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Impaired modulation of corticospinal excitability following subthreshold rTMS in focal hand dystonia
Human Movement Science 23 (2004) 527–538 www.elsevier.com/locate/humov
Impaired modulation of corticospinal excitability following subthreshold rTMS in focal hand dystonia Cathy M. Stinear *, Winston D. Byblow Department of Sport and Exercise Science, Human Motor Control Laboratory, University of Auckland–Tamaki, Private Bag 92019, Auckland, New Zealand
Abstract Previous studies have demonstrated that subthreshold 1 Hz repetitive transcranial magnetic stimulation (rTMS) causes a decrease in corticospinal excitability in neurologically normal subjects. The effects of subthreshold 1 Hz rTMS upon corticospinal excitability and intracortical inhibition in subjects with focal hand dystonia (FHD) is not yet clear. The purpose of this study was to examine the effects of low intensity 1 Hz rTMS upon these variables in control and FHD subjects. We recorded electromyographic (EMG) from the first dorsal interosseous (FDI) muscle of the dominant hands of seven control subjects, and seven affected hands of five FHD subjects. We used single and paired pulse TMS to examine motor evoked potential (MEP) amplitude, short interval intracortical inhibition (ICI) and silent period duration before, during and after 20 min of low intensity 1 Hz rTMS. MEP amplitude decreased significantly over the course of the rTMS in control subjects, but did not change in FHD subjects. Silent period duration was significantly longer in control subjects after rTMS, but there was no change in FHD subjects. There was no significant change in ICI after rTMS in either subject group, despite the rTMS intensity being set to preferentially activate intracortical inhibitory networks. This suggests that low intensity 1 Hz rTMS may have limited application in the normalisation of inhibitory function in FHD. Ó 2004 Elsevier B.V. All rights reserved.
*
Corresponding author. Tel.: +64 9 3737 599x86990; fax: +64 9 3737 043. E-mail address: [email protected] (C.M. Stinear).
0167-9457/$ - see front matter Ó 2004 Elsevier B.V. All rights reserved. doi:10.1016/j.humov.2004.08.022
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Keywords: Repetitive TMS; Focal hand dystonia; Intracortical inhibition
1. Introduction When transcranial magnetic stimulation (TMS) is delivered in trains of stimuli, with a frequency of around 1 Hz or higher, it is referred to as repetitive TMS (rTMS). The effects of rTMS on corticospinal excitability depend on a range of variables, including the frequency and intensity of stimulation. Generally, stimulation at frequencies around 5 Hz or higher produce an increase in corticospinal excitability, while stimulation at around 1 Hz tends to produce a decrease in corticospinal excitability (Wassermann & Lisanby, 2001). In neurologically normal subjects, subthreshold rTMS delivered to the hand area of M1 at 1 Hz has been shown to decrease corticospinal excitability (Maeda, Keenan, Tormos, Topka, & Pascual-Leone, 2000; Romero, Anschel, Sparing, Gangitano, & Pascual-Leone, 2002; Touge, Gerschlager, Brown, & Rothwell, 2001; Tsuji & Rothwell, 2002). This effect is positively correlated with the number of stimuli delivered (Touge et al., 2001), persists for between 10 (Romero et al., 2002; Tsuji & Rothwell, 2002) and 25 (Touge et al., 2001) minutes, and appears to be cortical in origin (Romero et al., 2002; Touge et al., 2001; Tsuji & Rothwell, 2002). Given that subthreshold 1 Hz rTMS appears to depress corticospinal excitability, it may have an application in the management of movement disorders associated with excessive corticospinal activity. One such disorder is focal hand dystonia (FHD), which is associated with impaired inhibitory function at multiple levels of the central nervous system (Berardelli et al., 1998). The clinical features of FHD are dominated by involuntary contractions of the hand and forearm musculature that result in awkward, uncoordinated movements of the wrist and/or fingers. These symptoms are due to the inappropriate co-contraction of antagonists and agonists, combined with generally excessive levels of muscle activity (Cohen & Hallett, 1988). This involuntary activity is typically painless, but can severely impair the performance of a particular manual task such as writing or playing a musical instrument (Brandfonbrener, 1995; Chen & Hallett, 1998; Fahn, Marsden, & DeLong, 1998; Lederman, 1991; Marsden & Sheehy, 1990; Newmark & Hochberg, 1987; Sheehy & Marsden, 1982; Sheehy, Rothwell, & Marsden, 1988). Task specificity is a distinctive feature of FHD. Recent work in our laboratory has demonstrated that the modulation of intracortical inhibitory function during the performance of a precise manual task is impaired in FHD patients (Stinear & Byblow, 2004). Subjects performed index finger flexion and extension, paced at 1 Hz by an auditory metronome. In control subjects, a spatially and temporally specific pattern of modulation of ICI was observed. In contrast, no significant modulation of ICI was observed in FHD patients during task performance, despite having normal levels of ICI at rest. Based on this observation, we suggested that deranged input to intracortical inhibitory networks may impair the modulation of intracortical inhibition in FHD during the performance
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of precise manual tasks (Stinear & Byblow, 2004). Given that rTMS seems to impact on the excitability of the corticospinal pathway, presumably through modulating the activity levels of inhibitory and excitatory inputs to this pathway, it is possible that rTMS may be useful in enhancing the modulation of intracortical inhibitory function. Two studies have investigated the effects of rTMS upon cortical function in patients with FHD. Siebner, Auer, and Conrad (1999) delivered rTMS to the hand area of M1 at 1 Hz and a stimulus intensity of 105% of rest threshold. Stimuli were delivered in 10 one-minute trains, and the average motor evoked potential (MEP) area for each train was determined. Rest threshold was determined and stimulus–response curves plotted before and 5 min after the delivery of rTMS. They found that, as expected, neurologically normal control subjects exhibited a significant decrease in MEP