Decreased cortical excitability of the lesioned hemisphere is a well-recognized neurophysiological consequence after stroke.1–3 Importantly, the level of excitability of the affected hemisphere correlates with motor function and predicts recovery.4–6 Accordingly, increasing the level of excitability of the lesioned hemisphere is thought to enhance stroke recovery.7 Noninvasive brain stimulation (NBS), including repetitive transcranial magnetic stimulation (rTMS) and transcranial direct current stimulation (tDCS), is an approach that has been shown to modulate corticomotor excitability. In general, high-frequency rTMS (>5 Hz) is excitatory, while low frequency (≤1 Hz) is inhibitory.8 Other rTMS parameters, such as intensity,9 the number of pulses,10,11 intertrain interval,12 and waveform of the pulses,13 also contribute to the magnitude of the effect. However, the frequency of the stimulation is the most critical parameter in determining the direction of the modulatory effects.8
In contrast to rTMS, the current delivered with tDCS represents a single polarity, and therefore pulse frequency is not a consideration. For tDCS, the polarity of the stimulation is the decisive factor in determining the direction of the effect. Anodal stimulation is excitatory, while cathodal stimulation is inhibitory.14,15 Both anodal stimulation of the lesioned primary motor cortex (M1) and cathodal stimulation of the nonlesioned M1 (the latter intended to restore the balance of interhemispheric excitability) have been shown to improve function of the hemiparetic upper extremity in persons with stroke.16
The mechanisms underlying effects of rTMS are different from those of tDCS. Transcranial magnetic stimulation uses a rapidly changing magnetic field to induce an electrical current in the brain. The stimulating current evokes action potentials in cortical axons, triggering the release of neurotransmitters.17 When applied in a repetitive manner, TMS is able to promote both short- and long-term neuroplasticity, defined as “the ability of the nervous system to respond to intrinsic or extrinsic stimuli by reorganizing its structure, function and connections.”18 The neurophysiologic mechanism underlying the effect of rTMS on neuroplasticity is only partly known. It is believed that rTMS induces modifications of membrane proteins, alterations of morphology, and modifications of synaptic transfer. Long-term plasticity induced by rTMS may result from long-term potentiation (LTP, enhanced signal transmission efficacy between neurons), or long-term depression (LTD, reduction in synaptic transmission efficacy) at the synaptic level.19
Unlike TMS, tDCS does not evoke action potentials in the underlying cortical axons. Rather, tDCS delivers a weak direct current (1–2 mA) via electrodes placed on the scalp. The cortical neurons under the electrodes are hyperpolarized or depolarized by a portion of the applied current that crosses the skull and intervening tissue. These neurons then become more or less likely to fire because of the alteration of membrane potentials. The neuroplasticity induced by tDCS is also thought to be similar to LTP or LTD.16 It is believed that anodal tDCS facilitates synaptic efficacy that is similar to LTP while cathodal tDCS reduces synaptic efficacy.
