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Department of Neuromodulation and Neurosurgery, Osaka University Graduate School of Medicine, Osaka, JapanDepartment of Rehabilitation Medicine, Nishinomiya Kyoritsu Neurosurgical Hospital, Nishinomiya, Hyogo, Japan
We conducted a randomized, double-blind, sham-controlled study to assess the efficacy in motor recovery and safety of daily repetitive transcranial magnetic stimulation (rTMS) in subacute stroke patients.
Forty-one patients were randomly assigned to a real or sham stimulation group. Each patient underwent regular rehabilitation accompanied by a series of 10 daily 5-Hz rTMS of the ipsilesional primary motor cortex (M1) or sham stimulation. The primary outcome was motor recovery evaluated by the Brunnstrom stages (BS). The secondary outcomes were improvement in the Fugl-Meyer Assessment (FMA), grip power, National Institutes of Health Stroke Scale (NIHSS), Functional Independence Measure (FIM), a quantitative measurement of finger tapping movement, and the incidence of adverse events.
Thirty-nine patients completed the study and were included in the analyses. The real rTMS group demonstrated additional improvement in the BS hand score at the last follow-up compared to the sham. The grip power, the NIHSS motor score, and the number of finger taps in the affected hand improved in the real stimulation group but not in the sham group. The BS upper limb scores, the FMA distal upper limb score, the NIHSS total score, and the FIM motor score showed improvement from baseline at the earlier time points after the real rTMS. There were no additional improvements in the other scores after the real rTMS compared to the sham. No serious adverse events were observed.
Our results suggest that dailyhigh-frequency rTMS of the ipsilesional M1 is tolerable and modestly facilitates motor recovery in the paralytic hand of subacute stroke patients.
Poststroke motor disturbance not only reduces the quality of life and activities of daily living of patients but also has a great social impact through lost productivity. With this in mind, efforts have been made to improve the functional outcomes of poststroke patients undergoing rehabilitation. One such approach is repetitive transcranial magnetic stimulation (rTMS), with the purpose of facilitating poststroke recovery of motor function. Two common approaches have been advocated. One of these is low-frequency rTMS (1 Hz or less) to the contralesional primary motor cortex (M1) area to decrease excessive excitability and thus decrease excessive interhemispheric inhibition to the ipsilesional side. The other approach involves high-frequency rTMS (greater than 1 Hz), or excitatory stimulation, to facilitate the decreased cortical excitability on the stroke-affected side.
we postulated that rather than rTMS at the chronic stage, the add-on effects of rTMS may be greater when it is applied at an earlier stage. To study the add-on effects of rTMS on ischemic and hemorrhagic subacute stroke patients, we undertook a randomized, double-blind, parallel study to test the hypothesis that 10 sessions of daily rTMS, combined with regular rehabilitation, improve the results of recovery of motor function in subacute stroke patients.
This was a randomized, double-blind, sham-controlled, parallel study conducted at 3 centers (a university hospital and 2 rehabilitation hospitals) in Japan from September, 2010, to December, 2012. We enrolled patients with the following conditions: (1) 20 years old and over, (2) motor disturbances in the upper limb caused by ischemic or hemorrhagic stroke (Brunnstrom stages [BS]
arm ≤ 5 or BS hand ≤ 5), and (3) within 8 weeks of stroke onset. The following conditions excluded patients from participating in the present study: (1) total paralysis of the upper limb (BS arm = 1 and BS hand = 1); (2) contraindications to transcranial magnetic stimulation, such as the implantation of a cardiac pacemaker; (3) previous rTMS; (4) aphasia, dementia, psychological disorders, or suicidal wishes; (5) a history of epilepsy; and (6) pregnancy.
This randomized controlled study was conducted in accordance with the Declaration of Helsinki and Japanese ethical guidelines for clinical studies. The study protocol was thoroughly reviewed and approved by the institutional review boards and the ethics committees of all the participating institutions (approval number, 09278-2). The protocol was finalized on September 1, 2010, and this clinical trial was registered with the Japanese University Hospital Medical Information Network Clinical Trials Registry, number UMIN000007594. All patients provided written informed consent and approval before enrollment.
