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J Appl Physiol 101: 500-505, 2006. First published May 4, 2006; doi:10.1152/japplphysiol.01399.2005
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Low-intensity repetitive transcranial magnetic stimulation decreases motor cortical excitability in humans

Gabrielle Todd, Stanley C. Flavel, and Michael C. Ridding

Research Centre for Human Movement Control, School of Molecular and Biomedical Science, The University of Adelaide, Adelaide, South Australia, Australia

Submitted 4 November 2005 ; accepted in final form 19 April 2006


   ABSTRACT
TOP
 ABSTRACT
METHODS
 RESULTS
 DISCUSSION
 GRANTS
 REFERENCES
 
Repetitive transcranial magnetic stimulation of the motor cortex (rTMS) can be used to modify motor cortical excitability in human subjects. At stimulus intensities near to or above resting motor threshold, low-frequency rTMS (~1 Hz) decreases motor cortical excitability, whereas high-frequency rTMS (5–20 Hz) can increase excitability. We investigated the effect of 10 min of intermittent rTMS on motor cortical excitability in normal subjects at two frequencies (2 or 6 Hz). Three low intensities of stimulation (70, 80, and 90% of active motor threshold) and sham stimulation were used. The number of stimuli were matched between conditions. Motor cortical excitability was investigated by measurement of the motor-evoked potential (MEP) evoked by single magnetic stimuli in the relaxed first dorsal interosseus muscle. The intensity of the single stimuli was set to evoke baseline MEPs of ~1 mV in amplitude. Both 2- and 6-Hz stimulation, at 80% of active motor threshold, reduced the magnitude of MEPs for ~30 min (P < 0.05). MEPs returned to baseline values after a weak voluntary contraction. Stimulation at 70 and 90% of active motor threshold and sham stimulation did not induce a significant group effect on MEP magnitude. However, the intersubject response to rTMS at 90% of active motor threshold was highly variable, with some subjects showing significant MEP facilitation and others inhibition. These results suggest that, at low stimulus intensities, the intensity of stimulation may be as important as frequency in determining the effect of rTMS on motor cortical excitability.

motor cortex; motor evoked potential; cortical plasticity

THE ORGANIZATION OF THE CEREBRAL cortex is plastic, that is, the cortex is capable of rapid and long-lasting reorganization in response to many different experiences. For example, studies in rats and monkeys have demonstrated that reorganization can occur in both the motor and sensory cortices under a wide range of natural and experimental conditions including immobilization (e.g., Ref. 6), injury and pathology (e.g., Refs. 13, 28), and learning and practice of motor skills (e.g., 19, for review see Ref. 27). A number of mechanisms are responsible for this reorganization. Rapid reorganization after acute interventions arises from changes in synaptic efficacy within the cortex that are brought about by processes such as long-term potentiation (LTP) and long-term depression (LTD). These phenomena are activity-dependent processes that involve strengthening (LTP) or weakening (LTD) of synaptic transmission and can persist for a substantial time (for review see Ref. 27).

Cortical reorganization has also been reported in humans with motor learning (e.g., Refs. 10, 17), amputation (e.g., Ref. 5, 23), and manipulation of sensory input (3, 23). In these studies, cortical reorganization was reflected by a change in motor cortical excitability that was investigated by recording the electromyographic (EMG) response [motor-evoked potential (MEP)] to transcranial magnetic stimulation (TMS) of the motor cortex. Recently, repetitive TMS (rTMS) has also been used to induce sustained changes in motor cortical excitability. The effect of rTMS on motor cortical excitability depends on variables such as the intensity and frequency of stimulation, the number of stimuli delivered, the pulse profile (monophasic or biphasic), and the pattern of stimulation (intermittent or continuous). Generally, low-frequency rTMS (~1 Hz) decreases motor cortical excitability when delivered at an intensity near or above resting motor threshold (30, 33). In one study, 10 min of subthreshold 1-Hz rTMS suppressed motor cortical excitability for a further 10 min (25). Higher frequency rTMS (5–20 Hz) results in a progressive increase in motor cortical excitability (20–22) that may lead to seizures at higher intensities of stimulation (32). For example, 5-Hz rTMS at an intensity of 90% of resting threshold increases motor cortical excitability but not if delivered at 90% of active motor threshold (21, 22).