Beyond the differences in mechanisms underlying rTMS and tDCS, rTMS is known to have finer spatial resolution than tDCS. Since rTMS provides more focused and localized stimulation, this approach may represent the more precise tool to modulate corticospinal excitability. However, the potential risk of triggering seizures and the cost of the equipment are limitations to the commonplace clinical use of rTMS.17 While high-frequency rTMS can be associated with increased seizure potential, studies have defined the safe parameters within which seizure risk can be minimized.8 Conversely, tDCS is relatively safe with the most serious risk being burn and skin irritation.20 In addition, the lower cost and portability of tDCS units make this approach more feasible for clinical use. However, the efficacy of tDCS for modulating corticomotor excitability is less well-established than rTMS.17 A meta-analysis on anodal tDCS revealed that the evidence for the efficacy of tDCS to increase corticospinal excitability in persons with stroke was limited.21
As part of the evaluation of the clinical efficacy of either rTMS or tDCS for improving motor task performance, 2 important neurophysiological questions should be addressed. First, in persons with stroke, when do the changes associated with each of the NBS techniques occur and what is the duration of these changes? Second, are there differences in the time course of changes in excitability associated with these 2 approaches? Previous studies have shown that both high-frequency rTMS and anodal tDCS are able to increase corticospinal excitability in healthy humans from 40% to 100% and the effects last 40 to 60 minutes after the cessation of stimulation.12,22–24 The aftereffects of the NBS techniques are less well-studied in individuals with stroke. A recent meta-analysis reported that anodal tDCS had favorable effects on motor evoked potentials (MEPs) in participants with chronic stroke based on 2 included studies.21 However, the 2 included studies consisted of a small number of participants (N = 6 for both).25,26 Another meta-analysis on the effects of rTMS revealed that there were no significant changes in neurophysiologic measurements based on the results of 3 included rTMS studies.27 Furthermore, most of the previous studies assessed the effects of NBS before, during, and immediately after the application of stimulation.26,28,29 Only a few studies have investigated the lasting effects on corticospinal excitability.25,30 Therefore, an examination of the effects of NBS on corticospinal excitability, in terms of magnitude and duration, is needed. Consequently, the purpose of this pilot study was to examine the persistence of aftereffects associated with a single session of high-frequency rTMS (5 Hz) and anodal tDCS on corticospinal excitability in participants with chronic stroke.
A sample of convenience that consisted of 10 participants with stroke was recruited (9 males and 1 female). Demographic data of the sample are summarized in Table 1. The inclusion criterion of the study were age between 18 and 90 years, more than 6 months poststroke, first-time stroke, and ability to perform a lateral pinch with the affected hand. Potential participants were excluded if they had any of the following conditions: severe medical conditions other than stroke, coexistence of other neurological or psychiatric conditions, any substantial decrease in alertness, deficits in language reception or attention that might interfere with instruction comprehension, and excessive pain in the affected upper limb. Participants were also excluded if they did not meet the TMS safety criterion, such as history of seizure or metal implants in the head.8 Level of motor impairment was quantified using the Fugl-Meyer upper extremity motor score.31
The study was conducted at University of Malaya Medical Center. Each participant visited the medical center twice, and each visit consisted of either a high-frequency rTMS or an anodal tDCS session. The order of each session was randomly counterbalanced among participants. The 2 visits were scheduled at least 1 week apart to allow a washout of any potential carry-over effects from the previous session. A 1-week interval was selected as an appropriate washout duration for NBS effect based on previous studies with a within-subject design.32,33 The institutional review board of University of Malaya Medical Center approved the experimental protocol and informed consent form. We obtained written informed consent from each participant at the beginning of the first visit.
The flow of the experimental procedure for each visit is illustrated in Figure 1. First, participants were screened with a TMS safety questionnaire to ensure their eligibility to participate in the TMS protocol. We then measured each participant's performance on Mini Mental Status Examination,34 Wechsler Digital Span memory test,35 Trail Making Test,36 visual-manual reaction time, and key pinch force. All tests were performed while participants were seated. These measurements were repeated again in the same order after the application of brain stimulation (see later). These behavioral tests assess both cognitive and motor domains of human behavior and were used in previous studies that examined the effects of NBS applied to M1.15,27,37,38
We then used single pulse TMS (Rapid2, Magstim, UK) to determine corticospinal excitability of the affected hemisphere, as indicated by the amplitude of the MEPs. The first dorsal interosseous (FDI) of the affected hand was the muscle selected for testing; 2 Ag/AgCl disposable surface electrodes (2 × 2.5 cm) were placed over the region of the FDI muscle belly and associated tendon, and a ground electrode was placed on the back of the hand. Surface electromyographic (EMG) signals were sampled at 4 kHz and band pass filtered at 2 to 10 kHz. The EMG data were graphically displayed during data collection and stored for off-line analysis. We first determined the hotspot of the FDI muscle on the scalp using single pulse TMS. The hotspot was defined as the optimal stimulation site that produced the most consistent and largest MEPs at a given level of TMS output. We then measured MEPs at the hotspot with an intensity of 120% of resting motor threshold (RMT). Resting motor threshold was defined as the lowest stimulus intensity that could evoke a MEP with peak-to-peak amplitude greater than 50 μV in 5 out of 10 consecutive trials with the participant at rest. We could not determine RMT in 3 out of 10 participants. For these participants, active motor threshold (AMT) was used and MEPs were measured at 120% of AMT. Conventionally, AMT is determined when the subject exerts a force of 5% to 10% of maximum voluntary contraction.33 We attempted to control the level of force exertion during active contraction (10% of voluntary contraction); however, it was challenging for these participants to maintain a stable level of force exertion or to produce a reliable maximum voluntary contraction. Therefore, maximal effort was used during determination of AMT. Motor evoked potential measurements for these 3 participants were under active contraction conditions throughout the experiment and the same instruction “push as hard as you can” was given during all sessions.
