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Exploring Theta Burst Stimulation as an intervention to improve motor recovery in chronic stroke
Clinical Neurophysiology 118 (2007) 333–342 www.elsevier.com/locate/clinph
Exploring Theta Burst Stimulation as an intervention to improve motor recovery in chronic stroke q P. Talelli b
a,*
, R.J. Greenwood b, J.C. Rothwell
a
a Institute of Neurology, University College London (UCL), UK The National Hospital for Neurology and Neurosurgery, University College London Hospitals (UCLH), UK
Accepted 24 October 2006 Available online 12 December 2006
Abstract Objective: To explore the effects of a single session of repetitive Transcranial Magnetic Stimulation, given as Theta Burst Stimulation, on behavioural and physiological measures of hand function in chronic stroke patients. Methods: Six chronic stroke patients with incomplete recovery of the hand were tested under three conditions: excitatory TBS over the stroke hemisphere (iTBSSH), inhibitory TBS (cTBSIH) over the intact hemisphere and sham stimulation. Behavioural outcomes included simple and choice reaction time paradigms. Physiological effects were assessed using single pulse TMS on both sides. Changes were sought for up to 40 min after TBS. Results: Immediately after iTBSSH simple reaction times in the paretic hands were decreased and, compared to sham stimulation, remained significantly shorter throughout the testing period. The amplitude of the MEPs at rest and during background contraction and the area under the Input–Output curves were also increased on the stroke side after iTBSSH. cTBSIH suppressed the MEPs evoked in the healthy hands but did not change motor behaviour or the electrophysiology of the paretic hands. No side effects were encountered. Conclusions: TBS seems safe in chronic stroke patients. iTBS over the stroke hemisphere transiently improved motor behaviour and corticospinal output in the paretic hands. Significance: Excitatory TBS may represent a useful rTMS protocol to apply to the stroke hemisphere in future longer term therapy trials. 2006 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved. Keywords: Transcranial Magnetic Stimulation; Stroke; Stroke rehabilitation; Theta Burst Stimulation
1. Introduction A number of reports have recently shown that noninvasive brain stimulation can transiently improve motor behaviour of the paretic hand in chronic stroke patients (Mansur et al., 2005; Takeuchi et al., 2005; Fregni et al., 2005; Hummel et al., 2005). The implication is that brain
q
The work has taken place at the Institute of Neurology. Corresponding author. Present address: Institute of Neurology, Sobell Department of Motor Neuroscience and Movement Disorders, Queen SQ, Box 146, London WC1N 3BG, UK. Tel.: +44 20 7837 3611x4468; fax: +44 20 7278 9836. E-mail address: [email protected] (P. Talelli). *
stimulation could enhance clinical outcome when added to behavioural interventions used in current rehabilitation protocols, probably by optimising plastic changes in the cortex. Whether this effect will prove sufficiently robust to be useful clinically remains to be clarified as do questions about the optimal stimulation site and paradigm, and which patients are most likely to benefit. Two general approaches are currently being used in the motor system. They are based on a model of interhemispheric rivalry between the motor areas of the stroke and intact hemisphere (Ward and Cohen, 2004; Murase et al., 2004) in which the stroke hemisphere is doubly disabled both by its own damage and by interfering output from the intact hemisphere. Therefore low-frequency
1388-2457/$32.00 2006 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.clinph.2006.10.014
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repetitive Transcranial Magnetic Stimulation (rTMS) (Mansur et al., 2005; Takeuchi et al., 2005) or cathodal Transcranial Direct Current Stimulation (TDCS) (Fregni et al., 2005) have been used in single-session designs to suppress excitability in the intact hemisphere (IH). Both appear to induce a transient functional benefit of 10–20%. Excitatory stimulation of the stroke hemisphere (SH) has mainly been tested in the form of anodal TDCS and seems to be equally effective in improving motor function in chronic stroke patients (Fregni et al., 2005; Hummel et al., 2005). To date, the role of high frequency rTMS on the stroke study has mainly been assessed in the form of changes in clinical outcomes after multiple sessions; (Uy et al., 2003; Khedr et al., 2005); little is known about the actual effects of rTMS on the injured corticospinal tract and its behavioural correlates. One recent study showed that motor behaviour and neurophysiological measures of chronically paretic hands improve during a short train of high frequency rTMS (Kim et al., 2006). However, the duration of the after effects was not reported. A very recent study showed that daily applications of inhibitory rTMS over the IH for 5 days may lead to consolidation of the benefits measured as simple motor reaction time, although the changes in a stroke-specific measure of hand function were less impressive and not clearly sustained after the end of the stimulation period (Fregni et al., 2006). These findings provide further support for the model of interhemispheric rivalry, but other recent evidence suggests that it may be an oversimplistic concept as in some circumstances the intact hemisphere may contribute to, rather than interfere with, control of the affected limbs. For example, brief functional disruption of contralesional motor areas impairs complex movements made with the paretic hand (Lotze et al., 2006). Aphasic patients may also perform worse after suppression of the right language area homologues (Martin et al., 2004; Winhuisen et al., 2005). To date only one study, using TDCS, has compared the effectiveness of suppressing the IH with facilitation of SH in patients with motor stroke; both approaches were found to be equally effective, with slightly greater improvement after suppression of the IH (Fregni et al., 2005). It is not yet known whether this is also true for rTMS, or whether application of excitatory rTMS protocols to the stroke hemisphere increases the risk of provoking a seizure. Theta Burst Stimulation (TBS) is a novel form of rTMS that employs very low intensity to increase or decrease motor cortical excitability in healthy subjects for up to 20 min after the end of stimulation (Huang et al., 2005). The nature of the effect depends on the stimulation pattern (see Section 2). Bezard et al. showed that the seizure risk from motor cortical stimulation in healthy baboons results from high stimulation intensities (Bezard et al., 1999). TBS could thus represent a good rTMS option for treating stroke patients: it has a robust effect that lasts long enough to be clinically useful and a theoretically safer profile. The present study was conducted to test this hypothesis by evaluating the effect of a single
session of TBS in a small population of unselected chronic stroke patients. We aimed to investigate if TBS can safely induce immediate improvements in the motor behaviour of the paretic hand, to identify power/duration differences between two interventions, excitation of the SH vs inhibition of the IH, and to study physiological equivalents of any behavioural effects. 2. Patients and methods 2.1. Patients Six patients (mean age 61.2 ± 13.6, 2 females 4 males) with a history of a single infarct within the Middle Cerebral Artery (MCA) territory initially causing hand weakness were recruited at least 1 year after the ictus. The National Institute of Health Stroke Scale (NIHSS) (Lyden et al., 1999), the arm section of the Motricity Index (MI) (Collin and Wade, 1990), the Action Research Arm Test (ARAT) (van Der Lee et al., 2001) and the 9-hole peg test (Heinemann et al., 1987) were employed to determine their neurological status and level of hand function at the time of enrolment. We did not include patients with history of TIAs, complete paralysis of the hand at recruitment, significant residual sensory deficit, aphasia or neglect (defined as score P2 in the respective item of the NIHSS), other neurological disease or major systemic illness, history of epilepsy or post-stroke seizures, accepted contraindications for TMS (pacemakers, metallic objects in the head), or large infarcts affecting the whole MCA territory. The last criterion was set to minimize the risk of rTMS-provoked seizures, which is thought to be higher in patients with large lesions involving the cortex (Silverman et al., 2002). Patients’ characteristics are summarized in Table 1; the location of the lesion is shown in Fig. 1. All patients had achieved substantial recovery of hand function but had some residual reduction in grip strength and/or dexterity of hand movements. All experimental procedures were carried out at the Institute of Neurology. Patients gave informed consent and the study was approved by the National Hospital for Neurology and Neurosurgery and Institute of Neurology Joint Research Ethics Committee. 2.2. Design Patients were invited to participate in five experiments. In the first three, we investigated the effect of TBS on the motor behaviour of the hand under three different conditions: suppression of the IH, facilitation of the SH and sham stimulation. In the last two experiments, we tested the effect of the two real TBS paradigms on corticospinal excitability, without including a sham condition, as subjects’ expectations are not expected to influence single pulse TMS measures, especially in naı¨ve individuals. Experiments were conducted at intervals of at least 10 days. The order was randomized and counterbalanced across subjects in both sets.