The participants were recruited from 2 hospitals specializing in rehabilitation, where they received daily rehabilitation. Randomization was performed using a computer-generated permuted-block method by a third-party statistician upon confirmation of patient eligibility, prior to the start of the study. Patients were randomly assigned to 1 of 2 treatment groups (real rTMS plus regular rehabilitation therapy versus sham stimulation plus regular rehabilitation therapy) according to age (<65 and ≥ 65 years old), severity of symptoms (BS hand score ≤ 3 [severe] and ≥ 4 [mild]), and institution. The patients were identified by sequential numbers assigned at randomization. An assignment notice was sent only to investigators who conducted the rTMS intervention. The patients and assessors were blinded to group assignment until the study was completed.
Stimulation sessions were undertaken daily for 10 consecutive days except for weekends, after which follow-up evaluations were undertaken over the next 2 weeks at each rehabilitation hospital. In principle, the stimulation began on a Monday (day 1) and finished on the Friday of the following week (day 12), with follow-ups until the Monday of the fourth week (day 29). Standard rehabilitation was undertaken on a daily basis, including weekends and public holidays, during and after the study period. Physical therapy and occupational therapy were provided, with speech therapy also undertaken by patients who required it. Therapies started in most cases within 1 hour of the completion of rTMS sessions. Daily rehabilitation consisted of 8 therapy sessions each lasting for 20 minutes. Of these sessions, occupational therapy made up 3 sessions per day, including gross motor training in the proximal upper extremity, motor training of hand dexterity, training of coordinated movement with both hands, and practices for activities of daily living.
The evaluations were performed by assessors who were blinded to the group assignment. Figure 1 shows the time schedule of the evaluations. All evaluations except for the finger tapping measurement were undertaken prior to rehabilitation sessions at baseline, and on days 5 (Assessment 1), 12 (Assessment 2), and 29 (Assessment 3). They included BS arm, BS hand, BS lower limb,
Three days prior to the start of stimulations, objective estimations of finger tapping movements were obtained using a system with magnetic sensors (UB-1; Finger Tapping Movement Analyzer; Hitachi Corporation, Tokyo, Japan) that continuously monitored the distance between 2 coils via a calibration method.
Using this system, we quantitatively measured the total distance traveled, the mean maximum amplitude, the mean maximum opening velocity, the mean maximum closing velocity, an estimate of total consumed energy (sum of squares of velocity), and the number of finger taps during 30 seconds with respect to the movement of the index finger and the thumb of both hands.
The same tests were undertaken after the full completion of the individual's stimulation series (days 15-17).
Prior to the stimulation period, the location of the M1 hand knob in the affected hemisphere was located using a transcranial magnetic stimulation navigation system (Brainsight; Rogue Research Inc., Montreal, Quebec, Canada). This location was then marked on the scalp and measured so that the same location could be rapidly determined without a navigation system. The rTMS was applied using a figure-8 coil (MC B-70; Medtronic Functional Diagnostics A/S, Skovlunde, Denmark; or no. 9925-00; Magstim Co Ltd, Whitland, United Kingdom) connected to a magnetic stimulator (MagPro, Medtronic Functional Diagnostics A/S; or Magstim Rapid, Magstim), which provided repetitive biphasic pulses. The patients were positioned in the supine position, and their heads were fixed. The predetermined target was located from the previously made marking, and fine adjustments in the coil location were made to confirm the optimal spot according to visual detection of muscle twitches if muscle twitches were observed. The resting motor threshold was defined as the minimal intensity necessary to induce at least 1 visible muscle twitch in the affected hand on a session by session basis, which corresponds to that determined using an electromyogram,
and the intensity of real rTMS was set to 90% of the resting motor threshold for that day. In patients without muscle twitches, the intensity of the real rTMS was set to 100 A/µs for the MagPro or maximum output for the Magstim Rapid, which is approximately equivalent to the stimulus intensity. Five hundred pulses per session were delivered to the M1 hand in the affected hemisphere (10 trains of 5 Hz for 10 seconds with a 50-second intertrain interval). Sham stimulations were applied with the same parameters as real stimulations, but the coil was placed at a 90° angle to the scalp.
