Transcranial direct current stimulation (tDCS) has the potential to improve upper limb motor outcomes after stroke. According to the assumption of interhemispheric inhibition, excessive inhibition from the motor cortex of the unaffected hemisphere to the motor cortex of the affected hemisphere may worsen upper limb motor recovery after stroke. We evaluated the effects of active cathodal tDCS of the primary motor cortex of the unaffected hemisphere (ctDCSM1UH) compared to sham, in subjects within 72 hours to 6 weeks post ischemic stroke. Cathodal tDCS was intended to inhibit the motor cortex of the unaffected hemisphere and hence decrease the inhibition from the unaffected to the affected hemisphere and enhance motor recovery. We hypothesized that motor recovery would be greater in the active than in the sham group. In addition, greater motor recovery in the active group might be associated with bigger improvements in measures in activity and participation in the active than in the sham group. We also explored, for the first time, changes in cognition and sleep after ctDCSM1UH. Thirty subjects were randomized to six sessions of either active or sham ctDCSM1UH as add-on interventions to rehabilitation. The NIH Stroke Scale (NIHSS), Fugl-Meyer Assessment of Motor Recovery after Stroke (FMA), Barthel Index (BI), Stroke Impact Scale (SIS), and Montreal Cognitive Assessment (MoCA) were assessed before, after treatment, and three months later. In the intent-to-treat (ITT) analysis, there were significant GROUP*TIME interactions reflecting stronger gains in the sham group for scores in NIHSS, FMA, BI, MoCA, and four SIS domains. At three months post intervention, the sham group improved significantly compared to posttreatment in FMA, NIHSS, BI, and three SIS domains while no significant changes occurred in the active group. Also at three months, NIHSS improved significantly in the sham group and worsened significantly in the active group. FMA scores at baseline were higher in the active than in the sham group. After adjustment of analysis according to baseline scores, the between-group differences in FMA changes were no longer statistically significant. Finally, none of the between-group differences in changes in outcomes after treatment were considered clinically relevant. In conclusion, active CtDCSM1UH did not have beneficial effects, compared to sham. These results were consistent with other studies that applied comparable tDCS intensities/current densities or treated subjects with severe upper limb motor impairments during the first weeks post stroke. Dose-finding studies early after stroke are necessary before planning larger clinical trials.
Stroke is a leading cause of disability worldwide. Hand paresis affects up to 80% of the subjects in the acute phase after ischemic stroke and substantially contributes to disability [
The motor cortex of the unaffected hemisphere (M1UH) may have a maladaptive role in motor recovery by overinhibition of the motor cortex of the affected hemisphere (M1AH) according to the theory of interhemispheric inhibition [
Only five studies focused on the effects of ctDCSM1UH in the subacute phase after stroke [
In addition to the paucity of data and the variety of paradigms in the few studies that addressed the effects of ctDCSUH in the subacute stage, a systematic review concluded that there is limited information about adverse events of tDCS in subjects post stroke [
The main objective of this study was to assess safety. Our primary findings, published elsewhere, showed that the active intervention was safe, compared to sham [
We hypothesized that motor recovery would be greater in the active than in the sham group. In addition, greater motor recovery in the active group might be associated with bigger improvements in measures in activity and participation in the active than in the sham group. Effects of ctDCSUH on cognition or sleep in stroke are largely unknown [
Here, we report the results of changes in the following secondary outcome measures of this pilot clinical trial: motor performance, spasticity, and use of the paretic upper limb in activities of daily living, as well as neurological impairment, disability, quality of life, sleep, and cognition.
The study was a randomized parallel, two-arm, double-blind, sham-controlled clinical trial performed at the Albert Einstein Hospital from April, 2015, to September, 2017. The protocol was approved by the hospital’s Ethics Committee and registered at clinicaltrials.gov (NCT 024555427). The research was conducted according to standards of the declaration of Helsinki and Brazilian regulations and with institutional guidelines. Informed consent was required from all participants and could be provided in writing by proxies for those unable to sign due to severe motor impairment. The independent Hospital Israelita Albert Einstein Institutional Review Board reviewed the clinical research and informed consent forms, every six months.