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Table 1 Patients’ characteristics at baseline No
Age
Months from stroke
Lesion location
BI (0–20)
NIHSS (0–36)
MI (0–20)
ARAT (0–57)
9-HPT*
Maximal* grip strength
1 2 3 4 5 6
68 71 40 45 48 74
17 12 14 13 108 21
L posterior MCA L striato-capsular L MCA L MCA L striato-capsular R internal capsule
19 19 20 20 20 18
6 5 4 2 4 5
76 84 84 92 76 70
41 55 54 57 57 43
0.21 0.90 0.39 0.36 0.52 0.08
0.61 0.38 0.36 0.35 0.57 0.21
Mean (SD)
57.7 (14.9)
19.3 (0.8)
4.3 (1.4)
80.3 (7.8)
51.2 (7.2)
0.377 (0.28)
0.413 (0.15)
31 (37.9)
SD, standard deviation; L, left; R, right; BI, Barthel Index; NIHSS, National Institute of Health Stroke Scale; MI, Motricity Index (arm subtotal); ARAT, Action Research Arm Test; 9-HPT, 9-hole peg test; *, values are expressed as paretic/healthy hand ratios.
2.2.1. Theta Burst Stimulation Theta Burst Stimulation (TBS) consists of repeating bursts of stimuli. Each burst consists of three stimuli repeating at 50 Hz; bursts are repeating at 5 Hz. The intensity of stimulation is set at 80% of the active motor threshold (AMT). In normal individuals a continuous train of 100 bursts (300 stimuli), named cTBS, can suppress corticospinal excitability for 20 min. With the intermittent pattern (iTBS) (20 trains of 10 bursts given with 8-s intervals (600 pulses in total)) corticospinal excitability is enhanced for a similar period of time (Huang et al., 2005). cTBS
Fig. 1. Schematic representation of lesion site and volume. Patients’ numbers correspond to those in Table 1.
was therefore used to suppress the IH (cTBSIH) and iTBS to facilitate the SH (iTBSSH). Patients were seated comfortably in an armchair. TBS was given using a 70 mm figure of eight coil connected to a Super Rapid Magstim package (Magstim Co, Whitland, Dyfeld, UK). The coil was held in a posterior–anterior plane over the motor-hotspot, defined as the location where TMS consistently produced the largest Motor Evoked Potential (MEP). Sham stimulation was delivered using a two-wings 90 positioning (Lisanby et al., 2001) at 50% of the maximum output; the stimulation paradigm used as sham (iTBS vs cTBS) and the stimulation side (stroke vs intact) were randomized. 2.2.2. Behavioural outcomes The main behavioural measures for the paretic hand were speed and force of reaction during a simple gripping task, i.e. simple reaction time (SRT) and simple reaction grip strength. Participants were seated with their elbows flexed at 90 and their forearms resting in a manipulandum coupled to an electronic grip dynamometer (Biometrics precision hand dynamometer G100, Biometrics Ltd., UK). The ‘‘Go’’ signal was an electrical stimulus, delivered to the skin over the ADM at a frequency of 0.3–0.5 Hz and an intensity of sensory threshold · 3 (re-adjusted when necessary to balance the perception on both sides) through Signal Software. Subjects were instructed to react by gripping the dynamometer ‘‘as fast and as hard as possible’’. Maximal grip force was calculated for both hands in the beginning of each session. Gripping correlates well with other measures of limb function even in chronic stages after stroke (Boissy et al., 1999). By asking the subjects to grip at their maximal force we hoped that they would maintain the amount of effort steady across sessions without having to provide visual feedback and thus avoid problems due to attentional or other cognitive differences (Price and Friston, 1999). We also included a choice reaction paradigm to evaluate more complex aspects of motor behaviour. To do this, the ‘‘Go’’ signal was randomly delivered to either hand; the participants were asked to grip the dynamometer accordingly to obtain a choice reaction time (CRT).
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In the beginning of each experiment, patients were allowed 10 min of familiarization with the tasks. Recordings were made before (T0) and during 40 min after TBS, at 7 min (T1), 20 min (T2) and 30 min (T3) and were separated by 2 min breaks to avoid fatigue. The exact time course is shown in Fig. 2A. The delay between TBS and T1 was inserted because there is unpublished evidence that early contraction of the target muscle (during the first 7 min after the stimulation) can modify the effect of cTBS. Such an effect has not been reported for iTBS (Huang, 2004). However, we used the same delay to standardize the experimental procedures across the conditions. Signals were amplified using DataLink software (DataLink Model DLK800, Biometrics Ltd., UK), acquired through a 1401 acquisition interface (Cambridge Electronic Design Ltd., Cambridge, UK) and recorded using Signal Software. In this way both the ‘‘Go’’ signal and the response waveform are recorded in the same frame. Reaction time was defined as the time between the ‘‘Go’’ signal
and the onset of the waveform. Error trials were excluded and analyzed separately. Analysis was based on mean values. After each session, patients were asked to complete a visual analogue scale (range 0–7) rating the level of fatigue and attention throughout the experiment. They were also asked to state whether they thought they had real or sham stimulation. 2.2.3. Electrophysiological outcomes For single pulse TMS measures, apart from AMT, the same coil type was connected to a monophasic Magstim 200 (Magstim Co, UK). Stimuli were delivered at a mean frequency of 0.2 Hz, i.e. every 5 s with 10% variation. The following measures were made: (1) Motor threshold at rest (RMT) bilaterally using validated criteria (Rothwell, 1997). Active thresholds (AMT) were measured using the Super Rapid
Fig. 2. Experimental design. An inhibitory rTMS protocol (cTBS) was given over the intact hemisphere and the excitatory protocol (iTBS) over the stroke hemisphere. The vertical time bar shows when each behavioural (A) and single pulse TMS (B) measure was made before and after TBS. The shaded area of the vertical bars indicates the period during which TBS was anticipated to have an effect on the outcome measures (based on previous experiments in normal individuals). The horizontal bars (A) indicate periods of rest to avoid fatigue during the behavioural tests. Rest periods were not necessary when assessing the effect of TBS on TMS measures. aMEPs, rMEPs and I/O curves were measured in the paretic hand after either cTBSIH or iTBSSH. Additionally, rMEPs were measured in the intact hand cTBSIH, but not after iTBSSH (B). rMEPs, MEPs at rest; aMEPs, MEPs during background contraction; I/O curves, Input–Output curves; SRT, single reaction time; CRT, choice reaction time. T0, baseline; T1, period of main TBS effect (gray areas); T2, 20 min post; T3, 30 min post.
