A burning question in the rehabilitation of stroke survivors is determining the most effective approach for improving recovery in persons who experience weakness of the arm and hand following a cerebrovascular accident (CVA). Two systematic reviews [
Recent studies on rehabilitation of arm function suggest that the effects of rTMS as a supplement to behavioral therapy may be influenced by time elapsed since stroke. In acute stroke, one trial compared 5 daily sessions of 1 Hz stimulations over the unaffected hemisphere versus 3 Hz over the affected hemisphere versus sham stimulation, showing enhanced recovery in both experimental groups [
To summarize, the role of rTMS as a practical and feasible treatment modality for stroke rehabilitation has not yet been established. In particular, the benefits of combining rTMS with behavioral interventions are unknown for individuals in the chronic phase of stroke or for those with severe impairments that do not respond to traditional rehabilitative interventions. More research is needed to determine the most effective applications of rTMS and to determine realistic treatment intensity.
The present study, therefore, focused on a less intensive treatment regimen that required a more realistic time commitment for persons with chronic stroke, including those with severe arm and hand impairment, who are discharged from in-patient rehabilitation and required to travel to the site of intervention. rTMS was delivered immediately prior to task-specific training of the arm, on a schedule of twice a week over a period of four weeks. A protocol employing inhibitory (low-frequency) rTMS of the undamaged hemisphere was chosen for this study for its lower risk profile and because the duration of its neurophysiological effects on the brain may exceed that of high-frequency rTMS over the lesioned hemisphere [
This was a feasibility study of an observer-blinded stratified block-randomized controlled trial with
This study was conducted at the McGill University Health Centre and approved by the institutional Research Ethics Board. Adults who had a first ischemic or hemorrhagic stroke at least 3 months previously that resulted in weakness of one arm were recruited through advertisements on hospital and community bulletin boards and by referral from hospital neurologists. All stroke diagnoses were confirmed by neuroimaging. Volunteers were excluded from participating if they met any of the following criteria: no residual motor impairment, complete paralysis of the hand and arm as measured by incapacity to produce the slightest voluntary contraction of any intrinsic hand muscle, previous cerebrovascular accident with persistent neurological sequelae, inability to provide informed consent, relative contraindications to rTMS (pacemaker, metal in the head, personal history of seizures, and taking medications known to lower the seizure threshold), other neurological disorders or major medical incapacity. Lesion location was confirmed by review of the clinical record. Eleven participants were recruited to the study over an 18-month period.
Subjects in both groups participated in a four-week, twice weekly functional enhancement program that included task-oriented training aimed at improving functional use of the affected arm. One group received
Evaluations were conducted by trained rehabilitation professionals upon entry in the study (median 39 months after stroke-range 17 to 301), upon completion of the intervention (mean 4 days after completion), and one month later (mean 34 days). Evaluators for postintervention and follow-up evaluations were unaware of the participants’ group assignment. Measures of capacity, motor impairment, and motor excitability were obtained before and at all evaluation time points after the intervention. Measures of motor excitability were also obtained immediately after a session of
The Box and Block Test (BBT) [
It was hypothesized that rTMS might improve functional outcome by promoting increased neural activity during motor skills training. To test this hypothesis, the effect of rTMS on corticomotor excitability was measured before and after the first rTMS session, administered prior to any task-oriented training. Corticomotor excitability was measured using motor evoked potentials (MEPs). Electromyographic signals were acquired using surface electrodes applied in a belly-tendon montage over the FDI muscles of the left and right hands. Signals were filtered between 1 and 1000 Hz, amplified, and digitized at a sampling rate of 20 kHz. Data were visually displayed and stored for later analysis in samples of 170 ms to include the window of time from 100 ms before TMS to 70 ms after TMS. Single TMS pulses were delivered using a Magstim 200 stimulator with a 70 mm figure-8 coil, with an interpulse interval of 5–10 seconds. The coil was oriented perpendicular to the central sulcus for optimal stimulation of the underlying cortical neurons [
Subjects were stratified according to two levels of arm deficit as measured by the Chedoke-McMaster Stroke Assessment hand subscale [
Analyses were done with SAS statistical software (version 9.1) and performed by an investigator blind to treatment allocation following intention-to-treat protocol. Change scores were calculated comparing baseline to postintervention (after the one-month series intervention), and baseline to the 4-week followup. Effect sizes and 95% confidence intervals were calculated for both groups for the BBT, as well as for the secondary outcome measures (grip strength, pinch strength, the WMFT, the MAL, and the SIS total score and SIS participation). To compare the MEP amplitudes before versus after stimulation at the baseline evaluation, the MEP amplitudes obtained at each intensity were averaged and the responsiveness of each subject’s ipsilesional motor cortex to rTMS (real or sham) was assessed using a
The charts of seventy-one persons were initially screened for eligibility into the study (Figure
Flow of subjects through the trial according to the CONSORT statement (rTMS, repetitive Transcranial Magnetic Stimulation).