The finger tapping measurement and the localization of the M1 hand knob were undertaken at Osaka University Hospital. Other evaluations, daily rTMS, and rehabilitation were undertaken at the 2 rehabilitation hospitals.
The primary end point was the BS. The secondary end points were the FMA score, handgrip strength score, NIHSS score, FIM score, the finger tapping measurement, and the incidence of adverse events. A target number of 20 real and 20 sham subjects were decided upon based on a previous rTMS study,
from which we expected BS improvements of 1.3 in a real stimulation group and of .35 in a sham stimulation group with the same standard deviation of 1.0. We calculated this sample size with a power of 80% at an α level of .05 to detect the effect of rTMS, allowing for a drop-out rate of 5%. The projected study period was 2 years, and no interim analysis was planned. Differences in baseline patient characteristics and scores between the 2 assigned groups were assessed with a 2-sample t-test for continuous data, Mann–Whitney's U-test for ordinal data (BS, FMA, NIHSS, and FIM scores), and Fisher's exact test for nominal data. Regarding analyses of rTMS efficacy, first, the improvement over time with respect to baseline scores was evaluated in each group using a paired t-test for the finger tapping measurement, a repeated measures analysis of variance (within-subject factor, day [baseline, days 5, 12, and 29]) for handgrip, and Friedman test for the other evaluations with ordinal scales (BS, FMA, NIHSS, and FIM). Second, in the improved scores except for the finger tapping measurement, we used the Dunnett multiple comparisons or Wilcoxon signed rank tests with the Bonferroni correction as post hoc analyses to evaluate improvement from the baseline score at each time point after stimulation. Third, differences in the improvement at the last evaluation time point between the 2 groups were evaluated by a 2-sample t-test for the finger tapping measurement and handgrip and Mann–Whitney's U-tests for the other evaluations. For all comparisons, findings with P values less than .05 were considered statistically significant. Data were analyzed with the JMP Pro 11.2.1 software (SAS Institute Inc., Cary, NC), and the Statistics Toolbox implemented in MATLAB 8.3.0 (MathWorks Inc., Natick, MA).
Figure 2 shows the trial profile. Forty-one patients were enrolled in the present study. Twenty patients were assigned to the real stimulation group and 21 to the sham stimulation group. Two subjects in the real stimulation group failed to complete the study. One patient did not like the stimulation sensation on the scalp after one 10-second train of stimulations on the first day of stimulations, and declined following stimulations. The other patient also temporarily refused other forms of treatment such as regular rehabilitation during the first week of the stimulation. Thirty nine patients were finally included in the analysis after the removal of these 2 patients because evaluations could not be performed at all after the beginning of interventions. Table 1 shows the baseline patient characteristics of the 39 patients analyzed. The mean age of the participants was 62.9 ± 13.8 years old, and the mean postonset duration at the start of the intervention was 45.5 ± 9.0 days (range, 25-56 days). One patient with partial damage of the M1 hand area was included in each group. There were no differences in the baseline characteristics, scores, and lesion size between the real and sham stimulation groups, except for the FIM cognitive score.
The BS of all regions (arm, hand, and lower limb) improved significantly over time with respect to baseline scores for both real and sham stimulation groups (Table 2). Figure 3 indicates changes over baseline scores in the BS. The multiple comparisons showed that the real stimulation group achieved earlier improvement from baseline in the BS arm and hand scores when compared to the sham stimulation group. The BS arm score was significantly improved at day 29 in the real stimulation group but not in the sham stimulation group. The BS hand score was significantly improved at days 12 and 29 in the real stimulation group but only at day 29 in the sham stimulation group. The BS lower limb score did not show a significant improvement at any of the time points after stimulation (Table 3). Improvement over baseline scores in the BS hand score at day 29 was significantly greater in the real stimulation group than in the sham stimulation group (P = .037). Although improvement in the BS arm score tended to be greater in the real stimulation group, the difference between the real and sham groups was not significant for the arm and lower limb scores (P = .294 and P = .747, respectively).
Significant improvement over time with respect to baseline.