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(biphasic stimulator) and thus were higher than the respective RMTs, which were measured using a Magstim 200 stimulator (monophasic). (2) Mean peak-to-peak MEP amplitude (20 trials) during rest (rMEP) bilaterally and with background muscle contraction of about 15% of the maximum (aMEP) on the SH. Stimulation intensity was set at 120% of the respective RMT. (3) Input–Output curves during rest (I/O) (Capaday, 1997) on the SH. Ten MEPs were collected at each stimulation intensity starting with 90% RMT and increasing stepwise by 10% RMT up to 150% RMT or the stimulator’s maximal output. The time course of the experiments is shown in Fig. 2B. Measures were performed before TBS (T0) and during the 20 min following the stimulation (T1), while some measures were repeated after the effect of TBS was expected to fade (T2). EMGs were recorded from the first dorsal interosseous (FDI) bilaterally. Signals were filtered (30 Hz–10KHz), amplified (Digitimer 360, Digitimer Ltd., Welwyn Garden City, Herts, UK) and then stored via Power 1401. Analysis was carried out using Signal Software. 2.3. Statistical analysis All data were logarithmically transformed to meet the assumptions for the use of parametric tests. However, the figures illustrating the results are based on raw data. Two-factor ANOVA with factors TIME (levels pre(T0) and post-stimulation (T1–T3)) and TBS (levels iTBSSH and cTBSIH for TMS measures and iTBSSH, cTBSIH and SHAM for behavioural measures) was employed for comparisons among the different conditions; one-factor analysis (TIME) of variance (ANOVA) was subsequently used to compare pre- and post-stimulation values at each condition; post hoc tests were carried out using Bonferroni correction. When only pairs of measures were compared, paired t-tests were used instead. Significance level was set at 0.05. The shape of the I/O curves was quite variable among patients; hence the data could not be fitted to a single model and the RMT could not be calculated using the x-interceptor method (Ray et al., 2002). We therefore compared the mean MEP amplitude at each stimulation intensity before and after TBS using ANOVA. We also calculated the area under the I/O curve (AUCI/O) as a gross measure of the overall corticospinal output. 3. Results There were no major adverse events. TBS was well tolerated by all patients. The main results are summarized in Fig. 3. In summary, iTBS over the stroke hemisphere (iTBSSH) was the only
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condition that significantly improved the motor behaviour and the physiological measures of the paretic hand. 3.1. Effect of TBS on motor behaviour Participants could not differentiate among the three stimulation patterns. There were no differences in fatigue (3.1 ± 1.1 after iTBSSH, 3.3 ± 1.25 after cTBSIH and 2.8 ± 0.98 after sham, ns) and attention ratings (3.8 ± 0.8 after iTBSSH, 4.5 ± 0.9 after cTBSIH and 3.6 ± 1.5 after sham, ns). Fig. 3A illustrates the effect of TBS on simple reaction time (SRT) in the paretic hand; SRT was shorter after iTBSSH whilst there was a tendency to increase over the testing period after cTBSIH and SHAM. A two-factor ANOVA showed significant main effects of TIME (F(3, 15) = 8.3; p = 0.002), TBS (F(2, 10) = 10; p = 0.004) and a significant TIME · TBS interaction (F(6, 30) = 2.99; p = 0.02). Subsequent one-factor ANOVAs revealed a significant main effect of TIME after iTBSSH (F(3, 15) = 4.9; p = 0.014); SRT was significantly shorter at T1 (mean change 90 ± 4%, p = 0.04) but not at T2 and T3. cTBSIH had no significant effect on SRT in the paretic hand. A significant main effect of TIME was found after SHAM (F(3, 15) = 8.4; p = 0.019); in this case SRTs in the paretic hands were prolonged although this was only marginally significant at T3 (p = 0.066). Post hoc comparisons revealed that at T1 SRTs were significantly shorter after iTBSSH compared with cTBSIH (p = 0.003) and SHAM (p = 0.007), while at T2 and T3 SRTs after iTBSSH were shorter compared to SHAM (p = 0.02 and p = 0.01, respectively) but not compared to cTBSIH. There was no difference at any time between cTBSIH and SHAM. Grip strength during the simple reaction task was not changed by TBS. A two-factor ANOVA showed only a significant main effect of TIME (F(3, 15) = 10.3, p = 0.001) but no TIME · TBS interaction; that was because grip strength decreased with time after cTBSIH (F(3, 15) = 5.8, p = 0.008), iTBSSH (F(3, 15) = 4.3, p = 0.03) and SHAM (F(3, 15) = 4.6, p = 0.017) (data not illustrated). No significant changes were seen in choice reaction times either in the paretic or the healthy hands in any of the conditions tested. 3.2. Effect of TBS on TMS measures Baseline measures of RMT (Table 2) were not significantly different between the two conditions (cTBSIH vs iTBSSH) on either side (IH, p = 0.59; SH, p = 0.62). The effect of TBS on MEP amplitude and I/O curves from the SH are shown in Figs. 3B and 4. iTBSSH increased corticospinal excitability on the stroke side whilst cTBSIH had no effect. A two-factor ANOVA on the resting MEP amplitude (Fig. 3B) showed a significant TIME · TBS interaction (F(2, 8) = 6.98, p = 0.018) that subsequent one-factor ANOVAs revealed was due to the fact that there was no effect of TIME after cTBSIH although this was
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Fig. 3. Effect of TBS on simple reaction time and electrophysiological measures in the paretic hand. (A) Mean simple reaction time (SRT) was significantly reduced immediately (T1 = 7 min) after iTBSSH (**); compared to cTBSIH SRTs were shorter only at T1 (*) whilst compared to Sham they were shorter throughout the testing period (*). (B) After iTBSSH the amplitude of rest MEPs (top) and active MEPs (bottom) evoked from the stroke hemisphere were significantly larger at T1 (**) but not after cTBSIH. The end of the period during which TBS was anticipated to have an effect on the outcome measures (based on previous experiments in normal individuals) has been marked on the x-axis ( // ). TBS, Theta Burst Stimulation; cTBSIH, continuous (inhibitory) pattern over the intact hemisphere; iTBSSH, intermittent (excitatory) pattern over the stroke hemisphere; *,**, significant <.05.
significant after iTBSSH (F(2, 8) = 6.5, p = 0.02). Post hoc t-tests indicated that MEPs were larger at 12 min (p = 0.029) but not at 7 min after iTBSSH. The facilitatory
effect of iTBSSH was also seen in the MEPs evoked during active contraction (Fig. 3B). A two-factor ANOVA showed a significant TIME · TBS interaction (F(2, 8) = 9.2,
Table 2 Motor thresholds at baseline RMT (monophasic stimulator) (% output)
iTBSSH cTBSIH
AMT (biphasic stimulator) (% output)
Stroke side
Intact side
Stroke side
Intact side
47.4 (12.8) 47 (11.4)
39.4 (12.7) 39.2 (12.1)
53.6 (11.1)a –
– 47.2 (11.4)
Values are means (standard deviation). RMT, resting motor threshold; AMT, active motor threshold; iTBSSH, excitatory TBS over the stroke hemisphere; cTBSIH, inhibitory TBS over the intact hemisphere. a Significantly higher compared to the healthy side (p = 0.021).
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Fig. 5. Effect of cTBSIH on the healthy hand. MEPs elicited in the healthy hands at 120% RMT were significantly reduced at T1 (**) and returned to baseline at T2. The end of the period during which TBS was anticipated to have an effect on the outcome measures (based on previous experiments in normal individuals) has been marked on the x-axis ( // ). TBS, Theta Burst Stimulation; cTBSIH, continuous (inhibitory) pattern over the intact hemisphere; RMT, resting motor threshold; **, significant <.05.
resting I/O curve (Fig. 4). The summary AUC data (Fig. 3C) show a significant TIME · TBS interaction (F(1, 4) = 20, p = 0.01); after iTBSSH, there was a significant increase in area (p = 0.014) whilst there was no change after cTBSIH. The lack of an effect of cTBSIH on MEPs from the SH was not due to a failure to suppress the IH, as resting MEPs evoked from the IH were smaller after cTBSIH (Fig. 5). A one-factor ANOVA showed a significant effect of TIME (F(2, 8) = 15.03, p = 0.002); post hoc t-tests revealed a significant decrease in amplitude at T1 (p = 0.028) but not at T2. 4. Discussion
Fig. 4. Effect of TBS on the Input–Output curves from the paretic hand. iTBSSH led to a significant increase in the area under the I/O curve from the paretic hand (C). There was a significant increase in the MEP amplitude elicited from the stroke hemisphere at 120% RMT (A). There were no significant effects after cTBSIH (B). TBS, Theta Burst Stimulation; cTBSIH, continuous (inhibitory) pattern over the intact hemisphere; iTBSSH, intermittent (excitatory) pattern over the stroke hemisphere; I/O curve, Input–Output curve; RMT, resting motor threshold; **, significant <.05.
p = 0.008) that was due to a significant effect of TIME after iTBSSH (one-factor ANOVA: F(2, 8) = 10.9, p = 0.005) but not after cTBSIH. Post hoc t-tests revealed that after iTBSSH MEPs were significantly bigger at T1 (p = 0.02) but not at T2. iTBSSH also increased the area under the
This study was designed to pilot the safety and efficacy of TBS in a small number of unselected chronic stroke patients. The lack of adverse events supports our hypothesis that TBS, which employs low stimulation intensities, is unlikely to be epileptogenic, at least when the lesion does not involve the whole MCA territory. Excitatory TBS over the stroke hemisphere (iTBSSH) transiently improved simple motor behaviour of the paretic hand in chronic stroke patients. In particular, iTBSSH shortened simple reaction time by an average of 10% in the first 20 min after the stimulation. This is a modest effect but within the range reported previously (Mansur et al., 2005; Takeuchi et al., 2005; Fregni et al., 2005; Hummel et al., 2005). Compared to the sham condition, the reaction time of the paretic hand remained significantly shorter when measured 30 min after the stimulation. To our knowledge, this is the first demonstration of a single session rTMS paradigm over the SH inducing a functional improvement that outlasts the period of stimulation. This effect was accompanied, as in normal individuals, by an enhancement of the corticospinal output of the SH. These preliminary results complement the previous reports using anodal (excitatory) TDCS over the SH (Fregni et al., 2005; Hummel et al., 2005) and support the use of stimulation of the SH in future longer term trials of the effectiveness of cortical stimulation in chronic stroke.