area over the course of the rTMS trains. In contrast, the FHD patients exhibited a significant increase in MEP area over the course of the rTMS. These authors found no change in rest threshold or the slope of the stimulus–response curves in either group after rTMS (Siebner, Auer, et al., 1999). The authors suggested their results were evidence of decreased intracortical inhibitory function associated with FHD (Siebner, Auer, et al., 1999). However, this was not tested directly. A subsequent study addressed this issue by exploring intracortical inhibitory and excitatory processes after rTMS (Siebner et al., 1999). Stimuli were delivered at 1 Hz for 20 min, at a stimulus intensity of 90% of rest threshold. Intracortical function was evaluated before, and 30 min after, rTMS using a paired-pulse technique and a range of inter-stimulus intervals (ISIs) including 1 and 3 ms. In a second experiment, the stimulus–response curve, silent period duration and a number of quantitative handwriting variables were determined before and immediately after rTMS, applied with the same stimulus protocol as in the first experiment. These authors report lower prerTMS levels of ICI in FHD patients than control subjects with interstimulus intervals of 1 and 3 ms. However, no data regarding the statistical significance of this effect were reported (Siebner, Tormos, et al., 1999). Before rTMS, FHD patients were found to have irregular pen stroke velocity profiles and a significantly higher number of direction inversions per stroke, compared with control subjects. After rTMS, half of the FHD patients demonstrated a shortlived improvement in handwriting variables, while the other half demonstrated no change (Siebner, Tormos, et al., 1999). Finally, there was a significant increase in silent period duration after rTMS in patients, but not controls, suggesting that rTMS increases cortical inhibitory function in FHD patients. The purpose of the present study was to re-examine the modulation of ICI by subthreshold 1 Hz rTMS in control and FHD subjects. A paired-pulse paradigm that would avoid any ÔfloorÕ effects with conditioning was used (Fisher, Nakamura, Bestmann, Rothwell, & Bostock, 2002). Prior to rTMS, the conditioning stimulus intensity was set so that the conditioned MEP response was approximately half the amplitude of the test MEP response (CS50). This allows both increases and decreases in ICI following rTMS to be observed. Furthermore, the intensity of the rTMS stimuli was set to CS50, so that it was well below rest threshold and preferentially activated low-threshold inhibitory intracortical interneurons.
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2. Method 2.1. Participants Five subjects with FHD participated in this experiment (one female, mean age 48 years, range 37–58 years). Two of these FHD subjects were bilaterally affected, giving a total of seven affected hands tested. Seven neurologically healthy, age-matched control subjects also participated (two females, mean age 47 years, range 37–56 years). Using a handedness questionnaire (Oldfield, 1971), all were deemed righthanded (mean control laterality quotient 88.7%, range 75.0–100.0%, mean FHD laterality quotient 84.4%, range 61.1–95.2%). The right hand of all subjects was tested, as was the left hand of two bilaterally affected FHD subjects. The extent of disability due to dystonia symptoms experienced by the subjects with FHD was quantified using the Fahn Arm Dystonia Scale (Fahn, 1989). The Auckland Ethics Committee approved the procedure in accordance with the Declaration of Helsinki, and informed consent was obtained from all participants. A summary of the nature, duration and severity of the FHD subjectsÕ symptoms is presented in Table 1. Fahn score is the functional ability score for each affected hand. The lower the score, the more impaired the function of the tested hand. The maximum score is 90. Two of the FHD subjects were undergoing botulinum toxin treatment (BTX). Care was taken to ensure that they were tested at least 10 weeks since their last treatment, and immediately prior to their next. 2.2. Procedure Subjects were seated comfortably, next to a table upon which they rested their dominant forearm and hand in a pronated position. Subjects were instructed to keep their hand and forearm muscles as relaxed as possible. Electromyography (EMG) data were collected from the first dorsal interosseous (FDI) of the dominant hand via a pair of 12 mm diameter surface Ag–AgCl Hydrospot electrodes (Physiometrix Inc., MA, USA). Signals were amplified by two Grass P511AC EMG amplifiers (Grass Instrument Division, RI, USA). The EMG data were bandpass filtered at Table 1 FHD patient characteristics Gender
Age (years)
Type
Affected hand(s)
Fahn score
Duration (years)
BTX
Instrument
M
45
WriterÕs
Bilateral
29
N
F M
58 46
WriterÕs WriterÕs and MusicianÕs
Unilateral Bilateral
L 74.1 R 68.8 R 79.4 L 63.0
8 17
Y N
Bagpipes
M
52
8
Y
Electric guitar
36
Unilateral dominant Unilateral dominant
R 63.0 R 58.5
M
WriterÕs and MusicianÕs MusicianÕs
R 76.5
7
N
Classical guitar
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30–1000 Hz, sampled at 4 kHz with a 12-bit MacLab A/D acquisition system and software, and stored to disk for subsequent analysis. 2.2.1. Single and paired-pulse TMS A pair of MagStim 200 magnetic stimulators (MagStim Company, Dyfed, UK, maximum output intensity 2.0 T) connected by a BiStim unit was used to stimulate the motor cortex via a figure-of-eight coil (7 cm coil diameter). The coil was held tangentially to the scalp and perpendicular to the central sulcus, so that the induced current flow was in a posterior to anterior direction. The optimal location for eliciting MEPs in FDI was determined by stimulating at sites over the contralateral motor cortex with the target muscle at rest. The location that produced the greatest peak-to-peak amplitudes in the FDI was considered optimal. Active threshold for FDI was then established at the optimal location by altering the stimulator output intensity initially in 5% and then in 1% increments, while the subject maintained an FDI activation level that was approximately 5% of maximum voluntary contraction (MVC). MVC was determined by having subjects abduct their index finger maximally against a fixed support, during which the rms EMG value over a 100 ms