Abbreviations: FIM, Functional Independence Measure; IQR, interquartile range; NIHSS, National Institutes of Health Stroke Scale; SD, standard deviation.
Data are expressed as medians [IQR] or means (SD). Both medians and means are indicated for each score of the Brunnstrom stages. Improvement over time with respect to a baseline score was statistically evaluated and each P value is shown.
* Significant improvement over time with respect to baseline.
Improvements in the FMA, Handgrip Strength, NIHSS, and FIM Scores
The FMA total score, FMA proximal upper limb score, FMA distal upper limb score, NIHSS total score, and FIM subscores improved significantly over time with respect to baseline scores for both real and sham stimulation groups. Handgrip strength scores for the nonaffected hand did not significantly improve over time for the real or for the sham stimulation group. Meanwhile, in the affected hand, only the real stimulation group showed an improvement in handgrip strength score. The NIHSS motor arm score significantly improved only in the real stimulation group but not in the sham stimulation group (Table 2). The multiple comparisons showed that the real stimulation group achieved earlier improvement from baseline in the FMA distal upper limb score, NIHSS total score, and FIM motor score when compared to the sham stimulation group. The FMA distal score significantly improved at days 12 and 29 in the real stimulation group but only at day 29 in the sham stimulation group. The NIHSS total score was significantly improved at all time points in the real stimulation group but not in the sham stimul ation group (Table 3). There were no significant differences between the real and sham stimulation groups in improvements in any of the secondary end points over baseline scores at day 29.
Finger Tapping Motion
There was a significant increase in the number of taps made in the real stimulation group (P = .006), whereas no significance was observed in the sham stimulation group (P = .092). The change from the baseline was not significantly different between the 2 groups (P = .068). No significant improvement was seen in the total distance traveled, mean maximum amplitude, mean maximum opening velocity, mean maximum closing velocity, or the estimate of total consumed energy (Table 4).
There were no serious adverse effects observed during or after the stimulations during the 2-week follow up period after completion of stimulations. As was previously mentioned, 1 subject withdrew from the protocol due to uncomfortableness. Incidentally, he later apparently demanded continuation of stimulations, after which he reportedly found the same stimulation pattern relaxing and enjoyable.
This double-blind randomized controlled study of daily rTMS targeting the M1 hand area demonstrated a facilitation effect on motor recovery in the paralytic hand of subacute ischemic and hemorrhagic stroke patients without any serious adverse events. The real stimulation provided better improvement in the BS hand score at the last follow-up compared to the sham. The handgrip strength score, the NIHSS motor arm score, and the number of taps significantly improved only after the real stimulation. The real stimulation showed earlier improvement in the BS arm score, BS hand score, FMA distal upper limb score, NIHSS total score, and FIM motor score. However, it did not show an effect on motor recovery in the paralytic leg, or scores for activities of daily living.
The effect of rTMS on poststroke motor recovery has been studied in around a dozen articles, in which high-frequency rTMS on the ipsilesional M1
was applied according to the interhemispheric balance hypothesis. A recent meta-analysis reported that rTMS had a positive effect on motor recovery in patients with stroke, especially for those with subcortical stroke.
A recent evidence-based guideline issued by a group of European experts stated there may be a possible effect of low-frequency rTMS on the contralesional M1 in acute motor stroke (recommendation level C) and a probable effect in chronic motor stroke (level B), while there may be a possible effect from high-frequency rTMS on the ipsilesional M1 in acute and chronic motor stroke (level C).
In our study, additional improvements in motor function were demonstrated in a double-blind, randomized manner. The results from our study indicated that the benefits of rTMS were more localized to the particular area being stimulated, in our cases, the affected hand (stimulation of the M1 hand knob). This finding is consistent with the results of a previous report, which tested the effects of high-frequency rTMS on the M1 corresponding to the paretic hand in poststroke patients in the subacute period.