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Unlike previous reports in which other forms of inhibitory cortical stimulation to the IH have been shown to have beneficial effects (Mansur et al., 2005; Takeuchi et al., 2005; Fregni et al., 2005), inhibitory TBS (cTBSIH) did not influence performance in the paretic hand, although it successfully suppressed excitability on the IH. Although negative, this result is important since it warns against the general conclusion that suppression of the IH is equivalent to stimulation of the SH. As detailed below, we hypothesize that because cTBS employs low stimulation intensities, it may not be the most effective paradigm to induce transcallosally mediated effects. 4.1. Mechanism of the effects One obvious explanation for the improvement seen in simple reaction times after iTBSSH would be an increase of the corticospinal output of the affected side. This was directly demonstrated as an increase in MEP amplitudes and I/O curves. Di Lazzaro et al. have shown in normal subjects and in a single patient studied 6 years after the stroke that TBS changes the amplitude of corticospinal volleys evoked by single TMS pulses, suggesting that TBS directly influences cortical excitability (Di Lazzaro et al., 2005; Di Lazzaro et al., 2006). Indeed, given the very low stimulus intensity used in TBS, it is unlikely to change the function of peripheral muscle or the excitability of spinal motoneurones. This would explain why MEPs to standard single TMS pulse were increased even during voluntary contraction of the target muscle, when any changes in spinal excitability should be masked. The implication is that in these partially recovered patients, areas of the motor cortex were still capable of responding in a relatively normal way to iTBS. iTBS is thought to work by facilitating synaptic transmission within the available neuronal pool, thus increasing the number of neurons that are activated trans-synaptically by a single TMS pulse (Huang et al., 2005). Our data suggest that in stroke patients, the ability for potentiation may be preserved (a) when parts of the cortex are spared and (b) regardless of the time post-stroke. Unlike previous studies that have mainly included patients with subcortical lesions we demonstrated that the effects were similar in three patients with partial cortical involvement. In addition, the effects were comparable in one patient who was studied almost 9 years after the stroke. The effect of iTBSSH on behaviour lasted about twice as long as the effect on corticospinal excitability, which was present for 7–20 min after stimulation. It is possible that iTBSSH affected behaviour by facilitating motor learning during performance of the tests. In other words, iTBSSH may facilitate strengthening of relevant synapses if they are repeatedly used during subsequent testing. In this way, the behavioural benefit would outlast the initial increase in neural excitability.
Despite the improvement in SRT after iTBSSH, force output was not maintained. On the contrary, there was a gradual decrease in the force that patients exerted over the same period. Such demanding repetitive tasks are known to lead to progressive force loss, both in normal individuals (Liu et al., 2003) and in stroke patients (Riley and Bilodeau, 2002). The dissociated effect on speed and force is puzzling. It could be that the task prioritised speed over force. If we had trained subjects only to maximise force then this might have improved rather than speed. Another possibility is that maximal force output is insensitive to changes in cortical excitability, which may explain the absence of an effect of stimulation on strength in previous reports (Takeuchi et al., 2005). However, increasing voluntary strength is an important goal in physiotherapy and correlates with the ability to perform functional tasks of daily living (Teixeira-Salmela et al., 1999). It remains an important outcome to investigate when exploring the effectiveness of rTMS and TDCS paradigms. cTBSIH did not produce any behavioural effect on the paretic side. This cannot be due to a lack of inhibitory effects of cTBS on the IH, since the size of MEPs elicited from this hemisphere was reduced after cTBSIH. The absence of either improvement or deterioration could theoretically mean that in relatively recovered patients the IH has minimal if any involvement in the motor control of simple movements of the paretic hand (Gerloff et al., 2006; Talelli et al., 2006). However, this contrasts with previous reports that inhibitory (cathodal) TDCS (Fregni et al., 2005) or (low-frequency) rTMS (Mansur et al., 2005; Takeuchi et al., 2005) of the IH improves the motor behaviour in the paretic hand. We assume that the effect of cTBSIH on the corticospinal output was not reflected in the transcallosal output to the SH. This may relate to the fact that TBS employs a very low intensity, well below the threshold for evoking activity in transcallosal connections and explain why only higher intensity 1 Hz rTMS has been reported to be effective. TDCS probably works by polarising the membranes of cortical neurones, which secondarily changes their firing rates and leads to long term changes in synaptic function (Nitsche et al., 2003). The transcallosally projecting neurons lie in layer III of the cortex, very near to the TDCS electrode, and may be readily influenced by the polarising current. It should also be noted that in previous studies patients had purely subcortical lesions whilst we included patients with cortical involvement. Choice reaction time (CRT) of the paretic hand neither improved nor deteriorated in any of the conditions. To date, there is one report of improved CRT after inhibitory 1 Hz rTMS over the motor cortex of the IH, but no details of the paradigm used are provided (Mansur et al., 2005). By contrast, Lotze et al. showed that disruption of motor areas of both the stroke and intact hemisphere could affect patients’ performance in a complex sequential finger task (Lotze et al., 2006). It may well be that control of complex behaviours, such as choice reaction, is more distributed among cortical areas
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than a simple reaction task. In that case, stimulation of just one area in a single-session design may have limited effects on behaviour. Perhaps several sessions or longer periods of stimulation may be needed to induce reorganisation at multiple distant sites and maximise behavioural outcomes. 4.2. Implications for stroke rehabilitation The present study supports previous reports that in chronic stroke patients transcranial stimulation over the stroke side can induce temporary improvements in functional performance. iTBS appears to work as in healthy cortex by increasing excitability at the stimulated site. Since it uses low intensity stimuli and is quick to apply, it may prove to be a useful form of rTMS to test in larger trials after stroke. We are therefore currently investigating whether these transient benefits can be transformed into longer lasting, even permanent changes, with repeated treatments. Previous reports have provided some evidence that this might be achievable with other non-invasive (Uy et al., 2003; Khedr et al., 2005) or invasive stimulation techniques (Brown et al., 2006). It is likely that the chances of beneficial results with non-invasive stimulation are related to the safety and power of the chosen paradigm. Disclosure The authors have reported no conflicts of interest. References Bezard E, Boraud T, Nguyen JP, Velasco F, Keravel Y, Gross C. Cortical stimulation and epileptic seizure: a study of the potential risk in primates. Neurosurgery 1999;45:346–50. Boissy P, Bourbonnais D, Carlotti MM, Gravel D, Arsenault BA. Maximal grip force in chronic stroke subjects and its relationship to global upper extremity function. Clin Rehabil 1999;13:354–62. Brown JA, Lutsep HL, Weinand M, Cramer SC. Motor cortex stimulation for the enhancement of recovery from stroke: a prospective, multicenter safety study. Neurosurgery 2006;58:464–73. Capaday C. Neurophysiological methods for studies of the motor system in freely moving human subjects. J Neurosci Methods 1997;74:201–18. Collin C, Wade D. Assessing motor impairment after stroke: a pilot reliability study. J Neurol Neurosurg Psychiatry 1990;53:576–9. Di Lazzaro V, Pilato F, Saturno E, Oliviero A, Dileone M, Mazzone P, et al. Theta-burst repetitive transcranial magnetic stimulation suppresses specific excitatory circuits in the human motor cortex. J Physiol 2005;565:945–50. Di Lazzaro V, Dileone M, Profice C, Pilato F, Rothwell JC. Direct demonstration that repetitive transcranial magnetic stimulation can enhance corticospinal excitability in stroke. Stroke 2006;37:2850–3. Fregni F, Boggio PS, Mansur CG, Wagner T, Ferreira MJ, Lima MC, et al. Transcranial direct current stimulation of the unaffected hemisphere in stroke patients. Neuroreport 2005;16:1551–5. Fregni F, Boggio PS, Valle AC, Rocha RR, Duarte J, Ferreira MJ, et al. A sham-controlled trial of a 5-day course of repetitive transcranial magnetic stimulation of the unaffected hemisphere in stroke patients. Stroke 2006;37:2115–22. Gerloff C, Bushara K, Sailer A, Wassermann EM, Chen R, Matsuoka T, et al. Multimodal imaging of brain reorganization in motor areas of
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Exploring Theta Burst Stimulation as an intervention to improve motor recovery in chronic stroke q P. Talelli b