The relationship between the frequency and intensity of stimulation and the induced excitability change has not been extensively explored. Evidence from studies employing rTMS to activate the premotor region suggests that the intensity of stimulation may be critically important in determining the effect of low- and high-frequency rTMS protocols (24). Here, we investigated the effect of rTMS stimulus intensity on motor cortical excitability at two frequencies of stimulation. We hypothesized that stimulation at 2 Hz would reduce motor cortical excitability and that stimulation at 6 Hz would increase excitability. A range of low-stimulus intensities (70–90% of active motor threshold) and sham stimulation were employed.


   METHODS
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 METHODS
RESULTS
 DISCUSSION
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Subjects (n = 31; 14 men, 17 women) participated in experiments (1 study per subject) that examined the effect of two stimulation frequencies and three intensities of stimulation (and sham stimulation) on motor cortical excitability. All experimental procedures were undertaken with approval of The University of Adelaide Human Research Ethics Committee and conducted according to the Declaration of Helsinki. Written, informed consent was obtained from the subjects.

EMG recordings.   EMG activity was recorded with surface electrodes (Ag-AgCl, 10-mm diameter) overlying the right first dorsal interosseus (FDI) and abductor digiti minimi (ADM) muscles. Surface EMG signals were amplified (x1000), filtered (20–1,000 Hz), and sampled (2,000 Hz) for later analysis using a data-acquisition system (CED 1902 and 1401 interface with Signal software, Cambridge Electronic Design, Cambridge, UK).

TMS.   Single TMS were delivered using a Magstim 200 or 2002 stimulator (Magstim, Whitland, UK) and a figure-of-eight focal coil (9-cm external diameter of wings). Stimuli were applied to the left hemisphere with the coil held at ~45° to the midline with the handle pointing posteriorly. This coil orientation induces a current in the brain that flows in a posterior-to-anterior direction and approximately perpendicular to the central sulcus, an orientation that is optimal for activating the hand region of the motor cortex. Resting motor threshold was determined at the optimal site for evoking responses in FDI and was defined as the minimum stimulus intensity at which 5 of 10 consecutive stimuli evoked an MEP of at least 50 µV in amplitude in the relaxed FDI muscle. To determine threshold, stimuli were first delivered at a clearly suprathreshold level. The stimulus intensity was then reduced in small increments until it was clearly below threshold. The TMS intensity was set to evoke an MEP of ~1 mV in amplitude in the target muscle (FDI) before the intervention.

The rTMS was delivered using either a Magstim Super Rapid or Super Rapid2 stimulator (Magstim). For both the 2- and 6-Hz protocols, a total of 600 stimuli were delivered over the FDI motor area on the scalp. The 2-Hz stimulation was applied for 15 s and repeated every 30 s for 10 min. The 6-Hz stimulation was applied for 5 s and repeated every 30 s for 10 min. This stimulation paradigm is based on that previously employed by Iyer et al. (14). The magnetic stimulus had a biphasic waveform with a pulse width of ~400 µs. The stimulus intensity was set to 70, 80, or 90% of active motor threshold. Active motor threshold was determined for FDI with single stimuli while subjects maintained a weak voluntary contraction (~10% of maximal voluntary force). Active motor threshold was defined as the minimum stimulus intensity required to evoke MEPs of at least 100 µV in amplitude in 5 of 10 successive trials.

Sham stimulation.   Sham stimulation was applied using a coil (placebo coil, PN 3285–00, Magstim) that is similar in appearance and operation to the normal figure-of-eight coil. The placebo coil provides slight sensory stimulation of the scalp and the normal sound made by the stimulator without stimulating the cortex.

