motor and cingulate cortex, would also be useful, as well as the comparison of the effect of rTMS and transcranial direct current stimulation (tDCS) on BR excitability.

Based on the results of the present study, experimental evaluation of the effect of 1Hz rTMS in patients with pathological hyperexcitability of BR (such as blepharospasm) could be proposed.

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Acknowledgement 

The authors thank Mr. G. Di Paola for help with the statistics, Drs. C. Da Ronch and Ms. E. Jenkins for reviewing the manuscript and for language assistance.

Supported by a grant by the Fondazione Cassa di Risparmio di Ferrara.

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☆ Preliminary results have been presented at the 57th Annual Meeting of the American Academy of Neurology (Miami 2005).

PII: S1388-2457(08)01006-7

doi:10.1016/j.clinph.2008.09.024

Clinical Neurophysiology
Volume 120, Issue 1 , Pages 174-180, January 2009

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