a,*
, R.J. Greenwood b, J.C. Rothwell
a
a Institute of Neurology, University College London (UCL), UK The National Hospital for Neurology and Neurosurgery, University College London Hospitals (UCLH), UK
Accepted 24 October 2006 Available online 12 December 2006
Abstract Objective: To explore the effects of a single session of repetitive Transcranial Magnetic Stimulation, given as Theta Burst Stimulation, on behavioural and physiological measures of hand function in chronic stroke patients. Methods: Six chronic stroke patients with incomplete recovery of the hand were tested under three conditions: excitatory TBS over the stroke hemisphere (iTBSSH), inhibitory TBS (cTBSIH) over the intact hemisphere and sham stimulation. Behavioural outcomes included simple and choice reaction time paradigms. Physiological effects were assessed using single pulse TMS on both sides. Changes were sought for up to 40 min after TBS. Results: Immediately after iTBSSH simple reaction times in the paretic hands were decreased and, compared to sham stimulation, remained significantly shorter throughout the testing period. The amplitude of the MEPs at rest and during background contraction and the area under the Input–Output curves were also increased on the stroke side after iTBSSH. cTBSIH suppressed the MEPs evoked in the healthy hands but did not change motor behaviour or the electrophysiology of the paretic hands. No side effects were encountered. Conclusions: TBS seems safe in chronic stroke patients. iTBS over the stroke hemisphere transiently improved motor behaviour and corticospinal output in the paretic hands. Significance: Excitatory TBS may represent a useful rTMS protocol to apply to the stroke hemisphere in future longer term therapy trials. 2006 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved. Keywords: Transcranial Magnetic Stimulation; Stroke; Stroke rehabilitation; Theta Burst Stimulation
1. Introduction A number of reports have recently shown that noninvasive brain stimulation can transiently improve motor behaviour of the paretic hand in chronic stroke patients (Mansur et al., 2005; Takeuchi et al., 2005; Fregni et al., 2005; Hummel et al., 2005). The implication is that brain
q
The work has taken place at the Institute of Neurology. Corresponding author. Present address: Institute of Neurology, Sobell Department of Motor Neuroscience and Movement Disorders, Queen SQ, Box 146, London WC1N 3BG, UK. Tel.: +44 20 7837 3611x4468; fax: +44 20 7278 9836. E-mail address: [email protected] (P. Talelli). *
stimulation could enhance clinical outcome when added to behavioural interventions used in current rehabilitation protocols, probably by optimising plastic changes in the cortex. Whether this effect will prove sufficiently robust to be useful clinically remains to be clarified as do questions about the optimal stimulation site and paradigm, and which patients are most likely to benefit. Two general approaches are currently being used in the motor system. They are based on a model of interhemispheric rivalry between the motor areas of the stroke and intact hemisphere (Ward and Cohen, 2004; Murase et al., 2004) in which the stroke hemisphere is doubly disabled both by its own damage and by interfering output from the intact hemisphere. Therefore low-frequency
1388-2457/$32.00 2006 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.clinph.2006.10.014
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repetitive Transcranial Magnetic Stimulation (rTMS) (Mansur et al., 2005; Takeuchi et al., 2005) or cathodal Transcranial Direct Current Stimulation (TDCS) (Fregni et al., 2005) have been used in single-session designs to suppress excitability in the intact hemisphere (IH). Both appear to induce a transient functional benefit of 10–20%. Excitatory stimulation of the stroke hemisphere (SH) has mainly been tested in the form of anodal TDCS and seems to be equally effective in improving motor function in chronic stroke patients (Fregni et al., 2005; Hummel et al., 2005). To date, the role of high frequency rTMS on the stroke study has mainly been assessed in the form of changes in clinical outcomes after multiple sessions; (Uy et al., 2003; Khedr et al., 2005); little is known about the actual effects of rTMS on the injured corticospinal tract and its behavioural correlates. One recent study showed that motor behaviour and neurophysiological measures of chronically paretic hands improve during a short train of high frequency rTMS (Kim et al., 2006). However, the duration of the after effects was not reported. A very recent study showed that daily applications of inhibitory rTMS over the IH for 5 days may lead to consolidation of the benefits measured as simple motor reaction time, although the changes in a stroke-specific measure of hand function were less impressive and not clearly sustained after the end of the stimulation period (Fregni et al., 2006). These findings provide further support for the model of interhemispheric rivalry, but other recent evidence suggests that it may be an oversimplistic concept as in some circumstances the intact hemisphere may contribute to, rather than interfere with, control of the affected limbs. For example, brief functional disruption of contralesional motor areas impairs complex movements made with the paretic hand (Lotze et al., 2006). Aphasic patients may also perform worse after suppression of the right language area homologues (Martin et al., 2004; Winhuisen et al., 2005). To date only one study, using TDCS, has compared the effectiveness of suppressing the IH with facilitation of SH in patients with motor stroke; both approaches were found to be equally effective, with slightly greater improvement after suppression of the IH (Fregni et al., 2005). It is not yet known whether this is also true for rTMS, or whether application of excitatory rTMS protocols to the stroke hemisphere increases the risk of provoking a seizure. Theta Burst Stimulation (TBS) is a novel form of rTMS that employs very low intensity to increase or decrease motor cortical excitability in healthy subjects for up to 20 min after the end of stimulation (Huang et al., 2005). The nature of the effect depends on the stimulation pattern (see Section 2). Bezard et al. showed that the seizure risk from motor cortical stimulation in healthy baboons results from high stimulation intensities (Bezard et al., 1999). TBS could thus represent a good rTMS option for treating stroke patients: it has a robust effect that lasts long enough to be clinically useful and a theoretically safer profile. The present study was conducted to test this hypothesis by evaluating the effect of a single
session of TBS in a small population of unselected chronic stroke patients. We aimed to investigate if TBS can safely induce immediate improvements in the motor behaviour of the paretic hand, to identify power/duration differences between two interventions, excitation of the SH vs inhibition of the IH, and to study physiological equivalents of any behavioural effects. 2. Patients and methods 2.1. Patients Six patients (mean age 61.2 ± 13.6, 2 females 4 males) with a history of a single infarct within the Middle Cerebral Artery (MCA) territory initially causing hand weakness were recruited at least 1 year after the ictus. The National Institute of Health Stroke Scale (NIHSS) (Lyden et al., 1999), the arm section of the Motricity Index (MI) (Collin and Wade, 1990), the Action Research Arm Test (ARAT) (van Der Lee et al., 2001) and the 9-hole peg test (Heinemann et al., 1987) were employed to determine their neurological status and level of hand function at the time of enrolment. We did not include patients with history of TIAs, complete paralysis of the hand at recruitment, significant residual sensory deficit, aphasia or neglect (defined as score P2 in the respective item of the NIHSS), other neurological disease or major systemic illness, history of epilepsy or post-stroke seizures, accepted contraindications for TMS (pacemakers, metallic objects in the head), or large infarcts affecting the whole MCA territory. The last criterion was set to minimize the risk of rTMS-provoked seizures, which is thought to be higher in patients with large lesions involving the cortex (Silverman et al., 2002). Patients’ characteristics are summarized in Table 1; the location of the lesion is shown in Fig. 1. All patients had achieved substantial recovery of hand function but had some residual reduction in grip strength and/or dexterity of hand movements. All experimental procedures were carried out at the Institute of Neurology. Patients gave informed consent and the study was approved by the National Hospital for Neurology and Neurosurgery and Institute of Neurology Joint Research Ethics Committee. 2.2. Design Patients were invited to participate in five experiments. In the first three, we investigated the effect of TBS on the motor behaviour of the hand under three different conditions: suppression of the IH, facilitation of the SH and sham stimulation. In the last two experiments, we tested the effect of the two real TBS paradigms on corticospinal excitability, without including a sham condition, as subjects’ expectations are not expected to influence single pulse TMS measures, especially in naı¨ve individuals. Experiments were conducted at intervals of at least 10 days. The order was randomized and counterbalanced across subjects in both sets.