Testing protocol.   The effect of rTMS stimulus intensity and frequency on motor cortical excitability was assessed in four studies. In the first, eight subjects [30 yr (SD 9)] participated in two experiments performed on separate days that were at least 48 h apart. MEP area and amplitude and resting motor threshold were measured before and after intermittent rTMS. rTMS was delivered for 10 min at an intensity of 80% of active motor threshold and at a frequency of 2 or 6 Hz. MEP area and amplitude were measured during sets of 15 stimuli delivered at ~0.2 Hz. After rTMS, MEP magnitude and resting motor threshold were measured at 0, 15, and 30 min post-rTMS. After the final measurement, subjects were asked to perform a 10-s voluntary contraction of FDI during weak index finger abduction (~20% of maximum voluntary force). After this weak contraction, MEP magnitude and resting motor threshold were again assessed at rest. Lastly, subjects performed a brief (2–3 s) maximal voluntary contraction of FDI (finger abduction).

The experimental protocol was similar in the following studies, except that no voluntary contractions were performed and the rTMS stimulus intensity was either 70% [n = 9; 23 yr (SD 5)] or 90% [n = 8; 24 yr (SD 8)] of active motor threshold or sham [n = 6; 33 yr (SD 11)]. Sham rTMS was delivered only at 6 Hz. For the other studies, the order of presentation of the 2- and 6-Hz stimulation was pseudorandom.

Data analysis.   For each muscle, the area and amplitude of MEPs were measured in each trial. Trials in which MEPs were preceded by EMG activity were excluded from the analysis. In the text, group data are presented as means (SD), whereas in the figures, they are means ± SE. Group data were first analyzed with four-way ANOVA for comparison of stimulus intensity (70, 80, and 90% of active motor threshold; between subject factor), muscle (FDI and ADM; within-subject factor), stimulus frequency (2 and 6 Hz; within-subject factor), and time (baseline, 0 min, 15 min, 30 min; within-subject factor) (SPSS 13.0 for Windows, SPSS). Data for FDI and ADM were then analyzed separately. For 80% of active motor threshold, a further two-way repeated-measures ANOVA was performed between stimulus frequency and time for inclusion of postcontraction data. Resting motor threshold was analyzed with a paired t-test for comparison of baseline data and the average resting motor threshold after rTMS. Analysis of single-subject data involved one-way ANOVA. Nonparametric data were transformed to ranks and repeated-measures ANOVA on ranks was performed. Post hoc discrimination between means was made with a Dunn's or Student-Newman-Keuls procedure (Sigmastat 3.11, Systat Software, Point Richmond, CA). Statistical significance was set at 5%.


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The area (F1,22 = 6.45, P = 0.019) and amplitude (F1,22 = 20.26, P < 0.001) of the MEP in FDI were significantly larger than in ADM. Thus data from FDI and ADM were analyzed separately. In FDI, MEP area differed between stimulus intensities when expressed relative to baseline (F2,22 = 3.50, P = 0.048). There was also a strong trend for altered MEP amplitude (F2,22 = 3.05, P = 0.068). In ADM, the area and amplitude of the MEPs remained unchanged across stimulus intensity, frequency, and time.

Stimulation at 80% of active motor threshold.   The average area and amplitude of baseline MEPs was 0.0046 mV·ms (SD 0.0010) and 1.0 mV (SD 0.3) for FDI and 0.0026 mV·ms (SD 0.0022) and 0.6 mV (SD 0.5) for ADM, respectively. At 80% of active motor threshold, both 2- and 6-Hz rTMS significantly reduced MEP area (F3,21 = 6.74, P = 0.002) and amplitude (F3,21 = 4.96, P = 0.009) in FDI (Figs. 1 and 2) but not in ADM (Fig. 2). Immediately after 2-Hz rTMS, the area and amplitude of the MEP in FDI were reduced to 79.0% (SD 27.5) and 81.6% (SD 29.2) of baseline, respectively. After 6-Hz rTMS, the area and amplitude were reduced to 75.3% (SD 31.3) and 82.0% (SD 33.8) of baseline, respectively. The magnitude and time course for the reduction in MEP area and amplitude were similar for the two frequencies of stimulation. At both frequencies, the area and amplitude of MEPs in FDI returned to baseline values after a 10-s weak voluntary contraction of FDI (Fig. 2). In the 2-Hz experiment, the average root-mean-square EMG amplitude during the contraction was 12.9% (SD 5.6) of that measured during a brief maximal voluntary contraction. Similarly, the average root-mean-square EMG amplitude was 14.2% (SD 4.7) for the 6-Hz experiment. Resting motor threshold increased after rTMS at both frequencies of stimulation. Resting motor threshold increased from a baseline value of 40.8% (SD 11.2) of stimulator output to an average of 41.8% (SD 11.8) after 2-Hz rTMS (P = 0.007). After 6-Hz rTMS, resting motor threshold increased from 41.1% (SD 11.8) to 42.1% (SD 12.0) (P = 0.015).