We repeated MEP measurements at 5 different time points: before (baseline), immediately after, 15 minutes after, 30 minutes after, and 60 minutes after the brain stimulation procedure (see later). Each block of MEP measurements consisted of 10 trials and the intertrial interval was approximately 5 seconds. Between blocks of MEP measurement, selected behavioral tests were repeated (Figure 1). The poststimulation behavioral tests were performed in the same order as at baseline (before brain stimulation). The order was also the same across the 2 visits and across participants. To ensure that the MEP measurement was reproducible across testing blocks and visits, several control procedures were implemented. First, we marked EMG electrode location on the skin with a waterproof marker pen to ensure that electrodes could be placed at the same location across tests. Second, we standardized participant position during all visits and all testing sessions as follows: participants were seated on a standard chair with their backs resting against the back of the chair. The test hand was placed on the armrest of the chair with the shoulder in approximately 0° degree of flexion and abduction, elbow in approximately 90° of flexion, and the forearm in pronated position. The same chair was used across visits. Finally, location of the hotspot for each participant was marked on the scalp directly using a waterproof marker. We positioned the TMS coil on the same spot across the testing blocks. During MEP testing, the coil was held at an angle of 45° away from the mid-sagittal line with the handle pointing backward. Location of the hotspot was determined at the beginning of each visit.
After the baseline MEP measurement, each participant went through 1 of the 2 randomly ordered brain stimulation procedures: 5-Hz rTMS or anodal tDCS. For the 5-Hz rTMS procedure, a figure-of-8 air-filled coil (Rapid2) was placed at the hotspot of the FDI muscle over the affected hemisphere. Five-hertz rTMS was delivered in the form of 24 10-second trains with a 30-second intertrain interval between trains (a total of 1200 pulses) (Rapid2). The intensity of stimulation was set at 90% of individual MT (resting or active). For the anodal tDCS procedure, a 1 mA direct current was applied for 20 minutes (BrainSTIM Transcranial Stimulator, EMS, Italy) via a 5×5-cm anodal electrode positioned over the hotspot of the FDI muscle of the affected hemisphere. The cathodal electrode (5 × 5 cm) was placed at the contralateral supraorbital region. While there is currently no consensus on the appropriate dose for NBS application,21,39,40 we chose these parameters based on previous studies that have shown positive effects of the adopted protocols in persons with stroke.25,41 Participants were followed up via phone calls after each visit to monitor any adverse events or side effects.
We used a Mann-Whitney U Test to compare the demographic and baseline data of participants from whom we could not obtain RMTs with data of participants from whom we could obtain RMTs. Peak-to-peak amplitudes of MEPs were averaged across all 10 trials at each time point and normalized to the baseline MEP (before stimulation). Averaged MEPs obtained at each test time for each visit were analyzed with a repeated-measures ANOVA in which type of stimulation (2 levels) and time (5 levels) were the factors of interest. Behavioral data were analyzed using a repeated-measures ANOVA with type of stimulation (2 levels) and time (2 levels) as the within-subject factors. Significance level for all tests was set at 0.05.