window was calculated. Active threshold (ATh) was defined as the percentage of maximum stimulator output (%MSO) that produced MEPs with a peakto-peak amplitude of 100 lV in four out of eight consecutive trials. A test stimulus intensity of 160% ATh was used to determine corticospinal excitability before, during and after the delivery of rTMS. The conditioning stimulus intensity was set to produce approximately 50% inhibition of the test MEP (CS50), with an ISI of 2.5 ms, as this has been shown to produce maximal ICI (Fisher et al., 2002). The conditioning stimulus intensity was initially set to 60% ATh and eight conditioned responses were collected and averaged. This was repeated with incremental increases in conditioning stimulus intensity (2% MSO steps) until the average conditioned MEP amplitude was between 40–60% of the average non-conditioned MEP amplitude. This intensity was designated CS50. Twelve non-conditioned MEPs and 12 conditioned MEPs were collected before the delivery of rTMS. Subjects were then asked to maintain a 5–20% MVC pinch grip, using visual feedback, while 12 stimuli were delivered at the test stimulus intensity. 2.2.2. Repetitive TMS Repetitive TMS was delivered via a figure-of-eight coil, identical to that used for the single and paired-pulse TMS, and a MagStim RapidStim unit (MagStim Company, Dyfed, UK). Active threshold was determined as described above, with single stimuli from the RapidStim unit delivered at a rate of approximately 0.2 Hz. The CS50 was expressed as a ratio of the ATh determined with the paired MagStim 200 stimulators. This ratio was then calculated for the ATh determined with the RapidStim unit, and the resulting intensity was set for the repetitive TMS. For example, if CS50 was found to be 0.6 ATh using the paired MagStim 200 stimulators, then the rTMS intensity was set to 0.6 of the ATh determined using the RapidStim unit. The rTMS intensity was therefore always subthreshold for the resting FDI muscle,
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and the EMG activity of the FDI was monitored online throughout the delivery of rTMS to ensure that it remained at rest. The rTMS stimuli were delivered at a frequency of 1 Hz, in four blocks of 300 stimuli. Between each block, 12 single test stimuli were delivered via the paired MagStim 200 stimulators. After the fourth block of rTMS, 12 single and 12 paired stimuli were delivered. The mean amplitude of the non-conditioned MEPs was then determined. If it was found to be different from the mean amplitude of the pre-rTMS non-conditioned MEPs, the test stimulus intensity was adjusted to match the pre-rTMS non-conditioned MEP amplitudes. A further 12 single and 12 paired stimuli were then delivered. Finally, the subject was asked to maintain a 5–20% MVC pinch grip, using visual feedback, while 12 stimuli were delivered at the pre-rTMS test stimulus intensity. 2.3. Data analysis The EMG activity in the 20 ms pre-trigger interval was checked and any trial with pretrigger EMG activity was discarded. The peak-to-peak amplitudes (mV) of the remaining MEPs were then trimmed of any outliers before being averaged for each condition (Wilcox, 2001). The mean non-conditioned MEP amplitude was then calculated for the pre-rTMS, during rTMS and post-rTMS conditions, for each subject. The degree of inhibition produced pre- and post-rTMS was then determined using the following formula: ICI ð%Þ ¼ 100 ððC=NCÞ 100Þ
ð1Þ
where NC = average non-conditioned MEP amplitude and C = average conditioned MEP amplitude. This results in a number that represents the degree of inhibition as a percentage, which at least partly compensates for interindividual variability in MEP amplitudes. The non-conditioned MEP amplitude data were analysed using a mixed repeated measures analysis of variance (ANOVA), with group (control, FHD) as the between subject factor, and time (pre, during 1, 2, 3, post) as the within subject factor. A two-sample, two-tailed t-test was used to test for a difference between groups in the pre-rTMS NC MEP amplitude. The degree of inhibition data were analysed using a mixed repeated measures ANOVA, with group (control, FHD) as the between subject factor, and time (pre, post, post-matched) as the within subject factor. Silent period duration data were analysed using a mixed repeated measures ANOVA, with group (control, FHD) as the between subject factor, and time (pre, post) as the within subject factor. Two-tailed, two-sample t-tests were used to test for between-group differences in ATh and rTMS stimulus intensity. Statistical significance was set at a = 0.05. 3. Results 3.1. Subject variables The ATh (%MSO) for FHD patients was significantly lower than that for the control subjects (FHD 30.3 ± 5.0% MSO, control 35.9 ± 4.0% MSO, p = 0.04). How-
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ever, there was no statistically significant difference in test stimulus intensity (FHD 51.0 ± 11.2% MSO, control 60.0 ± 4.2% MSO, p = 0.07). There was also no difference between groups in CS50 (FHD 26.3 ± 6.0% MSO, control 29.1 ± 5.1% MSO, p > 0.1) or rTMS intensity (FHD 36.4 ± 10.9% MSO, control 36.6 ± 7.1% MSO, p > 0.9). 3.2. Corticospinal excitability For the NC MEPs collected before, during and after rTMS, there was a significant effect of Group, with the MEPs recorded from the FHD group having a significantly higher amplitude than those recorded from the control group (control 0.5 ± 0.26 mV, FHD 1.4 ± 0.26 mV, F(1, 13) = 6.4, p < 0.05). There was no effect of time (F(3, 13) < 1, p > 0.6), and the interaction between Group and Time was also not significant (F(3, 13) < 1, p > 0.6). There was no difference in pre-rTMS NC MEP amplitude (control 0.83 ± 0.5 mV, FHD 1.3 ± 1.0 mV, p > 0.3). Therefore, the effect of Group upon NC MEP amplitude arose due to the MEPs recorded during and after rTMS being significantly smaller in the control group than the FHD group (Figs. 1 and 2). 3.3. Short interval intracortical inhibition (ICI) There was no difference between groups in the degree of ICI produced before rTMS (control 51 ± 3%, FHD 48 ± 5%, p > 0.5). The two-way repeated measures
Fig. 1. Example EMG traces from one control subject and one FHD subject, depicting non-conditioned MEP amplitude pre-rTMS, after each block of rTMS (during 1, 2, 3), and post-rTMS. Calibration bar 1 mV, 50 ms.