Figure 1
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  		Fig. 1. Examples of raw electromyograph data traces from the first dorsal interosseus (FDI) muscle in 1 subject. Traces show motor evoked potentials before (Pre) and after (Post) repetitive transcranial magnetic stimulation (rTMS). rTMS was delivered at 80% of active motor threshold and at a frequency of 2 and 6 Hz. Each trace is the average of 15 individual trials. Arrows, timing of single transcranial magnetic stimuli (TMS).

 

Figure 2
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  		Fig. 2. Group data showing the average area of the motor-evoked potential (MEP) in the FDI and abductor digiti minimi (ADM) muscles after 2- and 6-Hz rTMS at 80% of active motor threshold. A: 2 Hz. B: 6 Hz. MEP area after a weak 10-s voluntary contraction is also shown. Data are expressed as a percentage of baseline values. B, Baseline; Post Cont, after contraction. *Significant difference between baseline and post-rTMS values, P <0.05.

 
Stimulation at 70% of active motor threshold.   The average area and amplitude of baseline MEPs were 0.0040 mV·ms (SD 0.0014) and 0.9 mV (SD 0.3) for FDI and 0.0019 mV·ms (SD 0.0012) and 0.4 mV (SD 0.2) for ADM, respectively. At an intensity of 70% of active motor threshold, MEPs were unchanged in FDI after 2- or 6-Hz rTMS. After 2-Hz rTMS, resting motor threshold increased from a baseline value of 43.3% (SD 10.9) of stimulator output to an average of 44.8% (SD 10.9) (P = 0.02). Resting motor threshold also increased from a baseline value of 44.1% (SD 10.3) of stimulator output to an average of 45.2% (SD 10.5) after 6-Hz rTMS (P = 0.045).

Stimulation at 90% of active motor threshold.   The average area and amplitude of baseline MEPs were 0.0046 mV·ms (SD 0.0014) and 1.1 mV (SD 0.3) for FDI and 0.0044 mV·ms (SD 0.0059) and 0.8 mV (SD 0.8) for ADM, respectively. At 90% of active motor threshold, rTMS produced no significant group change in MEP magnitude at either frequency in FDI (Fig. 3). However, the response to rTMS at this intensity was variable, with some subjects showing significant MEP facilitation and others inhibition at one or more time points. In FDI, 2-Hz stimulation induced MEP facilitation in one subject and inhibition in two subjects (Fig. 3A; P < 0.05), whereas 6-Hz stimulation induced MEP facilitation in one subject and inhibition in three subjects (Fig. 3B; P < 0.05). Resting motor threshold remained unchanged after 2- and 6-Hz rTMS.


Figure 3
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  		Fig. 3. Individual subject and group data showing the area of the MEP in the FDI after 2- and 6-Hz rTMS at 90% of active motor threshold. A: 2 Hz. B: 6 Hz. Data are expressed as a percentage of baseline values. Dashed lines, subjects with significant MEP change from baseline values (P < 0.05).

 
Sham.   The average amplitude of baseline MEPs was 1.1 mV (SD 0.5) in FDI and 0.7 mV (SD 0.6) in ADM. Sham rTMS produced no group change in MEP magnitude in FDI and ADM. However, resting motor threshold increased from a baseline value of 40.8% (SD 9.7) of stimulator output to an average of 41.5% (SD 9.5) after sham stimulation (P = 0.047).