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Table 1 Patients’ characteristics at baseline No
Age
Months from stroke
Lesion location
BI (0–20)
NIHSS (0–36)
MI (0–20)
ARAT (0–57)
9-HPT*
Maximal* grip strength
1 2 3 4 5 6
68 71 40 45 48 74
17 12 14 13 108 21
L posterior MCA L striato-capsular L MCA L MCA L striato-capsular R internal capsule
19 19 20 20 20 18
6 5 4 2 4 5
76 84 84 92 76 70
41 55 54 57 57 43
0.21 0.90 0.39 0.36 0.52 0.08
0.61 0.38 0.36 0.35 0.57 0.21
Mean (SD)
57.7 (14.9)
19.3 (0.8)
4.3 (1.4)
80.3 (7.8)
51.2 (7.2)
0.377 (0.28)
0.413 (0.15)
31 (37.9)
SD, standard deviation; L, left; R, right; BI, Barthel Index; NIHSS, National Institute of Health Stroke Scale; MI, Motricity Index (arm subtotal); ARAT, Action Research Arm Test; 9-HPT, 9-hole peg test; *, values are expressed as paretic/healthy hand ratios.
2.2.1. Theta Burst Stimulation Theta Burst Stimulation (TBS) consists of repeating bursts of stimuli. Each burst consists of three stimuli repeating at 50 Hz; bursts are repeating at 5 Hz. The intensity of stimulation is set at 80% of the active motor threshold (AMT). In normal individuals a continuous train of 100 bursts (300 stimuli), named cTBS, can suppress corticospinal excitability for 20 min. With the intermittent pattern (iTBS) (20 trains of 10 bursts given with 8-s intervals (600 pulses in total)) corticospinal excitability is enhanced for a similar period of time (Huang et al., 2005). cTBS
Fig. 1. Schematic representation of lesion site and volume. Patients’ numbers correspond to those in Table 1.
was therefore used to suppress the IH (cTBSIH) and iTBS to facilitate the SH (iTBSSH). Patients were seated comfortably in an armchair. TBS was given using a 70 mm figure of eight coil connected to a Super Rapid Magstim package (Magstim Co, Whitland, Dyfeld, UK). The coil was held in a posterior–anterior plane over the motor-hotspot, defined as the location where TMS consistently produced the largest Motor Evoked Potential (MEP). Sham stimulation was delivered using a two-wings 90 positioning (Lisanby et al., 2001) at 50% of the maximum output; the stimulation paradigm used as sham (iTBS vs cTBS) and the stimulation side (stroke vs intact) were randomized. 2.2.2. Behavioural outcomes The main behavioural measures for the paretic hand were speed and force of reaction during a simple gripping task, i.e. simple reaction time (SRT) and simple reaction grip strength. Participants were seated with their elbows flexed at 90 and their forearms resting in a manipulandum coupled to an electronic grip dynamometer (Biometrics precision hand dynamometer G100, Biometrics Ltd., UK). The ‘‘Go’’ signal was an electrical stimulus, delivered to the skin over the ADM at a frequency of 0.3–0.5 Hz and an intensity of sensory threshold · 3 (re-adjusted when necessary to balance the perception on both sides) through Signal Software. Subjects were instructed to react by gripping the dynamometer ‘‘as fast and as hard as possible’’. Maximal grip force was calculated for both hands in the beginning of each session. Gripping correlates well with other measures of limb function even in chronic stages after stroke (Boissy et al., 1999). By asking the subjects to grip at their maximal force we hoped that they would maintain the amount of effort steady across sessions without having to provide visual feedback and thus avoid problems due to attentional or other cognitive differences (Price and Friston, 1999). We also included a choice reaction paradigm to evaluate more complex aspects of motor behaviour. To do this, the ‘‘Go’’ signal was randomly delivered to either hand; the participants were asked to grip the dynamometer accordingly to obtain a choice reaction time (CRT).
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In the beginning of each experiment, patients were allowed 10 min of familiarization with the tasks. Recordings were made before (T0) and during 40 min after TBS, at 7 min (T1), 20 min (T2) and 30 min (T3) and were separated by 2 min breaks to avoid fatigue. The exact time course is shown in Fig. 2A. The delay between TBS and T1 was inserted because there is unpublished evidence that early contraction of the target muscle (during the first 7 min after the stimulation) can modify the effect of cTBS. Such an effect has not been reported for iTBS (Huang, 2004). However, we used the same delay to standardize the experimental procedures across the conditions. Signals were amplified using DataLink software (DataLink Model DLK800, Biometrics Ltd., UK), acquired through a 1401 acquisition interface (Cambridge Electronic Design Ltd., Cambridge, UK) and recorded using Signal Software. In this way both the ‘‘Go’’ signal and the response waveform are recorded in the same frame. Reaction time was defined as the time between the ‘‘Go’’ signal
and the onset of the waveform. Error trials were excluded and analyzed separately. Analysis was based on mean values. After each session, patients were asked to complete a visual analogue scale (range 0–7) rating the level of fatigue and attention throughout the experiment. They were also asked to state whether they thought they had real or sham stimulation. 2.2.3. Electrophysiological outcomes For single pulse TMS measures, apart from AMT, the same coil type was connected to a monophasic Magstim 200 (Magstim Co, UK). Stimuli were delivered at a mean frequency of 0.2 Hz, i.e. every 5 s with 10% variation. The following measures were made: (1) Motor threshold at rest (RMT) bilaterally using validated criteria (Rothwell, 1997). Active thresholds (AMT) were measured using the Super Rapid
Fig. 2. Experimental design. An inhibitory rTMS protocol (cTBS) was given over the intact hemisphere and the excitatory protocol (iTBS) over the stroke hemisphere. The vertical time bar shows when each behavioural (A) and single pulse TMS (B) measure was made before and after TBS. The shaded area of the vertical bars indicates the period during which TBS was anticipated to have an effect on the outcome measures (based on previous experiments in normal individuals). The horizontal bars (A) indicate periods of rest to avoid fatigue during the behavioural tests. Rest periods were not necessary when assessing the effect of TBS on TMS measures. aMEPs, rMEPs and I/O curves were measured in the paretic hand after either cTBSIH or iTBSSH. Additionally, rMEPs were measured in the intact hand cTBSIH, but not after iTBSSH (B). rMEPs, MEPs at rest; aMEPs, MEPs during background contraction; I/O curves, Input–Output curves; SRT, single reaction time; CRT, choice reaction time. T0, baseline; T1, period of main TBS effect (gray areas); T2, 20 min post; T3, 30 min post.