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Fig. 2. Non-conditioned MEP amplitude (mV) before, during and after rTMS. The rTMS was delivered in four blocks of 5 min duration, and MEPs were recorded after each block. Error bars = SEM, *p < 0.05.
ANOVA revealed no effect of matching or group on the degree of ICI produced post-rTMS with unmatched and matched test MEP amplitudes (both p > 0.25). Therefore, the unmatched and matched post-rTMS ICI data were pooled, and a two-way repeated measures ANOVA was used to test for the effects of group (control, FHD) and time (pre-rTMS, post-rTMS) upon ICI (Fig. 2). There was no effect of time or group, and the interaction between them was not significant (all p > 0.19). 3.4. Silent period duration There was no effect of group (control, FHD) or time (pre-rTMS, post-rTMS) upon the pre-trigger EMG or MEP amplitude in the active trials used to determine SP duration (all p > 0.3). There was also no significant difference between groups in the test stimulus intensity used for these trials (control 53.2 ± 6.1% MSO, FHD 45.4 ± 7.6% MSO, p > 0.07). There was a significant effect of time upon silent period duration, with silent period duration being significantly longer after rTMS (prerTMS 136.6 ± 9.8 ms, post-rTMS 146.4 ± 10.9 ms, F(1, 13) = 5.57, p < 0.05). The interaction between group and time was also significant (control pre-rTMS 130.2 ± 13.9 ms, post-rTMS 150.0 ± 17.2 ms; FHD pre-rTMS 137.9 ± 14.2 ms, post-rTMS 142.7 ± 13.5 ms, F(1, 13) = 5.9, p < 0.05). This interaction arose because silent period duration was significantly longer post-rTMS for control subjects, while there was no significant change in silent period duration for FHD subjects (Figs. 4 and 5).
4. Discussion The present study has confirmed some of the findings of previous studies, by demonstrating a decrease in corticospinal excitability in response to subthreshold 1 Hz
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rTMS in control subjects (Touge et al., 2001; Tsuji & Rothwell, 2002). However, it differs from previous studies with FHD subjects (Siebner, Auer, et al., 1999; Siebner, Tormos, et al., 1999) in that it does not demonstrate any effect of rTMS upon corticospinal excitability, ICI or SP duration in these subjects. This is probably due to some important technical differences between this study, and those by Siebner, Auer, et al. (1999) and Siebner, Tormos, et al. (1999). Siebner, Auer, et al. (1999) delivered 1 Hz rTMS at an intensity of 105% RTh, and showed that MEP area increased in FHD subjects, and decreased in control subjects. Similarly, the present study demonstrates a significant decrease in control MEP amplitude, and no change in FHD MEP amplitude (Fig. 2). While the rTMS intensity used in the present study is considerably lower (around 85% ATh), together these studies suggest that 1 Hz rTMS at or below RTh does not produce a decrease in corticospinal excitability in FHD subjects, as it does in control subjects. Unfortunately, the second study by Siebner, Tormos, et al. (1999) that used a subthreshold rTMS intensity (90% RTh), examined changes in threshold rather than MEP amplitude, and cannot be used to shed any further light upon this issue. Siebner, Tormos, et al. (1999) report a ÔnormalisationÕ of ICI in FHD subjects following subthreshold 1 Hz rTMS, although no statistical analysis of this finding was reported. In contrast, the present study did not demonstrate any effect of rTMS upon ICI in either the control or FHD group (Fig. 3). This may be due, in part, to the difference in conditioning stimulus and rTMS intensities used. Siebner, Tormos, et al. (1999) set the conditioning stimulus intensity to 80% RTh, and rTMS intensity to 90% RTh. These intensities are considerably higher than those used in the present study (conditioning stimulus and rTMS intensity around 85% ATh). The rTMS intensity used in the present study was sufficient to inhibit test MEP amplitude by around 50%. We suggest that the rTMS preferentially activated the intracortical inhibitory interneurons responsible for ICI, as its intensity was also well below both rest and active thresholds. Despite this, rTMS did not produce any significant modulation of ICI, in either group.
Fig. 3. Degree of ICI pre- and post-rTMS. There was no effect of rTMS or group upon ICI. Error bars = SEM.
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Fig. 4. Example EMG traces from one control subject and one FHD subject, depicting silent period duration pre- and post-rTMS. Calibration bar 1 mV, 50 ms.
Fig. 5. Silent period duration (ms) pre- and post-rTMS. Error bars = SEM, *p < 0.05.
In contrast, rTMS decreased corticospinal excitability in the control group, perhaps via the inhibitory processes underlying SP duration. There was a significant increase in control group SP duration after rTMS, which may contribute to the decrease in MEP amplitude observed in these subjects (Fig. 5). This finding is in contrast to previous studies of neurologically normal subjects that showed no change in SP duration following 1 Hz rTMS at intensities just above (Romeo et al., 2000) or below RTh (Touge et al., 2001). The difference in these results is probably due to the much lower rTMS intensity used in the present study. Like Touge et al. (2001), we also found that there was no change in corticospinal excitability before and after rTMS when the target muscle was voluntarily activated. It seems that rTMS reduced corticospinal excitability in control subjects at rest, but that this effect was abolished by activation. In conclusion, the present study has shown 1 Hz rTMS at intensities well below RTh and ATh can reduce corticospinal excitability in control subjects, and that this may be due to an increase in the inhibitory processes responsible for the cortical silent period. However, these effects were not observed in FHD subjects. Furthermore, rTMS did not alter ICI in either control or FHD subjects. These findings suggest that subthreshold 1 Hz rTMS may have limited application in the treatment of FHD.
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Acknowledgments CMS is supported by the Foundation for Research, Science and Technology. This project was supported by grants from Mr P. Baines, the University of Auckland Graduate Research Fund, and the Neurological Foundation of New Zealand.