   DISCUSSION
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GRANTS
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In the present study, we investigated the effect of stimulus strength on rTMS-induced changes in motor cortical excitability at two frequencies of stimulation. Additionally, we employed very low intensities of stimulation that have rarely been used in rTMS protocols applied to the primary motor cortex. The results obtained with these different stimulation protocols were compared with that seen with sham stimulation. The major, unexpected finding was that both 2- and 6-Hz stimulation at an intensity of 80% of active motor threshold induced depression of MEPs in the target muscle that lasted for ~30 min after the end of the stimulation period.

Effect of rTMS at 80% of active motor threshold.   A number of previous studies have demonstrated that low-frequency (~1 Hz) rTMS can induce a lasting depression of motor cortex excitability. For example, Romero et al. (25) demonstrated that 600 stimuli delivered at 1 Hz and an intensity of 90% of resting motor threshold reduced MEPs for ~10 min after the end of the stimulation period. In contrast, higher frequency stimulation can induce an increase in motor cortical excitability. For example, Peinemann et al. (21) demonstrated that 1,800 stimuli delivered intermittently at 5 Hz and an intensity of 90% of resting motor threshold facilitated MEPs for 30 min. At the same intensity, 1,600 stimuli delivered intermittently at 20 Hz also facilitated MEPs for several minutes after the end of stimulation (9). Here, we have demonstrated that both 2- and 6-Hz rTMS delivered at an intensity of 80% of active motor threshold reduced MEPs by up to 30% for 30 min after stimulation. The effect of 6-Hz stimulation was the reverse of what we hypothesized and suggests that the effect of rTMS on cortical excitability may depend on a complex relationship between stimulation frequency and intensity. It seems likely that at these very low stimulus intensities, the intensity of stimulation may be more important than frequency in determining the effect on cortical excitability. A possible explanation for this is that intracortical inhibitory networks within the motor cortex have a lower activation threshold than excitatory networks (37). The reduction in MEP magnitude seen after rTMS at both frequencies of stimulation was associated with a very small increase in the resting motor threshold. This suggests that the stimulus we employed had a small effect on the excitability of intrinsic elements within the cortex (for review see Ref. 35). However, this is unlikely given that resting motor threshold also increased slightly after sham stimulation. Few other studies employing rTMS have reported changes in resting threshold (12, 18).

The significant inhibition of the MEP observed in FDI was not present in ADM. This localization of the effect to the target muscle has also been observed by other studies (e.g., Ref. 21) and could relate to differences in MEP magnitude between the two muscles. The average amplitude of the baseline MEP in the target muscle (FDI) was 1 mV, whereas in ADM the average size was only 0.6 mV. Within a subject, smaller MEPs vary more in area and amplitude from trial to trial than larger ones (31). Thus any inhibition in ADM may have been masked by the greater variability in MEP size. Additionally, the intensity of repetitive stimulation was established relative to the active motor threshold of FDI. Stimulation applied over a nonoptimal scalp site for evoking responses in ADM may have resulted in a lower effective intensity of rTMS for this muscle.

Site of excitability change.   Although not tested in the present study, there are several pieces of evidence that suggest that the reduction in MEP magnitude induced by rTMS is due to a change in cortical excitability. First, the threshold for evoking descending activity in the corticospinal pathway is close to active motor threshold (7). Therefore, rTMS at 80% of active motor threshold is unlikely to induce descending activity in corticospinal neurons. This is further supported by the finding of unchanged H reflexes after a low-intensity rTMS protocol, which results in inhibition of MEPs (11). Second, suprathreshold 5-Hz rTMS can produce a lasting facilitation of TMS evoked MEPs but not in the response to transcranial electrical stimulation (TES) (2). Given the different modes by which TMS and TES activate the corticospinal pathway (1, 4, 7, 8, 29; for review see Ref. 36), this finding provides evidence that, even at higher intensities, the effects of rTMS are due largely to changes within the cortex. Third, rTMS is known to affect the excitability of intracortical inhibitory and facilitatory elements (e.g., Refs. 11, 22, 34).