Of the eleven subjects recruited, two subjects withdrew from the study before the postintervention evaluation (Figure
Subjects’ characteristics are presented in Table
Baseline characteristics of study subjects who completed the study.
Characteristics | rTMS group |
|
---|---|---|
|
|
|
Age in years, mean (SD) range | 74 (8) 66–83 | 60 (11) 47–76 |
Gender, men/women | 3 (75)/1 (25) | 3 (60)/2 (40) |
Side of hemiplegia, left/right | 1 (25)/3 (75) | 1 (25)/4 (75) |
Number of months after stroke at baseline, mean (SD) range | 134 (125) 32–315 | 95 (117) 18–301 |
Number of comorbid conditions, 0/1-2/3-4/>4 | 1/0/3/0 | 1/3/0/1 |
Right handedness | 4 | 5 |
SD: standard deviation.
Of the nine subjects who completed the intervention protocol, all attended the twelve treatment sessions as scheduled and complete data were collected at the three time points (baseline, postintervention, and followup) on all outcome measures for these participants. No subjects reported experiencing headaches or any sort of discomfort following the rTMS or the behavioral intervention.
Scores for both groups on motor impairment and capacity measures are presented in Table
Scores on measures of motor impairment and capacity at baseline, postintervention, and follow-up evaluations.
Test |
|
| ||
---|---|---|---|---|
Mean (SD) baseline | Mean (SD) postintervention | Mean (SD) baseline | Mean (SD) postintervention | |
BBT affected (number of blocks) | 22.8 (20.2) | 27.0 (20.2) | 27.5 (18.9) | 31.5 (19.2) |
Grip strength (kg) | 19.3 (17.0) | 18.8 (12.8) | 14.2 (15.0) | 15.1 (12.7) |
Pinch strength kg (kg) | 5.3 (2.5) | 5.6 (2.4) | 5.5 (4.6) | 6.0 (3.6) |
SIS (/80) | 66.2 (16.4) | 69.6 (15.1) | 66.5 (10.3) | 71.2 (4.6) |
SIS participation (/40) | 31.8 (9.5) | 35.0 (7.3) | 28.2 (10.1) | 28.5 (10.8) |
WMFT functional scale (/75) | 53.6 (32.2) | 63.8 (27.0) | 69.5 (27.8) | 75.0 (24.8) |
WMFT times tasks (sec.) | 16.4 (22.2) | 16.4 (27.5) | 4.5 (6.5) | 3.9 (2.1) |
MAL quality of movement (/70) | 24.8 (26.4) | 37.4 (27.9) | 35.8 (24.8) | 31.2 (17.6) |
FU: followup. ES: effect size. CI: confidence interval. SD: standard deviation. BBT: Box and Blocks Test. SIS: Stroke Impact Scale. WMFT: Wolf Motor Function Test. sec: seconds. MAL: Motor Activity Log.
Table
Within and between-group comparisons for measures of motor impairment and capacity at baseline, postintervention, and follow-up evaluations.