Chang et al. reported that real rTMS, in conjunction with motor practice, had produced a greater improvement in the arm score of the Motricity Index, but not in the lower limb score, up to 3 months after onset of stroke. Moreover, grip strengthin the affected hand improved only in the real stimulation group over baseline in that study. Sasaki et al
also reported improvement in grip strength and finger tapping frequency in acute or subacute stroke patients after a 5-session high-frequency rTMS, which is consistent with our results. Our results could reinforce the evidence of the positive effects on motor recovery after multisession high-frequency rTMS during the subacute period while the patient was undergoing rehabilitation.
We focused on the subacute period after stroke in the present study, because the period within several months after stroke onset is thought of as a golden period for initiating exogenous restorative therapies, as endogenous repair-related events reach peak levels,
This would indicate that high-frequency rTMS should probably be initiated at least by the subacute period.
A recent study has suggested a spinal mechanism for the effect of rTMS. It is reported that high-frequency rTMS of the ipsilesional M1 had suppressed F-waves, which was presumed to result from an enhanced inhibitory effect on spinal excitability.
In our study, the quantitative measurement of finger tapping movement showed that significant increases were seen in the number of taps in the real stimulation group, which has also been observed in a previous study.
This may be partially due to the attenuation of spasticity after high-frequency rTMS.
In the present study, the direct comparison between the real and sham stimulation groups revealed that the significant, but modest, positive effect was limited to improvement in the BS hand score. Although components of the upper limb in other scores tended to show greater improvement after the real stimulation, there were no significant differences in FMA, NIHSS, and FIM scores between the 2 groups. Similar findings were seen in the above-mentioned study reported by Chang et al.
Additional motor recovery seen in the present study was still modest; therefore, the efficacy of rTMS needs to be improved. To improve the efficacy of rTMS, there are some possible methods that can be utilized. As suprathreshold stimulation has been said to provide more favorable results,
the efficacy of rTMS may be improved by a higher intensity of stimulation within the guidelines on the safe use of rTMS. Moreover, some researchers have recently examined the efficacy of coupling inhibitory and facilitatory rTMS suggesting more favorable outcomes when compared to single-session rTMS alone.
One of major clinical advantages of rTMS is its noninvasive nature. The present study and previous studies have not reported any serious adverse events after rTMS for the treatment of poststroke patients.
The use of daily high-frequency rTMS during the subacute period seems to be safe in poststroke patients.
Our study has several potential limitations. First, our study was limited to evaluations over 4 weeks. Outcomes over a longer follow-up period should be considered for evaluation in future studies. Second, the small positive result in the BS hand score should be interpreted with caution. The dissociation between the results of the BS hand score and FMA distal upper limb score may be caused by the difference in characteristics of each score; the BS score is a 6-point scale, whereas the FMA distal upper limb score consists of 3-point scales in 8 motor tasks (total score of 24). Alternatively there is a possibility of overestimation due to rough evaluation of BS. Third, baseline cognitive condition in activities of daily living was unbalanced in the allocated groups. The stroke type and location of our subjects was heterogeneous, and the number of subjects was small for subgroup analysis. Three stratification factors were not optimal for the small number of subjects in the present study. Further studies in larger populations with optimal stratification factors such as a stroke location should be conducted to clarify the various roles of rTMS in poststroke patients.
Our results suggest that daily high-frequency rTMS of the ipsilesional M1 is tolerable and modestly facilitates motor recovery in the paralytic hand of subacute ischemic and hemorrhagic stroke patients. Further studies investigating more effective conditions are also required to establish rTMS therapy as a practical clinical utility.
The authors would like to express appreciation to Ms. Yuko Fukumoto for her administrative assistance, to the administrative and rehabilitation staff of the participating institutions for their efforts, and also to all of the study participants for their enthusiastic participation in the study.
Long-term effects of rTMS on motor recovery in patients after subacute stroke.
Grant support: This study was partly supported by the Strategic Research Program for Brain Sciences by the Ministry of Education, Culture, Sports, Science and Technology of Japan ( 15dm0107049h0003 ), the General Insurance Association of Japan , and Japan Agency for Medical Research and Development ( 15hk0102029h0001 ).
Disclosure: The Department of Neuromodulation and Neurosurgery, Osaka University Graduate School of Medicine, is a joint research chair established with sponsorship by Teijin Pharma Limited.