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(biphasic stimulator) and thus were higher than the respective RMTs, which were measured using a Magstim 200 stimulator (monophasic). (2) Mean peak-to-peak MEP amplitude (20 trials) during rest (rMEP) bilaterally and with background muscle contraction of about 15% of the maximum (aMEP) on the SH. Stimulation intensity was set at 120% of the respective RMT. (3) Input–Output curves during rest (I/O) (Capaday, 1997) on the SH. Ten MEPs were collected at each stimulation intensity starting with 90% RMT and increasing stepwise by 10% RMT up to 150% RMT or the stimulator’s maximal output. The time course of the experiments is shown in Fig. 2B. Measures were performed before TBS (T0) and during the 20 min following the stimulation (T1), while some measures were repeated after the effect of TBS was expected to fade (T2). EMGs were recorded from the first dorsal interosseous (FDI) bilaterally. Signals were filtered (30 Hz–10KHz), amplified (Digitimer 360, Digitimer Ltd., Welwyn Garden City, Herts, UK) and then stored via Power 1401. Analysis was carried out using Signal Software. 2.3. Statistical analysis All data were logarithmically transformed to meet the assumptions for the use of parametric tests. However, the figures illustrating the results are based on raw data. Two-factor ANOVA with factors TIME (levels pre(T0) and post-stimulation (T1–T3)) and TBS (levels iTBSSH and cTBSIH for TMS measures and iTBSSH, cTBSIH and SHAM for behavioural measures) was employed for comparisons among the different conditions; one-factor analysis (TIME) of variance (ANOVA) was subsequently used to compare pre- and post-stimulation values at each condition; post hoc tests were carried out using Bonferroni correction. When only pairs of measures were compared, paired t-tests were used instead. Significance level was set at 0.05. The shape of the I/O curves was quite variable among patients; hence the data could not be fitted to a single model and the RMT could not be calculated using the x-interceptor method (Ray et al., 2002). We therefore compared the mean MEP amplitude at each stimulation intensity before and after TBS using ANOVA. We also calculated the area under the I/O curve (AUCI/O) as a gross measure of the overall corticospinal output. 3. Results There were no major adverse events. TBS was well tolerated by all patients. The main results are summarized in Fig. 3. In summary, iTBS over the stroke hemisphere (iTBSSH) was the only
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condition that significantly improved the motor behaviour and the physiological measures of the paretic hand. 3.1. Effect of TBS on motor behaviour Participants could not differentiate among the three stimulation patterns. There were no differences in fatigue (3.1 ± 1.1 after iTBSSH, 3.3 ± 1.25 after cTBSIH and 2.8 ± 0.98 after sham, ns) and attention ratings (3.8 ± 0.8 after iTBSSH, 4.5 ± 0.9 after cTBSIH and 3.6 ± 1.5 after sham, ns). Fig. 3A illustrates the effect of TBS on simple reaction time (SRT) in the paretic hand; SRT was shorter after iTBSSH whilst there was a tendency to increase over the testing period after cTBSIH and SHAM. A two-factor ANOVA showed significant main effects of TIME (F(3, 15) = 8.3; p = 0.002), TBS (F(2, 10) = 10; p = 0.004) and a significant TIME · TBS interaction (F(6, 30) = 2.99; p = 0.02). Subsequent one-factor ANOVAs revealed a significant main effect of TIME after iTBSSH (F(3, 15) = 4.9; p = 0.014); SRT was significantly shorter at T1 (mean change 90 ± 4%, p = 0.04) but not at T2 and T3. cTBSIH had no significant effect on SRT in the paretic hand. A significant main effect of TIME was found after SHAM (F(3, 15) = 8.4; p = 0.019); in this case SRTs in the paretic hands were prolonged although this was only marginally significant at T3 (p = 0.066). Post hoc comparisons revealed that at T1 SRTs were significantly shorter after iTBSSH compared with cTBSIH (p = 0.003) and SHAM (p = 0.007), while at T2 and T3 SRTs after iTBSSH were shorter compared to SHAM (p = 0.02 and p = 0.01, respectively) but not compared to cTBSIH. There was no difference at any time between cTBSIH and SHAM. Grip strength during the simple reaction task was not changed by TBS. A two-factor ANOVA showed only a significant main effect of TIME (F(3, 15) = 10.3, p = 0.001) but no TIME · TBS interaction; that was because grip strength decreased with time after cTBSIH (F(3, 15) = 5.8, p = 0.008), iTBSSH (F(3, 15) = 4.3, p = 0.03) and SHAM (F(3, 15) = 4.6, p = 0.017) (data not illustrated). No significant changes were seen in choice reaction times either in the paretic or the healthy hands in any of the conditions tested. 3.2. Effect of TBS on TMS measures Baseline measures of RMT (Table 2) were not significantly different between the two conditions (cTBSIH vs iTBSSH) on either side (IH, p = 0.59; SH, p = 0.62). The effect of TBS on MEP amplitude and I/O curves from the SH are shown in Figs. 3B and 4. iTBSSH increased corticospinal excitability on the stroke side whilst cTBSIH had no effect. A two-factor ANOVA on the resting MEP amplitude (Fig. 3B) showed a significant TIME · TBS interaction (F(2, 8) = 6.98, p = 0.018) that subsequent one-factor ANOVAs revealed was due to the fact that there was no effect of TIME after cTBSIH although this was
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Fig. 3. Effect of TBS on simple reaction time and electrophysiological measures in the paretic hand. (A) Mean simple reaction time (SRT) was significantly reduced immediately (T1 = 7 min) after iTBSSH (**); compared to cTBSIH SRTs were shorter only at T1 (*) whilst compared to Sham they were shorter throughout the testing period (*). (B) After iTBSSH the amplitude of rest MEPs (top) and active MEPs (bottom) evoked from the stroke hemisphere were significantly larger at T1 (**) but not after cTBSIH. The end of the period during which TBS was anticipated to have an effect on the outcome measures (based on previous experiments in normal individuals) has been marked on the x-axis ( // ). TBS, Theta Burst Stimulation; cTBSIH, continuous (inhibitory) pattern over the intact hemisphere; iTBSSH, intermittent (excitatory) pattern over the stroke hemisphere; *,**, significant <.05.
significant after iTBSSH (F(2, 8) = 6.5, p = 0.02). Post hoc t-tests indicated that MEPs were larger at 12 min (p = 0.029) but not at 7 min after iTBSSH. The facilitatory
effect of iTBSSH was also seen in the MEPs evoked during active contraction (Fig. 3B). A two-factor ANOVA showed a significant TIME · TBS interaction (F(2, 8) = 9.2,
Table 2 Motor thresholds at baseline RMT (monophasic stimulator) (% output)
iTBSSH cTBSIH
AMT (biphasic stimulator) (% output)
Stroke side
Intact side
Stroke side
Intact side
47.4 (12.8) 47 (11.4)
39.4 (12.7) 39.2 (12.1)
53.6 (11.1)a –
– 47.2 (11.4)
Values are means (standard deviation). RMT, resting motor threshold; AMT, active motor threshold; iTBSSH, excitatory TBS over the stroke hemisphere; cTBSIH, inhibitory TBS over the intact hemisphere. a Significantly higher compared to the healthy side (p = 0.021).
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Fig. 5. Effect of cTBSIH on the healthy hand. MEPs elicited in the healthy hands at 120% RMT were significantly reduced at T1 (**) and returned to baseline at T2. The end of the period during which TBS was anticipated to have an effect on the outcome measures (based on previous experiments in normal individuals) has been marked on the x-axis ( // ). TBS, Theta Burst Stimulation; cTBSIH, continuous (inhibitory) pattern over the intact hemisphere; RMT, resting motor threshold; **, significant <.05.
resting I/O curve (Fig. 4). The summary AUC data (Fig. 3C) show a significant TIME · TBS interaction (F(1, 4) = 20, p = 0.01); after iTBSSH, there was a significant increase in area (p = 0.014) whilst there was no change after cTBSIH. The lack of an effect of cTBSIH on MEPs from the SH was not due to a failure to suppress the IH, as resting MEPs evoked from the IH were smaller after cTBSIH (Fig. 5). A one-factor ANOVA showed a significant effect of TIME (F(2, 8) = 15.03, p = 0.002); post hoc t-tests revealed a significant decrease in amplitude at T1 (p = 0.028) but not at T2. 4. Discussion
Fig. 4. Effect of TBS on the Input–Output curves from the paretic hand. iTBSSH led to a significant increase in the area under the I/O curve from the paretic hand (C). There was a significant increase in the MEP amplitude elicited from the stroke hemisphere at 120% RMT (A). There were no significant effects after cTBSIH (B). TBS, Theta Burst Stimulation; cTBSIH, continuous (inhibitory) pattern over the intact hemisphere; iTBSSH, intermittent (excitatory) pattern over the stroke hemisphere; I/O curve, Input–Output curve; RMT, resting motor threshold; **, significant <.05.
p = 0.008) that was due to a significant effect of TIME after iTBSSH (one-factor ANOVA: F(2, 8) = 10.9, p = 0.005) but not after cTBSIH. Post hoc t-tests revealed that after iTBSSH MEPs were significantly bigger at T1 (p = 0.02) but not at T2. iTBSSH also increased the area under the
This study was designed to pilot the safety and efficacy of TBS in a small number of unselected chronic stroke patients. The lack of adverse events supports our hypothesis that TBS, which employs low stimulation intensities, is unlikely to be epileptogenic, at least when the lesion does not involve the whole MCA territory. Excitatory TBS over the stroke hemisphere (iTBSSH) transiently improved simple motor behaviour of the paretic hand in chronic stroke patients. In particular, iTBSSH shortened simple reaction time by an average of 10% in the first 20 min after the stimulation. This is a modest effect but within the range reported previously (Mansur et al., 2005; Takeuchi et al., 2005; Fregni et al., 2005; Hummel et al., 2005). Compared to the sham condition, the reaction time of the paretic hand remained significantly shorter when measured 30 min after the stimulation. To our knowledge, this is the first demonstration of a single session rTMS paradigm over the SH inducing a functional improvement that outlasts the period of stimulation. This effect was accompanied, as in normal individuals, by an enhancement of the corticospinal output of the SH. These preliminary results complement the previous reports using anodal (excitatory) TDCS over the SH (Fregni et al., 2005; Hummel et al., 2005) and support the use of stimulation of the SH in future longer term trials of the effectiveness of cortical stimulation in chronic stroke.