All participants tolerated both protocols well with no serious adverse effects reported. One participant reported fatigue after the rTMS session but the symptom diminished after a few hours.
Resting Versus Active MT Subgroup
We first compared the baseline characteristics of the 3 participants from whom RMT could not be elicited from the ipsilesional M1 with those of the rest of the participants. Participants who were tested using AMT instead of RMT tended to have lower Fugl-Meyer upper extremity motor scores (mean ± SD = 33.5 ± 2.1 vs 51.3 ± 11.9, respectively) but the difference failed to reach significance (P = 0.06). Other baseline data, including age, months poststroke, and prestimulation MEP amplitudes, were similar between the 2 subgroups.
Changes in Corticospinal Excitability
We first performed a subgroup analysis, using a repeated-measures ANOVA with type of stimulation and time as the within-subject factors and stimulus condition (RMT vs AMT) as the between-subject factor. The 2 subgroups responded similarly to the NBS as confirmed by a nonsignificant Condition effect (P = 0.46), Condition × Type × Time interaction (P = 0.07), Condition × Type interaction (P = 0.14), and Condition × Time interaction (P = 0.23). We, therefore, combined the 2 conditions (RMT and AMT) for further analysis.
The evolution of MEPs after each type of stimulation relative to the baseline MEP (prestimulation) is illustrated in Figure 2. Repeated-measures ANOVA with type of stimulation and time as the within-subject factors showed that both 5-Hz rTMS and anodal tDCS led to a significant increase in MEPs (F4,36 = 5.53, P = 0.02). There was no significant Type × Time interaction (F4,36 = 0.76, P = 0.46) or main effect of Type (F1,9 = 1.08, P = 0.33), suggesting that the effect of each stimulation protocol was similar to the other. Post hoc comparison showed that MEPs increased from T0 (baseline) to T3 (30 minutes post) (P = 0.03), and from T0 to T4 (60 minutes post) (P = 0.01). The increases from T2 (15 minutes post) to T4 (60 minutes post), and T3 (30 minutes post) to T4 (60 minutes post) were also significant (P = 0.01 and 0.02, respectively). The increase from T0 (baseline) to T1 (immediately post) tended to be significant (P = 0.07). Individual MEP amplitudes before and after rTMS (Figure 3A) and tDCS (Figure 3B) are illustrated in Figure 3. There was substantial variability of MEP amplitudes among participants both before and after stimulation.
Changes in Behaviors
No behavioral measure showed a statistically significant change after stimulation. We did not observe any reliable improvements or deteriorations in any behaviors after either type of stimulation.
In this pilot study, we compared the aftereffects of 5-Hz rTMS and anodal tDCS. We found that in participants with chronic stroke, both 5-Hz rTMS and anodal tDCS were effective in enhancing corticospinal excitability of the affected M1. The facilitative effects lasted up to 60 minutes poststimulation. Our single session brain stimulation intervention was safe as no changes in cognitive behavior were observed. Our study provides confirmatory data for previously reported findings on the facilitative effect of NBS in participants with chronic stroke. These data represent novel results related to the time course of NBS effects in persons with stroke, specifically the delayed emergence of the facilitative effects of NBS. These findings also demonstrate that the effects of 5-Hz rTMS and anodal tDCS are similar, and there are no changes in motor performance associated with these forms of NBS when stimulation is not accompanied by motor practice.