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Impaired modulation of corticospinal excitability following subthreshold rTMS in focal hand dystonia Cathy M. Stinear *, Winston D. Byblow Department of Sport and Exercise Science, Human Motor Control Laboratory, University of Auckland–Tamaki, Private Bag 92019, Auckland, New Zealand
Abstract Previous studies have demonstrated that subthreshold 1 Hz repetitive transcranial magnetic stimulation (rTMS) causes a decrease in corticospinal excitability in neurologically normal subjects. The effects of subthreshold 1 Hz rTMS upon corticospinal excitability and intracortical inhibition in subjects with focal hand dystonia (FHD) is not yet clear. The purpose of this study was to examine the effects of low intensity 1 Hz rTMS upon these variables in control and FHD subjects. We recorded electromyographic (EMG) from the first dorsal interosseous (FDI) muscle of the dominant hands of seven control subjects, and seven affected hands of five FHD subjects. We used single and paired pulse TMS to examine motor evoked potential (MEP) amplitude, short interval intracortical inhibition (ICI) and silent period duration before, during and after 20 min of low intensity 1 Hz rTMS. MEP amplitude decreased significantly over the course of the rTMS in control subjects, but did not change in FHD subjects. Silent period duration was significantly longer in control subjects after rTMS, but there was no change in FHD subjects. There was no significant change in ICI after rTMS in either subject group, despite the rTMS intensity being set to preferentially activate intracortical inhibitory networks. This suggests that low intensity 1 Hz rTMS may have limited application in the normalisation of inhibitory function in FHD. Ó 2004 Elsevier B.V. All rights reserved.
*
Corresponding author. Tel.: +64 9 3737 599x86990; fax: +64 9 3737 043. E-mail address: [email protected] (C.M. Stinear).
0167-9457/$ - see front matter Ó 2004 Elsevier B.V. All rights reserved. doi:10.1016/j.humov.2004.08.022
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Keywords: Repetitive TMS; Focal hand dystonia; Intracortical inhibition
1. Introduction When transcranial magnetic stimulation (TMS) is delivered in trains of stimuli, with a frequency of around 1 Hz or higher, it is referred to as repetitive TMS (rTMS). The effects of rTMS on corticospinal excitability depend on a range of variables, including the frequency and intensity of stimulation. Generally, stimulation at frequencies around 5 Hz or higher produce an increase in corticospinal excitability, while stimulation at around 1 Hz tends to produce a decrease in corticospinal excitability (Wassermann & Lisanby, 2001). In neurologically normal subjects, subthreshold rTMS delivered to the hand area of M1 at 1 Hz has been shown to decrease corticospinal excitability (Maeda, Keenan, Tormos, Topka, & Pascual-Leone, 2000; Romero, Anschel, Sparing, Gangitano, & Pascual-Leone, 2002; Touge, Gerschlager, Brown, & Rothwell, 2001; Tsuji & Rothwell, 2002). This effect is positively correlated with the number of stimuli delivered (Touge et al., 2001), persists for between 10 (Romero et al., 2002; Tsuji & Rothwell, 2002) and 25 (Touge et al., 2001) minutes, and appears to be cortical in origin (Romero et al., 2002; Touge et al., 2001; Tsuji & Rothwell, 2002). Given that subthreshold 1 Hz rTMS appears to depress corticospinal excitability, it may have an application in the management of movement disorders associated with excessive corticospinal activity. One such disorder is focal hand dystonia (FHD), which is associated with impaired inhibitory function at multiple levels of the central nervous system (Berardelli et al., 1998). The clinical features of FHD are dominated by involuntary contractions of the hand and forearm musculature that result in awkward, uncoordinated movements of the wrist and/or fingers. These symptoms are due to the inappropriate co-contraction of antagonists and agonists, combined with generally excessive levels of muscle activity (Cohen & Hallett, 1988). This involuntary activity is typically painless, but can severely impair the performance of a particular manual task such as writing or playing a musical instrument (Brandfonbrener, 1995; Chen & Hallett, 1998; Fahn, Marsden, & DeLong, 1998; Lederman, 1991; Marsden & Sheehy, 1990; Newmark & Hochberg, 1987; Sheehy & Marsden, 1982; Sheehy, Rothwell, & Marsden, 1988). Task specificity is a distinctive feature of FHD. Recent work in our laboratory has demonstrated that the modulation of intracortical inhibitory function during the performance of a precise manual task is impaired in FHD patients (Stinear & Byblow, 2004). Subjects performed index finger flexion and extension, paced at 1 Hz by an auditory metronome. In control subjects, a spatially and temporally specific pattern of modulation of ICI was observed. In contrast, no significant modulation of ICI was observed in FHD patients during task performance, despite having normal levels of ICI at rest. Based on this observation, we suggested that deranged input to intracortical inhibitory networks may impair the modulation of intracortical inhibition in FHD during the performance
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of precise manual tasks (Stinear & Byblow, 2004). Given that rTMS seems to impact on the excitability of the corticospinal pathway, presumably through modulating the activity levels of inhibitory and excitatory inputs to this pathway, it is possible that rTMS may be useful in enhancing the modulation of intracortical inhibitory function. Two studies have investigated the effects of rTMS upon cortical function in patients with FHD. Siebner, Auer, and Conrad (1999) delivered rTMS to the hand area of M1 at 1 Hz and a stimulus intensity of 105% of rest threshold. Stimuli were delivered in 10 one-minute trains, and the average motor evoked potential (MEP) area for each train was determined. Rest threshold was determined and stimulus–response curves plotted before and 5 min after the delivery of rTMS. They found that, as expected, neurologically normal control subjects exhibited a significant decrease in MEP area over the course of the rTMS trains. In contrast, the FHD patients exhibited a significant increase in MEP area