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Unlike previous reports in which other forms of inhibitory cortical stimulation to the IH have been shown to have beneficial effects (Mansur et al., 2005; Takeuchi et al., 2005; Fregni et al., 2005), inhibitory TBS (cTBSIH) did not influence performance in the paretic hand, although it successfully suppressed excitability on the IH. Although negative, this result is important since it warns against the general conclusion that suppression of the IH is equivalent to stimulation of the SH. As detailed below, we hypothesize that because cTBS employs low stimulation intensities, it may not be the most effective paradigm to induce transcallosally mediated effects. 4.1. Mechanism of the effects One obvious explanation for the improvement seen in simple reaction times after iTBSSH would be an increase of the corticospinal output of the affected side. This was directly demonstrated as an increase in MEP amplitudes and I/O curves. Di Lazzaro et al. have shown in normal subjects and in a single patient studied 6 years after the stroke that TBS changes the amplitude of corticospinal volleys evoked by single TMS pulses, suggesting that TBS directly influences cortical excitability (Di Lazzaro et al., 2005; Di Lazzaro et al., 2006). Indeed, given the very low stimulus intensity used in TBS, it is unlikely to change the function of peripheral muscle or the excitability of spinal motoneurones. This would explain why MEPs to standard single TMS pulse were increased even during voluntary contraction of the target muscle, when any changes in spinal excitability should be masked. The implication is that in these partially recovered patients, areas of the motor cortex were still capable of responding in a relatively normal way to iTBS. iTBS is thought to work by facilitating synaptic transmission within the available neuronal pool, thus increasing the number of neurons that are activated trans-synaptically by a single TMS pulse (Huang et al., 2005). Our data suggest that in stroke patients, the ability for potentiation may be preserved (a) when parts of the cortex are spared and (b) regardless of the time post-stroke. Unlike previous studies that have mainly included patients with subcortical lesions we demonstrated that the effects were similar in three patients with partial cortical involvement. In addition, the effects were comparable in one patient who was studied almost 9 years after the stroke. The effect of iTBSSH on behaviour lasted about twice as long as the effect on corticospinal excitability, which was present for 7–20 min after stimulation. It is possible that iTBSSH affected behaviour by facilitating motor learning during performance of the tests. In other words, iTBSSH may facilitate strengthening of relevant synapses if they are repeatedly used during subsequent testing. In this way, the behavioural benefit would outlast the initial increase in neural excitability.
Despite the improvement in SRT after iTBSSH, force output was not maintained. On the contrary, there was a gradual decrease in the force that patients exerted over the same period. Such demanding repetitive tasks are known to lead to progressive force loss, both in normal individuals (Liu et al., 2003) and in stroke patients (Riley and Bilodeau, 2002). The dissociated effect on speed and force is puzzling. It could be that the task prioritised speed over force. If we had trained subjects only to maximise force then this might have improved rather than speed. Another possibility is that maximal force output is insensitive to changes in cortical excitability, which may explain the absence of an effect of stimulation on strength in previous reports (Takeuchi et al., 2005). However, increasing voluntary strength is an important goal in physiotherapy and correlates with the ability to perform functional tasks of daily living (Teixeira-Salmela et al., 1999). It remains an important outcome to investigate when exploring the effectiveness of rTMS and TDCS paradigms. cTBSIH did not produce any behavioural effect on the paretic side. This cannot be due to a lack of inhibitory effects of cTBS on the IH, since the size of MEPs elicited from this hemisphere was reduced after cTBSIH. The absence of either improvement or deterioration could theoretically mean that in relatively recovered patients the IH has minimal if any involvement in the motor control of simple movements of the paretic hand (Gerloff et al., 2006; Talelli et al., 2006). However, this contrasts with previous reports that inhibitory (cathodal) TDCS (Fregni et al., 2005) or (low-frequency) rTMS (Mansur et al., 2005; Takeuchi et al., 2005) of the IH improves the motor behaviour in the paretic hand. We assume that the effect of cTBSIH on the corticospinal output was not reflected in the transcallosal output to the SH. This may relate to the fact that TBS employs a very low intensity, well below the threshold for evoking activity in transcallosal connections and explain why only higher intensity 1 Hz rTMS has been reported to be effective. TDCS probably works by polarising the membranes of cortical neurones, which secondarily changes their firing rates and leads to long term changes in synaptic function (Nitsche et al., 2003). The transcallosally projecting neurons lie in layer III of the cortex, very near to the TDCS electrode, and may be readily influenced by the polarising current. It should also be noted that in previous studies patients had purely subcortical lesions whilst we included patients with cortical involvement. Choice reaction time (CRT) of the paretic hand neither improved nor deteriorated in any of the conditions. To date, there is one report of improved CRT after inhibitory 1 Hz rTMS over the motor cortex of the IH, but no details of the paradigm used are provided (Mansur et al., 2005). By contrast, Lotze et al. showed that disruption of motor areas of both the stroke and intact hemisphere could affect patients’ performance in a complex sequential finger task (Lotze et al., 2006). It may well be that control of complex behaviours, such as choice reaction, is more distributed among cortical areas
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than a simple reaction task. In that case, stimulation of just one area in a single-session design may have limited effects on behaviour. Perhaps several sessions or longer periods of stimulation may be needed to induce reorganisation at multiple distant sites and maximise behavioural outcomes. 4.2. Implications for stroke rehabilitation The present study supports previous reports that in chronic stroke patients transcranial stimulation over the stroke side can induce temporary improvements in functional performance. iTBS appears to work as in healthy cortex by increasing excitability at the stimulated site. Since it uses low intensity stimuli and is quick to apply, it may prove to be a useful form of rTMS to test in larger trials after stroke. We are therefore currently investigating whether these transient benefits can be transformed into longer lasting, even permanent changes, with repeated treatments. Previous reports have provided some evidence that this might be achievable with other non-invasive (Uy et al., 2003; Khedr et al., 2005) or invasive stimulation techniques (Brown et al., 2006). It is likely that the chances of beneficial results with non-invasive stimulation are related to the safety and power of the chosen paradigm. Disclosure The authors have reported no conflicts of interest. References Bezard E, Boraud T, Nguyen JP, Velasco F, Keravel Y, Gross C. Cortical stimulation and epileptic seizure: a study of the potential risk in primates. Neurosurgery 1999;45:346–50. Boissy P, Bourbonnais D, Carlotti MM, Gravel D, Arsenault BA. Maximal grip force in chronic stroke subjects and its relationship to global upper extremity function. Clin Rehabil 1999;13:354–62. Brown JA, Lutsep HL, Weinand M, Cramer SC. Motor cortex stimulation for the enhancement of recovery from stroke: a prospective, multicenter safety study. Neurosurgery 2006;58:464–73. Capaday C. Neurophysiological methods for studies of the motor system in freely moving human subjects. J Neurosci Methods 1997;74:201–18. Collin C, Wade D. Assessing motor impairment after stroke: a pilot reliability study. J Neurol Neurosurg Psychiatry 1990;53:576–9. Di Lazzaro V, Pilato F, Saturno E, Oliviero A, Dileone M, Mazzone P, et al. Theta-burst repetitive transcranial magnetic stimulation suppresses specific excitatory circuits in the human motor cortex. J Physiol 2005;565:945–50. Di Lazzaro V, Dileone M, Profice C, Pilato F, Rothwell JC. Direct demonstration that repetitive transcranial magnetic stimulation can enhance corticospinal excitability in stroke. Stroke 2006;37:2850–3. Fregni F, Boggio PS, Mansur CG, Wagner T, Ferreira MJ, Lima MC, et al. Transcranial direct current stimulation of the unaffected hemisphere in stroke patients. Neuroreport 2005;16:1551–5. Fregni F, Boggio PS, Valle AC, Rocha RR, Duarte J, Ferreira MJ, et al. A sham-controlled trial of a 5-day course of repetitive transcranial magnetic stimulation of the unaffected hemisphere in stroke patients. Stroke 2006;37:2115–22. Gerloff C, Bushara K, Sailer A, Wassermann EM, Chen R, Matsuoka T, et al. Multimodal imaging of brain reorganization in motor areas of
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