TEST |
Within group |
Within group |
Between group | |||
---|---|---|---|---|---|---|
Post- | FU | Post- | FU | Postintervention | FU | |
ES (95% CI) | ES (95% CI) | ES (95% CI) | ES (95% CI) | ES (95% CI) | ES (95% CI) | |
BBT affected | 0.49* (−0.08–1.06) | 0.05 (−0.72–0.8) | 0.98* (0.28–1.69) | 0.37* (0.08–0.66) | 0.00 (−0.51–0.51) | 0.02 (−0.76–0.81) |
Grip strength | 0.15 (−0.24–0.53) | 0.24 (−0.16–0.61) | −0.10 (−0.23–0.03) | −0.30 (−0.61–0.01) | −0.09 (−0.48−0.29) | −0.18 (−0.59–0.22) |
Pinch strength | 0.51* (0.09–0.94) | 0.66* (0.13–1.19) | 0.54* (0.12–0.97) | 0.05 (−0.17–0.27) | −0.01 (−0.28–0.26) | −0.23 (−0.52–0.07) |
SIS | 0.78* (0.08–1.49) | −0.06 (−0.48–0.36) | 0.93* (0.26–1.60) | 0.15 (−0.11–0.41) | −0.38 (−1.00–0.24) | 0.08 (−0.40–0.56) |
SIS participation | 0.08 (−0.23–0.38) | −0.05 (−1.25–1.15) | 0.71* (0.07–1.36) | 0.38* (−0.06–0.82) | 0.35 (−0.22–0.93) | 0.22 (−1.03–1.47) |
WMFT functional | 1.18* (0.23–2.14) | 0.93* (0.17–1.69) | 1.63* (0.50–2.76) | 1.06* (0.30–1.81) | 0.13 (−0.20–0.47) | 0.34 (−0.13–0.80) |
WMFT time | −0.72 (−1.33–0.12) | 0.41 (0.05–0.77) | 0.00 (−1.09–1.09) | −0.41 (−1.55–0.70) | 0.24 (−0.88–1.36) | −0.82 (−2.01–0.37) |
MAL quality | −0.30 (−0.96–0.35) | 0.02 (−0.86–0.91) | 1.20* (0.30–2.10) | 1.46* (0.41–2.51) | 0.67 (−0.11–1.45) | 0.46 (−0.52–1.45) |
FU: followup. ES: effect size. SD: standard deviation. BBT: Box and Blocks Test. SIS: Stroke Impact Scale. WMFT: Wolf Motor Function Test. MAL: Motor Activity Log.
*Indicates statistically significant ES.
Upon examination of the effect sizes obtained from within group analyses, participants in both randomization groups exhibited improvements on the BBT, in pinch strength, on the WMFT (functional score), and the on the SIS at the postintervention evaluation. In addition, the group randomized to the
For the
Comparisons of the recruitment curves in the lesioned hemisphere before and after rTMS at the baseline evaluation revealed that they were significantly higher after the
This pilot study aimed to evaluate the effects of rTMS combined with task-oriented training in hemiparetic persons in the postacute stages of stroke recovery. Specifically, we looked at recruitment rate, feasibility of the intervention, including intensity and duration of treatment, and acceptability and feasibility of assessment schedule. An intention-to-treat analysis was also performed to determine the effects of rTMS combined with task-oriented training on arm function.
Recruitment rate was disappointing, that is, 11 persons over an 18-month period. Over 50% of the persons screened for eligibility were not eligible to participate. Although we had specific and relatively stringent criteria for inclusion into the study, these criteria do not differ significantly from those used in similar studies [
Another recruitment strategy was posting advertisements on bulletin boards and on our laboratory website. Only a handful of persons called to enquire about the study and of those who did, none were eligible to participate. Brochures explaining the study were distributed in neurologists’ offices and to health professionals working with persons with stroke. They were also distributed in two rehabilitation centers. Professionals referred most of the persons screened for eligibility to us and they referred all of the eleven participants in this study. Other common, unavoidable reasons limiting recruitment were presence of comorbidities, some of which were simply incompatible with the use of TMS. Two subjects initially randomized did not complete the study as planned. Although the reason for their withdrawal was not directly related to the study itself, it is reasonable to assume that health problems prevented their travelling to the research site and tolerating over two hours of therapy two times per week.