over the course of the rTMS. These authors found no change in rest threshold or the slope of the stimulus–response curves in either group after rTMS (Siebner, Auer, et al., 1999). The authors suggested their results were evidence of decreased intracortical inhibitory function associated with FHD (Siebner, Auer, et al., 1999). However, this was not tested directly. A subsequent study addressed this issue by exploring intracortical inhibitory and excitatory processes after rTMS (Siebner et al., 1999). Stimuli were delivered at 1 Hz for 20 min, at a stimulus intensity of 90% of rest threshold. Intracortical function was evaluated before, and 30 min after, rTMS using a paired-pulse technique and a range of inter-stimulus intervals (ISIs) including 1 and 3 ms. In a second experiment, the stimulus–response curve, silent period duration and a number of quantitative handwriting variables were determined before and immediately after rTMS, applied with the same stimulus protocol as in the first experiment. These authors report lower prerTMS levels of ICI in FHD patients than control subjects with interstimulus intervals of 1 and 3 ms. However, no data regarding the statistical significance of this effect were reported (Siebner, Tormos, et al., 1999). Before rTMS, FHD patients were found to have irregular pen stroke velocity profiles and a significantly higher number of direction inversions per stroke, compared with control subjects. After rTMS, half of the FHD patients demonstrated a shortlived improvement in handwriting variables, while the other half demonstrated no change (Siebner, Tormos, et al., 1999). Finally, there was a significant increase in silent period duration after rTMS in patients, but not controls, suggesting that rTMS increases cortical inhibitory function in FHD patients. The purpose of the present study was to re-examine the modulation of ICI by subthreshold 1 Hz rTMS in control and FHD subjects. A paired-pulse paradigm that would avoid any ÔfloorÕ effects with conditioning was used (Fisher, Nakamura, Bestmann, Rothwell, & Bostock, 2002). Prior to rTMS, the conditioning stimulus intensity was set so that the conditioned MEP response was approximately half the amplitude of the test MEP response (CS50). This allows both increases and decreases in ICI following rTMS to be observed. Furthermore, the intensity of the rTMS stimuli was set to CS50, so that it was well below rest threshold and preferentially activated low-threshold inhibitory intracortical interneurons.
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2. Method 2.1. Participants Five subjects with FHD participated in this experiment (one female, mean age 48 years, range 37–58 years). Two of these FHD subjects were bilaterally affected, giving a total of seven affected hands tested. Seven neurologically healthy, age-matched control subjects also participated (two females, mean age 47 years, range 37–56 years). Using a handedness questionnaire (Oldfield, 1971), all were deemed righthanded (mean control laterality quotient 88.7%, range 75.0–100.0%, mean FHD laterality quotient 84.4%, range 61.1–95.2%). The right hand of all subjects was tested, as was the left hand of two bilaterally affected FHD subjects. The extent of disability due to dystonia symptoms experienced by the subjects with FHD was quantified using the Fahn Arm Dystonia Scale (Fahn, 1989). The Auckland Ethics Committee approved the procedure in accordance with the Declaration of Helsinki, and informed consent was obtained from all participants. A summary of the nature, duration and severity of the FHD subjectsÕ symptoms is presented in Table 1. Fahn score is the functional ability score for each affected hand. The lower the score, the more impaired the function of the tested hand. The maximum score is 90. Two of the FHD subjects were undergoing botulinum toxin treatment (BTX). Care was taken to ensure that they were tested at least 10 weeks since their last treatment, and immediately prior to their next. 2.2. Procedure Subjects were seated comfortably, next to a table upon which they rested their dominant forearm and hand in a pronated position. Subjects were instructed to keep their hand and forearm muscles as relaxed as possible. Electromyography (EMG) data were collected from the first dorsal interosseous (FDI) of the dominant hand via a pair of 12 mm diameter surface Ag–AgCl Hydrospot electrodes (Physiometrix Inc., MA, USA). Signals were amplified by two Grass P511AC EMG amplifiers (Grass Instrument Division, RI, USA). The EMG data were bandpass filtered at Table 1 FHD patient characteristics Gender
Age (years)
Type
Affected hand(s)
Fahn score
Duration (years)
BTX
Instrument
M
45
WriterÕs
Bilateral
29
N
F M
58 46
WriterÕs WriterÕs and MusicianÕs
Unilateral Bilateral
L 74.1 R 68.8 R 79.4 L 63.0
8 17
Y N
Bagpipes
M
52
8
Y
Electric guitar
36
Unilateral dominant Unilateral dominant
R 63.0 R 58.5
M
WriterÕs and MusicianÕs MusicianÕs
R 76.5
7
N
Classical guitar
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30–1000 Hz, sampled at 4 kHz with a 12-bit MacLab A/D acquisition system and software, and stored to disk for subsequent analysis. 2.2.1. Single and paired-pulse TMS A pair of MagStim 200 magnetic stimulators (MagStim Company, Dyfed, UK, maximum output intensity 2.0 T) connected by a BiStim unit was used to stimulate the motor cortex via a figure-of-eight coil (7 cm coil diameter). The coil was held tangentially to the scalp and perpendicular to the central sulcus, so that the induced current flow was in a posterior to anterior direction. The optimal location for eliciting MEPs in FDI was determined by stimulating at sites over the contralateral motor cortex with the target muscle at rest. The location that produced the greatest peak-to-peak amplitudes in the FDI was considered optimal. Active threshold for FDI was then established at the optimal location by altering the stimulator output intensity initially in 5% and then in 1% increments, while the subject maintained an FDI activation level that was approximately 5% of maximum voluntary contraction (MVC). MVC was determined by having subjects abduct their index finger maximally against a fixed support, during which the rms EMG value over a 100 ms window was calculated. Active threshold (ATh) was defined