We included subjects in the acute (up to 7 days) or early subacute (from 7 days to 3 months) phases after stroke [
Exclusion criteria are as follows: advanced systemic disease; clinical instability such as uncontrolled cardiac arrhythmia or heart failure; dementia; history of prior stroke affecting the corticospinal tract of M1UH; strokes affecting the cerebellum or cerebellar pathways; contraindications to tDCS [
Demographic characteristics, history of hypertension, diabetes mellitus or prior stroke, handedness, performance of thrombolysis for ischemic strokes, time from stroke, and side, type, and etiology of stroke were registered in all subjects. Involvement of primary motor cortex and/or the posterior limb of the internal capsule in brain MRIs (fluid-attenuated inversion recovery images) performed on 3T scanners prior to treatment was also assessed by an experienced neuroradiologist, blinded to group assignment.
Recruitment was performed from our hospital admissions and from the community [
The randomization table was kept in a locked cabinet and in password-protected files, accessible only to the investigator who administered tDCS and the principal investigator.
Patients and researchers who administered physical therapy or evaluated outcomes were not aware of group assignment.
Participants underwent three sessions of treatment per week over two weeks (total of six sessions) (Figure
Experimental paradigm. ctDCSM1UH: cathodal transcranial direct stimulation of the motor cortex in the unaffected hemisphere.
In the active group, tDCS was applied for 20 minutes, and in the sham group, for 30 seconds including the ramping [
To date, there is no consensus or guidelines regarding the optimal intensity (i.e., 1 mA versus 2 mA), interval between sessions (i.e., every other day or consecutive sessions), duration (i.e., 15, 20 min, 30 min, or 40 min), or best timing to deliver physical therapy (concomitant with stimulation versus after the stimulation) [
The primary outcome of this study was safety, and the results were published elsewhere [
Sample size was not formally determined based on prior data because the main goal of this study was to assess safety. Measures of efficacy were secondary outcomes. The results of this pilot study were expected to contribute to sample size estimation for future, larger trials. It has been estimated that, for a parallel, pilot clinical trial, at least 12 subjects should be included per group [
Between-group differences in baseline characteristics were assessed with chi-square tests for categorical variables, and unpaired
Outcomes were analyzed with Generalized Estimating Equations (GEE) with factors time (preintervention, postintervention, and after 3 months) and group (active or sham). GEE is used to analyze correlated data, particularly when analysis of variance assumptions are not met [
In addition, we evaluated Minimal Clinically Important Differences (MCID) of the following outcomes described for subjects in the early phase post stroke: FMA (9 points) [
Intention-to-treat (ITT) and per-protocol analyses were performed. Missing observations were imputed with the Last Observation Carried Forward (LOCF). A per-protocol analysis was performed on data from patients who completed at least five sessions of treatment and all sessions of evaluation of outcomes.
Supplementary Figure
Table
Characteristics of the subjects.