The nine participants that completed the study attended all eight treatment sessions and evaluations as per schedule and did not experience adverse events related to the rTMS stimulations or the behavioral intervention. Hence, administering low-frequency rTMS for a period of twenty minutes two times a week followed by a ninety-minute task-oriented intervention is both feasible and acceptable in terms of subject safety and tolerance.
This study provided evidence that a twenty-minute session of low-frequency rTMS with an intensity equal to 110% of the motor threshold applied to the unlesioned side has a transient effect on excitability of the corticomotor pathways in patients of an advanced age with chronic stroke. This implies that the uninjured hemisphere is receptive to modulation in the short term. Although rTMS had transient effects on the brain, our study failed to demonstrate a significant effect of rTMS as an adjunct to task-oriented therapy. The effect size obtained from the comparison of
Our results are in accordance with those of three randomized trials that evaluated the effects of high-frequency rTMS over the lesioned hemisphere [
On the other hand, a study that investigated the long-term effects of rTMS (10 daily sessions of 1 Hz rTMS over the intact motor cortex) as an adjuvant to physical therapy in chronic stroke patients with mild motor disabilities found greater behavioral and neurophysiologic outcomes after
Another trial also looked at the effects of low-frequency rTMS (10 daily sessions of 1 Hz rTMS) to the contralesional motor cortex at an early stage of mild to severe hemiparesis. There were significant improvements in performance on the Jebsen-Taylor test pinch force in the
We chose to implement a more realistic treatment regimen, one that would resemble a protocol that could be offered on an outpatient basis for persons with chronic stroke. Although its potency to improve function was not demonstrated, the intervention, as delivered, proved to be acceptable for persons who have been discharged home and who travel to the treatment site.
Besides our limited sample size, there may be several reasons explaining failure to detect an rTMS effect. The dose and intensity of the rTMS, although based on empirical data, may not have been optimal. Indeed studies differ greatly on this aspect and one cannot draw conclusions at this time as to the best approach to promote lasting changes in corticomotor pathways. The exact parameters with which to administer the rTMS are not well established and effects may vary greatly depending on interindividual variability such as the site and size of the lesion and the severity of the impairment, as well as intraindividual variability [
Examination of within group effect sizes indicated that our task-oriented arm intervention had an effect on arm function. Participants in both groups exhibited improvement on the BBT and effect sizes were medium to large for the
Preliminary evidence from this study suggests that an rTMS protocol that was potent enough to induce transient increases in cortical excitability of the lesioned cerebral hemisphere in persons with stroke, nevertheless, did not show promising results when used as an adjunct to task-specific training aimed at improving arm function. Our results suggest that task-oriented therapy itself can have a beneficial effect on arm function even in older individuals with chronic stroke, at least in the short term.
At this time, studies looking at the adjunctive role of rTMS to arm therapy after stroke vary greatly in (1) the type of subjects they include (time after stroke, level of severity, site, and size of lesion), (2) the parameters of rTMS administration, and (3) the type of behavioral therapy (robotic, constraint induced, and task-oriented). It is therefore difficult at this time to draw conclusions regarding the clinical indications for the combined use of rTMS modality and behavioral therapy.
Further studies should investigate the influence of interindividual characteristics such as the size and site of lesion on the response to rTMS as well as behavioral therapy, as the specific parameter with which to administer both types of treatment may vary greatly between individuals. An in-depth understanding of the mechanisms of action of each approach is essential to guide the development of these combined treatment approaches.
The authors declare that there is no conflict of interests regarding the publication of this paper.
The authors wish to thank Aisha Bassett, and Roslyn Tetteh for their assistance with participant recruitment and data collection. Johanne Higgins was supported by a postdoctoral fellowship from the Canadian Institutes of Health Research and the Heart and Stroke Foundation of Canada. Haiqun Xie was supported by the Fonds de recherche en Santé du Québec. This work was supported by a grant from the Canadian Institutes of Health Research MOP-84354.