as the percentage of maximum stimulator output (%MSO) that produced MEPs with a peakto-peak amplitude of 100 lV in four out of eight consecutive trials. A test stimulus intensity of 160% ATh was used to determine corticospinal excitability before, during and after the delivery of rTMS. The conditioning stimulus intensity was set to produce approximately 50% inhibition of the test MEP (CS50), with an ISI of 2.5 ms, as this has been shown to produce maximal ICI (Fisher et al., 2002). The conditioning stimulus intensity was initially set to 60% ATh and eight conditioned responses were collected and averaged. This was repeated with incremental increases in conditioning stimulus intensity (2% MSO steps) until the average conditioned MEP amplitude was between 40–60% of the average non-conditioned MEP amplitude. This intensity was designated CS50. Twelve non-conditioned MEPs and 12 conditioned MEPs were collected before the delivery of rTMS. Subjects were then asked to maintain a 5–20% MVC pinch grip, using visual feedback, while 12 stimuli were delivered at the test stimulus intensity. 2.2.2. Repetitive TMS Repetitive TMS was delivered via a figure-of-eight coil, identical to that used for the single and paired-pulse TMS, and a MagStim RapidStim unit (MagStim Company, Dyfed, UK). Active threshold was determined as described above, with single stimuli from the RapidStim unit delivered at a rate of approximately 0.2 Hz. The CS50 was expressed as a ratio of the ATh determined with the paired MagStim 200 stimulators. This ratio was then calculated for the ATh determined with the RapidStim unit, and the resulting intensity was set for the repetitive TMS. For example, if CS50 was found to be 0.6 ATh using the paired MagStim 200 stimulators, then the rTMS intensity was set to 0.6 of the ATh determined using the RapidStim unit. The rTMS intensity was therefore always subthreshold for the resting FDI muscle,
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and the EMG activity of the FDI was monitored online throughout the delivery of rTMS to ensure that it remained at rest. The rTMS stimuli were delivered at a frequency of 1 Hz, in four blocks of 300 stimuli. Between each block, 12 single test stimuli were delivered via the paired MagStim 200 stimulators. After the fourth block of rTMS, 12 single and 12 paired stimuli were delivered. The mean amplitude of the non-conditioned MEPs was then determined. If it was found to be different from the mean amplitude of the pre-rTMS non-conditioned MEPs, the test stimulus intensity was adjusted to match the pre-rTMS non-conditioned MEP amplitudes. A further 12 single and 12 paired stimuli were then delivered. Finally, the subject was asked to maintain a 5–20% MVC pinch grip, using visual feedback, while 12 stimuli were delivered at the pre-rTMS test stimulus intensity. 2.3. Data analysis The EMG activity in the 20 ms pre-trigger interval was checked and any trial with pretrigger EMG activity was discarded. The peak-to-peak amplitudes (mV) of the remaining MEPs were then trimmed of any outliers before being averaged for each condition (Wilcox, 2001). The mean non-conditioned MEP amplitude was then calculated for the pre-rTMS, during rTMS and post-rTMS conditions, for each subject. The degree of inhibition produced pre- and post-rTMS was then determined using the following formula: ICI ð%Þ ¼ 100 ððC=NCÞ 100Þ
ð1Þ
where NC = average non-conditioned MEP amplitude and C = average conditioned MEP amplitude. This results in a number that represents the degree of inhibition as a percentage, which at least partly compensates for interindividual variability in MEP amplitudes. The non-conditioned MEP amplitude data were analysed using a mixed repeated measures analysis of variance (ANOVA), with group (control, FHD) as the between subject factor, and time (pre, during 1, 2, 3, post) as the within subject factor. A two-sample, two-tailed t-test was used to test for a difference between groups in the pre-rTMS NC MEP amplitude. The degree of inhibition data were analysed using a mixed repeated measures ANOVA, with group (control, FHD) as the between subject factor, and time (pre, post, post-matched) as the within subject factor. Silent period duration data were analysed using a mixed repeated measures ANOVA, with group (control, FHD) as the between subject factor, and time (pre, post) as the within subject factor. Two-tailed, two-sample t-tests were used to test for between-group differences in ATh and rTMS stimulus intensity. Statistical significance was set at a = 0.05. 3. Results 3.1. Subject variables The ATh (%MSO) for FHD patients was significantly lower than that for the control subjects (FHD 30.3 ± 5.0% MSO, control 35.9 ± 4.0% MSO, p = 0.04). How-
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ever, there was no statistically significant difference in test stimulus intensity (FHD 51.0 ± 11.2% MSO, control 60.0 ± 4.2% MSO, p = 0.07). There was also no difference between groups in CS50 (FHD 26.3 ± 6.0% MSO, control 29.1 ± 5.1% MSO, p > 0.1) or rTMS intensity (FHD 36.4 ± 10.9% MSO, control 36.6 ± 7.1% MSO, p > 0.9). 3.2. Corticospinal excitability For the NC MEPs collected before, during and after rTMS, there was a significant effect of Group, with the MEPs recorded from the FHD group having a significantly higher amplitude than those recorded from the control group (control 0.5 ± 0.26 mV, FHD 1.4 ± 0.26 mV, F(1, 13) = 6.4, p < 0.05). There was no effect of time (F(3, 13) < 1, p > 0.6), and the interaction between Group and Time was also not significant (F(3, 13) < 1, p > 0.6). There was no difference in pre-rTMS NC MEP amplitude (control 0.83 ± 0.5 mV, FHD 1.3 ± 1.0 mV, p > 0.3). Therefore, the effect of Group upon NC MEP amplitude arose due to the MEPs recorded during and after rTMS being significantly smaller in the control group than the FHD group (Figs. 1 and 2). 3.3. Short interval intracortical inhibition (ICI) There was no difference between groups in the degree of ICI produced before rTMS (control 51 ± 3%, FHD 48 ± 5%, p > 0.5). The two-way repeated measures
Fig. 1. Example EMG traces from one control subject and one FHD subject, depicting non-conditioned MEP amplitude pre-rTMS, after each block of rTMS (during 1, 2, 3), and post-rTMS. Calibration bar 1 mV, 50 ms.