Effect of voluntary contraction.   In the present study, we demonstrated that a 10-s weak voluntary contraction of FDI reversed the MEP inhibition induced by 2- or 6-Hz rTMS at an intensity of 80% of active motor threshold. Similarly, Touge and colleagues (30) demonstrated that voluntary contraction disrupted the development of MEP inhibition induced by subthreshold 1-Hz rTMS. This suggests that voluntary contraction may normalize or reset the excitability of cortical elements responsible for the MEP. What, then, is the functional relevance of rTMS-induced changes in motor cortical excitability induced at rest? It has been shown that performance on relatively simple tasks such as self-paced finger tapping is not affected by rTMS protocols that produce motor cortex inhibition (18, 26). However, and in contrast to this finding, it has recently been shown that an increase in motor cortical excitability induced by a period of peripheral stimulation can facilitate performance on a more complex sensorimotor task (16). Therefore, the functional significance of rTMS-induced cortical excitability change needs further investigation, especially given the opportunities for therapeutic intervention.

Effect of rTMS at 90% of active motor threshold.   At a stimulus intensity of 90% of active motor threshold, intermittent stimulation at 2 or 6 Hz produced no group effect on MEP magnitude. This confirms previous findings using similar frequencies of stimulation (1 or 5 Hz) applied over either the motor cortex or dorsolateral prefrontal cortex (24). However, rTMS of premotor cortex at 90% of active motor threshold can affect the excitability of the ipsilateral motor cortex, with 1-Hz stimulation reducing excitability and 5-Hz stimulation increasing excitability (24). However, these effects are not seen with premotor stimulation delivered at 80% of active motor threshold (24). These findings suggest that different cortical regions involved in the generation and execution of movements may have differing thresholds for rTMS-induced excitability changes. Examination of the individual data revealed that there were individual subjects in whom this rTMS protocol produced significant effects on MEP magnitude. Approximately one-half of the subjects showed either significant MEP inhibition or facilitation at one or more time points. This large intersubject variability has also been seen in other studies where rTMS has been delivered at higher stimulus intensities (90% of resting motor threshold) across a range of frequencies (1–15 Hz) (9, 15, 25). These findings may suggest that a stimulus intensity of 90% of active motor threshold may fall around a threshold, above which excitatory effects are favored and below which inhibitory effects are favored.

Effect of rTMS at 70% of active motor threshold.   Stimulation at an intensity of 70% of active motor threshold produced no significant group effect on MEP magnitude. Therefore, it is likely that this intensity of stimulation, at least with these protocols, is not sufficient to affect the cortical circuitry important for MEP generation. At this intensity, both 2- and 6-Hz rTMS resulted in a small increase in resting motor threshold. Again, this suggests that these paradigms are capable of affecting the excitability of intrinsic elements within the cortex.

In summary, we have demonstrated that both 2- and 6-Hz repetitive stimulation delivered at an intensity of 80% of active motor threshold are capable of reducing motor cortical excitability for ~30 min. Stimulation at 70% of active motor threshold had no significant effect on MEP magnitude nor did stimulation at a higher intensity (90% of active motor threshold). However, the effects of stimulation at 90% of active motor threshold were highly variable between subjects, with some showing inhibitory effects and others facilitatory effects. These findings suggest that 1) the intensity of rTMS may be at least as important as frequency for determining the outcome of rTMS on motor cortical excitability in paradigms involving low stimulus intensities, and 2) there may be certain stimulation intensity thresholds, above and below which the effect of stimulation on motor cortical excitability can reverse.


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This work was supported by the Australian Research Council. M. C. Ridding holds an Australian Research Council Queen Elizabeth II Fellowship.


   FOOTNOTES
 

Address for reprint requests and other correspondence: G. Todd, Discipline of Physiology, The School of Molecular and Biomedical Sciences, The Univ. of Adelaide, Adelaide, South Australia 5005, Australia (e-mail: gabrielle.todd{at}adelaide.edu.au)

The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.


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