Characteristic | Active tDCS | Sham tDCS | |
---|---|---|---|
Gender (female/male) | 8/7 | 4/11 | 0.1361 |
Age, years ( | 0.9912 | ||
Education, years ( | 9.3 ± 4.1 | 7.5 ± 4.9 | 0.3053 |
Ethnicity, | 0.4784 | ||
White | 9 (60) | 9 (60) | |
Black | 6 (40) | 5 (33.3) | |
Asian | 0 (0) | 1 (6.7) | |
Hypertension, | 10 (66.7) | 12 (80) | 0.6825 |
Diabetes mellitus, | 7 (46.7) | 6 (40) | 0.7131 |
Right-handedness, | 12 (85.7) | 13 (92.9) | >0.9995 |
Previous stroke, | 2 (13.3) | 1 (7.1) | >0.9995 |
Time since stroke, median (IQR) | 37 (23.5; 45.5) | 26.5 (20.8; 37.3) | 0.1553 |
Thrombolysis, | 3 (20) | 2 (13.3) | >0.9995 |
Lesion side (right/left/bilateral) | 7; 8; 0 | 7; 7; 1 | 0.4844 |
HADS—depression, median (IQR) | 3 (1; 6.5) | 1.5 (0; 5.3) | 0.2463 |
HADS—total score, median (IQR) | 9 (4; 12) | 4 (2; 11) | 0.1143 |
Lesion site | |||
Corticosubcortical | 9 (60) | 5 (35.7) | 0.1911 |
Subcortical | 6 (40) | 9 (64.3) | 0.1911 |
Involved M1 | 6 (40) | 4 (28.6) | 0.7005 |
Involved PLIC | 8 (53.3) | 13 (92.9) | 0.0355 |
Stroke etiology, TOAST | 0.6104 | ||
Large-artery atherosclerosis | 2 (13.4) | 2 (13.3) | |
Small-vessel occlusion | 0 (0) | 1 (6.7) | |
Other determined etiology | 2 (13.4) | 1 (6.7) | |
Undetermined etiologya | 1 (6.7) | 1 (6.7) | |
Undetermined etiologyb | 10 (66.7) | 10 (66.7) |
tDCS: transcranial direct current stimulation. HADS: Hospital Anxiety Depression Scale. SD: standard deviation. IQR: interquartile range. M1: primary motor cortex. PLIC: posterior limb of the internal capsule. TOAST: according to criteria from the Trial of Org 10172 in Acute Stroke Treatment. 1Chi-square test. 2Student’s
Tables
Outcomes assessed before the first session of treatment (Pre), after the last session of treatment (Post), and three months later (Post3m): intention-to-treat analysis, Generalized Estimating Equation model. Median and interquartile ranges are given.
Active | Sham | ||||||||
---|---|---|---|---|---|---|---|---|---|
Outcomes | Pre | Post | Post3m | Pre | Post | Post3m | Group | Time | Interaction |
NIHSStotal | 6 (3; 13) | 3 (3; 11) | 4 (3; 11) | 5 (4; 10) | 5 (3; 10) | 4 (1; 8) | 0.173 | <0.001 | <0.001 |
NIHSS5 | 2 (1; 4) | 1 (0; 4) | 1 (1; 4) | 2 (1; 4) | 1 (1; 4) | 1 (1; 4) | 0.866 | <0.001 | <0.001 |
FMA | 46 (8; 56.8) | 51 (16.8; 61.5) | 52 (16.8; 61.8) | 22.5 (8.8; 43.5) | 38.5 (20.5; 55.8) | 43 (16.8; 57.3) | 0.015 | <0.001 | <0.001 |
mRS | 3 (2; 4) | 3 (2; 4) | 3 (2; 4) | 4 (3; 4) | 3 (3; 3) | 3 (2; 3) | 0.689 | 0.012 | 0.910 |
BI | 80 (47.5; 95) | 85 (57.5; 100) | 92.5 (61.3; 100) | 65 (47.5; 77.5) | 77.5 (67.5; 90) | 85 (75; 100) | 0.654 | <0.001 | <0.001 |
MASshoulder | 0 (0; 1) | 0 (0; 0) | 0 (0; 0) | 0 (0; 1) | 0 (0; 0) | 0 (0; 0.5) | 0.717 | 0.010 | 0.176 |
MAS elbow | 0 (0; 1.25) | 0.5 (0; 1) | 0.5 (0; 1.25) | 1 (0; 2) | 1 (0; 2) | 1 (0; 2) | 0.279 | 0.588 | 0.975 |
MAS wrist | 0.5 (0; 2.25) | 0 (0; 1) | 0 (0; 1.25) | 1 (0.8; 2) | 1 (0; 2) | 2 (0; 2) | 0.148 | 0.039 | 0.296 |
MAS fingers | 0.5 (0; 1.25) | 0 (0; 1) | 0 (0; 1) | 1 (0; 1) | 0 (0; 1) | 1 (0; 1.3) | 0.587 | 0.016 | 0.702 |
MALquantitative | 1.05 (0; 1.97) | 2.41 (0; 3.5) | 2.25 (0; 3.89) | 0.1 (0; 0.4) | 0.6 (0; 1.9) | 0.8 (0; 3.5) | 0.261 | 0.087 | 0.211 |
MALqualitative | 0.89 (0; 1.67) | 2.16 (0; 3.58) | 2.41 (0; 3.65) | 0 (0; 0.2) | 0.7 (0; 1.3) | 0.9 (0; 3.1) | 0.264 | 0.095 | 0.183 |