We found that 5-Hz rTMS at 90% of motor threshold led to a 2-fold increase in MEPs. Our results were similar to previous studies.25,29 Compared with the protocol used by Kim et al,29 who used 80% RMT for 160 pulses, our rTMS protocol was higher in dose (90% RMT for 1200 pulses). However, in the Kim et al29 study, participants engaged in a motor task practice between rTMS trains that might have boosted the excitability effect. Evidence has shown that voluntary motor activity influences cortical plasticity induced by NBS.42 In addition, the higher frequency used by Kim et al29 may have also contributed to the more efficient enhancement observed in their study. As was the case for rTMS, anodal tDCS was also associated with increased cortical excitability, with an increase in MEP amplitude of approximately 1.6 times compared with baseline. Previous studies also reported a nearly 2-fold increase in MEPs after 20 minutes of 1 mA anodal tDCS over the affected M1.25,30 Our data and previous studies confirm that high-frequency rTMS and anodal tDCS have efficacy as tools to upregulate primary motor cortex excitability of the affected hemisphere in individuals with chronic stroke.
On average, MEP amplitudes increased by 100% after rTMS and 60% after tDCS; however, we found no significant differences between 5-Hz rTMS and anodal tDCS in effect on MEP amplitudes. However, we did observe a trend for 5-Hz rTMS to be associated with larger increases in MEPs than the anodal tDCS (medium Cohen's effect size f = 0.34).43 The lack of a significant difference between the stimulation conditions may have been due to high between-subject variability (see Figure 3) or small sample size. A recent report by Simis et al32 compared 10-Hz rTMS versus anodal tDCS in young healthy adults. The authors found that 10-Hz rTMS resulted in higher MEP amplitudes than anodal tDCS. The post hoc analysis revealed that 10-Hz rTMS led to an increase in MEP amplitudes while anodal tDCS led to a decrease. The authors attributed the decrease in MEP amplitudes after anodal tDCS to homeostatic effects.32 We did not find a decrease in MEP amplitudes after 20 minutes of anodal tDCS. The differences in tested population and methodology may have contributed to the discrepancy between the study and that of Simis et al.32 Lesioned brains are known to have a lower excitation level than that of nonlesioned brains.2,4,7 It has been well established that the prestimulation excitation state of the cortex modulated the effects of NBS.24,44,45 Therefore, it is reasonable to observe different responses to NBS between participants poststroke and healthy individuals. Further studies are warranted to determine the optimal parameters for NBS in both populations.
Time and Duration Effects
Both 5-Hz rTMS and anodal tDCS were able to enhance corticospinal excitability that lasted 60 minutes poststimulation. Our findings were consistent with previous studies,10,30,46 in which a facilitative effect was reported to last up to 40 to 90 minutes. The long-lasting effect of these NBS techniques is critical for stroke rehabilitation. These techniques are suggested to be administered prior to physical practice37 and most rehabilitation sessions are about 45 to 60 minutes in duration.47 However, recent evidence has suggested that tDCS may be most beneficial when applied concurrently with physical practice.48 Regardless of the timing, in order for these techniques to maximally enhance the benefits of physical practice, their effects need to be relatively long-lasting.
Notably, we found no significant increases in MEPs from baseline (T0) to immediately after stimulation (T1) (P = 0.07) or from baseline (T0) to 15 minutes after (T2) (P = 0.09), suggesting that our stimulation protocols had a delayed effect on corticospinal excitability. The small sample size may be the primary reason for the nonsignificant immediate effect. However, participants' characteristics (lesion location and severity) may also play a role in modulating the response to NBS. Lesion location (cortical vs subcortical) has been shown to be crucial in determining the effects of NBS.49 Suzuki et al30 found a significant increase in MEP amplitudes at 0 minute and 10 minutes after anodal tDCS application in a group of patients with subcortical lesions. The participants in the Suzuki et al30 study were also relatively high functioning with the capability to perform independent finger movements with the affected hand. Hummel et al25 also showed that a single session of anodal tDCS improved hand function and increased cortical excitability measured immediately after stimulation. All participants in that study had subcortical lesions and relatively high motor function (averaged Fugl-Meyer upper extremity motor score = 62.7).25 In contrast, the participants recruited in our study consisted of 2 participants with cortical lesions and our sample had relatively more severe motor impairment (averaged Fugl-Meyer upper extremity motor score = 50.2). In addition to participants' characteristics, our selection of neurophysiologic outcome (MEP amplitudes) may not be sensitive enough to capture the immediate effect. Hosomi et al50 demonstrated that only intracortical facilitation showed a significant change after a single session of 5-Hz rTMS applied to the ipsilesional M1 whereas other outcomes (RMT, MEP amplitude, cortical silent period, short interval cortical inhibition) remained the same.