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Fig. 2. Non-conditioned MEP amplitude (mV) before, during and after rTMS. The rTMS was delivered in four blocks of 5 min duration, and MEPs were recorded after each block. Error bars = SEM, *p < 0.05.
ANOVA revealed no effect of matching or group on the degree of ICI produced post-rTMS with unmatched and matched test MEP amplitudes (both p > 0.25). Therefore, the unmatched and matched post-rTMS ICI data were pooled, and a two-way repeated measures ANOVA was used to test for the effects of group (control, FHD) and time (pre-rTMS, post-rTMS) upon ICI (Fig. 2). There was no effect of time or group, and the interaction between them was not significant (all p > 0.19). 3.4. Silent period duration There was no effect of group (control, FHD) or time (pre-rTMS, post-rTMS) upon the pre-trigger EMG or MEP amplitude in the active trials used to determine SP duration (all p > 0.3). There was also no significant difference between groups in the test stimulus intensity used for these trials (control 53.2 ± 6.1% MSO, FHD 45.4 ± 7.6% MSO, p > 0.07). There was a significant effect of time upon silent period duration, with silent period duration being significantly longer after rTMS (prerTMS 136.6 ± 9.8 ms, post-rTMS 146.4 ± 10.9 ms, F(1, 13) = 5.57, p < 0.05). The interaction between group and time was also significant (control pre-rTMS 130.2 ± 13.9 ms, post-rTMS 150.0 ± 17.2 ms; FHD pre-rTMS 137.9 ± 14.2 ms, post-rTMS 142.7 ± 13.5 ms, F(1, 13) = 5.9, p < 0.05). This interaction arose because silent period duration was significantly longer post-rTMS for control subjects, while there was no significant change in silent period duration for FHD subjects (Figs. 4 and 5).
4. Discussion The present study has confirmed some of the findings of previous studies, by demonstrating a decrease in corticospinal excitability in response to subthreshold 1 Hz
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rTMS in control subjects (Touge et al., 2001; Tsuji & Rothwell, 2002). However, it differs from previous studies with FHD subjects (Siebner, Auer, et al., 1999; Siebner, Tormos, et al., 1999) in that it does not demonstrate any effect of rTMS upon corticospinal excitability, ICI or SP duration in these subjects. This is probably due to some important technical differences between this study, and those by Siebner, Auer, et al. (1999) and Siebner, Tormos, et al. (1999). Siebner, Auer, et al. (1999) delivered 1 Hz rTMS at an intensity of 105% RTh, and showed that MEP area increased in FHD subjects, and decreased in control subjects. Similarly, the present study demonstrates a significant decrease in control MEP amplitude, and no change in FHD MEP amplitude (Fig. 2). While the rTMS intensity used in the present study is considerably lower (around 85% ATh), together these studies suggest that 1 Hz rTMS at or below RTh does not produce a decrease in corticospinal excitability in FHD subjects, as it does in control subjects. Unfortunately, the second study by Siebner, Tormos, et al. (1999) that used a subthreshold rTMS intensity (90% RTh), examined changes in threshold rather than MEP amplitude, and cannot be used to shed any further light upon this issue. Siebner, Tormos, et al. (1999) report a ÔnormalisationÕ of ICI in FHD subjects following subthreshold 1 Hz rTMS, although no statistical analysis of this finding was reported. In contrast, the present study did not demonstrate any effect of rTMS upon ICI in either the control or FHD group (Fig. 3). This may be due, in part, to the difference in conditioning stimulus and rTMS intensities used. Siebner, Tormos, et al. (1999) set the conditioning stimulus intensity to 80% RTh, and rTMS intensity to 90% RTh. These intensities are considerably higher than those used in the present study (conditioning stimulus and rTMS intensity around 85% ATh). The rTMS intensity used in the present study was sufficient to inhibit test MEP amplitude by around 50%. We suggest that the rTMS preferentially activated the intracortical inhibitory interneurons responsible for ICI, as its intensity was also well below both rest and active thresholds. Despite this, rTMS did not produce any significant modulation of ICI, in either group.
Fig. 3. Degree of ICI pre- and post-rTMS. There was no effect of rTMS or group upon ICI. Error bars = SEM.
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Fig. 4. Example EMG traces from one control subject and one FHD subject, depicting silent period duration pre- and post-rTMS. Calibration bar 1 mV, 50 ms.
Fig. 5. Silent period duration (ms) pre- and post-rTMS. Error bars = SEM, *p < 0.05.
In contrast, rTMS decreased corticospinal excitability in the control group, perhaps via the inhibitory processes underlying SP duration. There was a significant increase in control group SP duration after rTMS, which may contribute to the decrease in MEP amplitude observed in these subjects (Fig. 5). This finding is in contrast to previous studies of neurologically normal subjects that showed no change in SP duration following 1 Hz rTMS at intensities just above (Romeo et al., 2000) or below RTh (Touge et al., 2001). The difference in these results is probably due to the much lower rTMS intensity used in the present study. Like Touge et al. (2001), we also found that there was no change in corticospinal excitability before and after rTMS when the target muscle was voluntarily activated. It seems that rTMS reduced corticospinal excitability in control subjects at rest, but that this effect was abolished by activation. In conclusion, the present study has shown 1 Hz rTMS at intensities well below RTh and ATh can reduce corticospinal excitability in control subjects, and that this may be due to an increase in the inhibitory processes responsible for the cortical silent period. However, these effects were not observed in FHD subjects. Furthermore, rTMS did not alter ICI in either control or FHD subjects. These findings suggest that subthreshold 1 Hz rTMS may have limited application in the treatment of FHD.
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Acknowledgments CMS is supported by the Foundation for Research, Science and Technology. This project was supported by grants from Mr P. Baines, the University of Auckland Graduate Research Fund, and the Neurological Foundation of New Zealand.
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