MoCA | 18 (9; 24) | 19 (10; 23) | 21 (8; 24) | 16 (8; 20) | 20 (12; 23) | 19 (13; 23) | 0.728 | <0.001 | 0.001 |
tDCS: transcranial direct current stimulation. NIHSS total: National Institutes of Health Stroke Scale total score (0-42). NIHSS5: National Institutes of Health Stroke Scale, motor score (0-5). FMA: Fugl-Meyer Assessment of Motor Recovery after Stroke, upper limb motor score. mRS: Modified Rankin Scale. BI: Barthel Index. MAS: Modified Ashworth Scale. MALqualitative: subscale qualitative of Motor Activity Log. MALquantitative: subscale quantitative of Motor Activity Log. MoCA: Montreal Cognitive Assessment.
Minimal clinically important differences for secondary outcomes. Intention-to-treat analysis, Generalized Estimating Equations model with binomial distribution.
Outcome | Active | Sham | |||||
---|---|---|---|---|---|---|---|
Pre-post | Post-3m | Pre-post | Post-3m | Group time interaction | |||
Fugl-Meyer Assessment | 6 (42.9) | 0 (0) | 8 (57.1) | 0 (0) | 0.727 | 0.001 | 0.727 |
Motor activity log, qualitative | 5 (35.7) | 0 (0) | 4 (28.6) | 3 (21.4) | 0.433 | 0.068 | 0.114 |
National Institutes of Health Stroke Scale | 2 (13.3) | 0 (0) | 2 (13.3) | 2 (13.3) | 0.421 | 0.839 | 0.472 |
Modified Rankin Scale | 5 (33.3) | 4 (26.7) | 7 (46.7) | 4 (26.7) | 0.576 | 0.328 | 0.647 |
Barthel Index | 1 (7.1) | 0 (0) | 2 (14.3) | 1 (7.1) | 0.382 | 0.967 | 0.987 |
Immediately post treatment, both groups significantly improved compared to pretreatment in NIHSStotal, NIHSS5, FMA, and BI scores, as well as in three SIS domains (“activities of daily living,” “hand function,” and “physical”). MoCA scores improved significantly in the sham group (
At three months post intervention, the sham group improved significantly compared to posttreatment in FMA (Figure
Absolute values of the Fugl-Meyer Assessment (FMA) of motor recovery after stroke scores at specific time points, for each participant in the active and sham groups.
Absolute values of NIHSS (item 5a) scores at specific time points, for each participant in the Active and sham groups. NIHSS: National Institute of Health Stroke Scale.
Supplementary Tables
Due to the imbalance in FMA scores (
Table
Overall, ctDCSM1UH was not beneficial, compared to sham, in any of the outcomes assessed in this study. There were no significant between-group differences in MCID for FMA, MAL, NIHSS, MRS, or BI. Also, there were no consistent between-group differences in spasticity, use of the paretic limb in activities of daily living, overall neurological impairments, cognition, or quality of sleep. Lower FMA scores in the sham group at baseline were consistent with a greater involvement of the PLIC in this group, compared to the active group. Between-group differences in FMA after treatment favoured the sham group but were no longer statistically significant after adjustments for baseline scores.
The only outcome that improved significantly in the active but not in the sham group was the “recovery” domain of the SIS, according to both ITT and per-protocol analyses. The reason for this finding is unclear, given that no between-group differences were found in other SIS domains or in other outcomes that impact recovery.