Nevertheless, our participants showed a significant increase from baseline to the later time points (30 and 60 minutes after). We assessed participants' behaviors between MEP testing blocks (see Figure 1); therefore, it might be that the additional physical movements between blocks contributed to this delayed increase in MEP amplitudes. Our design did not allow us to differentiate whether the delayed effect was a result of additional physical movements42 or if it reflected a unique response to NBS in persons with chronic stroke compared with healthy adults who usually showed a greater response immediately after NBS application.51,52 Therefore, we recommend future studies to control for lesion location and stroke severity, to incorporate more neurophysiologic outcomes, and to standardize participants' activity between testing blocks such that the time and duration effects of NBS in stroke may be further elucidated. Information about the time and duration effects of NBS on corticospinal excitability is important to allow clinicians to structure physical or occupational therapy sessions to best take advantage of NBS as an adjunct to rehabilitation.
We found little to no changes in behaviors after either type of stimulation. We did not expect to observe significant improvements in the motor behavior with our single session intervention. Previous studies that showed improved motor behaviors after a single session of NBS often incorporated physical task training29,53,54 or included high-functioning participants.55 Our findings suggest that a single session of NBS without physical task practice may not be sufficient to induce behavioral changes in the selected outcomes included in this study for participants with moderate motor impairment. This result further confirms the complementary role of NBS and physical training in stroke rehabilitation. These techniques should be considered as a complementary treatment to conventional behavioral therapy rather than as a stand-alone treatment. Nevertheless, our results suggest that the stimulation protocols used in this study were well-tolerated and caused no detrimental effects on cognition or motor functions.
There are a few limitations in this study. First, we recruited a small group of participants with chronic stroke. Their responses and experiences with the NBS procedure may not be representative of the larger population. Our small sample size might have contributed to the nonstatistical difference in the changes of MEPs between rTMS and tDCS and between baseline and immediately after stimulation. We did not include a sham stimulation condition or blinding of the assessors because of limited resources. These procedures could have reduced potential bias and are recommended for future studies. The participants whose MTs and MEPs were determined under active contraction conditions could not maintain a stable level of force exertion. We measured their MEPs under maximal effort conditions instead of 5% to 10% of maximum voluntary contraction. This might have resulted in high variability in the MEP data. The use of maximal effort may have also resulted in fatigue that could have further increased variability. Our single session intervention did not lead to significant changes in motor behavior. This study was not designed to compare the clinical effectiveness of the 2 NBS techniques on behavioral outcomes. Future studies may incorporate longer treatment duration (multiple sessions) in conjunction with physical training to induce modifications in behaviors to comprehensively assess the effectiveness of the 2 techniques. The order of testing of the outcome measures was the same throughout the study, while this was a standardized approach, we cannot rule out the possibility that tests performed early in the testing session influenced outcomes of the tests performed later in the testing session.
In conclusion, we compared 2 safe and effective NBS techniques to enhance corticospinal excitability of ipsilesional primary motor cortex in individuals with chronic stroke. Both 5-Hz rTMS and anodal tDCS were equally effective and resulted in effects that lasted up to 60 minutes poststimulation. These results may provide valuable information for future studies investigating NBS application in stroke rehabilitation. Future studies would be of value to compare rTMS versus tDCS when each is combined with motor practice.
The authors thank Dr Jill C. Stewart for her constructive comments on the manuscript. This research was supported by University of Malaya Small Research Fund (UM BKP 001-2012A) awarded to Hui-Ting Goh.
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lasting effect; neuromodulation; stroke recovery; transcranial direct current stimulation; transcranial magnetic stimulation
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