On the other hand, performance in the MoCA test improved in the sham but not in the active group, immediately after the end of treatment, according to ITT analysis. The lack of improvement in the active group might reflect a negative effect of ctDCSM1UH on cognition, possibly by disturbing functional connectivity among brain areas other than M1[
In opposition to the lack of consistent between-group differences immediately post treatment, at three months later, both ITT and per-protocol analyses showed greater improvements in the sham than in the active group in NIHSStotal, NIHSS5, BI, and three SIS domains (“activities of daily living,” “physical,” and “recovery”). The “physical status” domain evaluates the strength, activity of daily life, mobility, and upper extremity performance. There were no significant between-group differences in any of these outcomes prior to treatment; therefore, these results could point to a detrimental effect of ctDCSM1UH. However, the lack of significant differences in MCID for NIHSStotal and BI [
The number of individuals included per group in this study was greater than in other studies that included patients in the subacute phase, except for Hesse et al. that included 32 patients in each group [
Despite these differences in the study design compared to prior research in the early phase after stroke, our results point to the same direction of all studies that chose stimulus intensities
Plasticity mechanisms are highly active during the first weeks after stroke. It is possible that ctDCSM1UH during this critical period does not have a positive impact on these mechanisms and the interhemispheric inhibition theory does not play an important role in many patients with stroke as previously argued [
On the other hand, Khedr et al. [
The lack of significant effects of cTDCS in the early phase after stroke [
Overall, these results, together with our observations, provide key information for the design of future studies aiming at efficacy on motor outcomes: administration of ctDCSM1UH at stimulus intensities of at least 2 mA, current densities greater than 0.057 mA/cm2 in patients with residual upper function, without severe deficits, may be associated with a greater likelihood of success. Tailoring the type of tDCS (cathodal or anodal) to each individual according to the severity of their deficits and/or phase after stroke is more likely to lead to benefit than applying these treatments to very different groups of subjects with stroke, a very heterogeneous condition. Clinical, neuroimaging, and neurophysiologic tools are expected to provide information about the underlying mechanisms of recovery that will allow the selection of the right patient to the right intervention at the right dose [
These conclusions cannot be extrapolated to other neuromodulation interventions such as rTMS [
These results should be viewed with caution considering the limitations of this study. First, behavioral measures were secondary outcomes and were collected in a relatively small sample of patients with a main goal of assessing the estimate of effect that would allow a formal sample size calculation for a further larger study. Second, we did not conduct a stratified randomization according to the level of impairment, and there was an imbalance in FMA scores at baseline. However, we also analyzed the data considering baseline FMA as a covariate, and there were no between-group differences. Third, biomarkers such as cortical excitability or severity of motor impairment were not part of the eligibility criteria. Until now, there is no consensus about evidence-based biomarkers that should be used in trials of neuromodulation in stroke. There is a deep need for clinical, imaging, or other variables that can help tailor treatments [
In summary, our data provide evidence that CtDCSM1UH in the early phase after stroke did not have consistent beneficial effects on motor impairments, disability, or quality of life, immediately after treatment or three months later. Early phase dose-finding studies after stroke are necessary before planning larger clinical trials.
The data that support the findings of this study are available from the corresponding author upon request.
The authors declare that they have no conflict of interest.
DSB and ABC collected the data, performed stimulation therapy, analyzed and interpreted the data, and prepared the text of the manuscript. JP prepared Figure
This study was funded by the Hospital Israelita Albert Einstein (grant 2250-14). DSB received a scholarship from PROUNIEMP. ABC received a scholarship from Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq/305568/2016-7). JP received a scholarship from Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES). We thank Alda Castro, Karina Correa, and Raul Valiente for assistance in recruitment.
Figure S1. Flow of subjects throughout the study, Figure S2. Changes in Fugl-Meyer Assessment of Motor Recovery after Stroke (FMA) and NIH Stroke Scale (item 5) scores at specific time points, according to intention to treat (ITT, left) and per protocol (right) analyses. Error bars represent the standard error for 15 patients in each group (n= 30, ITT, left), 9 patients in the active group and 11 patients in the sham group (n=20, per protocol, right).