Journal of Hand Therapy

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1 Journal of Hand Therapy 26 (2013) 162e171 Contents lists available at SciVerse ScienceDirect Journal of Hand Therapy journal homepage: JHT READ FOR CREDIT ARTICLE #261. Scientific/Clinical Article A meta-analysis of the efficacy of anodal transcranial direct current stimulation for upper limb motor recovery in stroke survivors Andrew J. Butler PT, MBA, PhD, FAHA a,b, *, Margaret Shuster DPT c, Erin O Hara DPT c, Kevin Hurley DPT c, Dionne Middlebrooks DPT c, Karen Guilkey DPT c a Department of Physical Therapy, School of Nursing and Health Professions, Georgia State University, Atlanta, Georgia b Atlanta Veterans Affairs Medical Center, Rehabilitation Research and Development Center of Excellence, Decatur, Georgia c Division of Physical Therapy, Department of Rehabilitation Medicine, Emory University School of Medicine, Atlanta, Georgia article info abstract Article history: Received 13 July 2012 Accepted 13 July 2012 Available online 8 September 2012 Keywords: Motor control Upper limb Study Design: Systematic review and meta-analysis. Introduction: Prior reviews on the effects of anodal transcranial direct current stimulation (a-tdcs) have shown the effectiveness of a-tdcs on corticomotor excitability and motor function in healthy individuals but nonsignificant effect in subjects with stroke. Purpose: To summarize and evaluate the evidence for the efficacy of a-tdcs in the treatment of upper limb motor impairment after stroke. Methods: A meta-analysis of randomized controlled trials that compared a-tdcs with placebo and change from baseline. Results: A pooled analysis showed a significant increase in scores in favor of a-tdcs (standard mean difference [SMD] ¼ 0.40, 95% confidence interval [CI] ¼ 0.10e0.70, p ¼ 0.010, compared with baseline). A similar effect was observed between a-tdcs and sham (SMD ¼ 0.49, 95% CI ¼ 0.18e0.81, p ¼ 0.005). Conclusion: This meta-analysis of eight randomized placebo-controlled trials provides further evidence that a-tdcs may benefit motor function of the paretic upper limb in patients suffering from chronic stroke. Level of Evidence: Level 1a. Published by Elsevier Inc. on behalf of Hanley & Belfus, an imprint of Elsevier Inc. Introduction Stroke is a leading cause of long-term disability in the United States. An estimated 6.4 million Americans are affected by the longterm effects of stroke. 1,2 In addition, 50e60% of stroke survivors exhibit some degree of motor impairment and require at least partial assistance in activities of daily living (ADLs). 3,4 In particular, the loss of upper limb motor function can pose significant challenges to ADL performance and thus also has a direct impact on quality of life. Without treatment, functional limitations can persist or worsen over time, leading to increased dependence and caregiver burden. Effective interventions for the upper limb after stroke are limited. 5 Transcranial direct current stimulation (tdcs) is * Corresponding author. Department of Physical Therapy, School of Nursing and Health Professions, 140 Decatur Street, Ste. 819, Atlanta, GA address: andrewbutler@gsu.edu (A.J. Butler). a noninvasive procedure used to polarize underlying brain regions through the application of weak direct currents through electrodes on the scalp. The current induces intracerebral current flow, which either increases or decreases the neuronal excitability in the specific area being stimulated based on the type of stimulation that is being used. This weak current can induce focal changes of cortical excitability that lasts beyond the period of stimulation. Several studies have shown that this technique might modulate cortical excitability in the human motor cortex. 6 Animal experiments have demonstrated that anodal tdcs (a-tdcs) results in neuronal depolarization, whereas cathodal tdcs hyperpolarizes cortical neurons. Furthermore, these excitability changes can be capitalized on for use in functional rehabilitation models. For example, by using the increased neural excitability due to a-tdcs delivered to the primary motor cortex, it is possible to facilitate the performance of skilled motor tasks of the contralateral upper limb. 7,8 Recent literature into the application of tdcs in people with arm and hand impairments after stroke has shown promising results on upper limb function measures such as the JebseneTaylor Hand /$ e see front matter Published by Elsevier Inc. on behalf of Hanley & Belfus, an imprint of Elsevier Inc.

2 A.J. Butler et al. / Journal of Hand Therapy 26 (2013) 162e Function Test (JTT), 9,10 Box and Block Test (BBT), 11 FugleMeyer (FM) Test, 12 reaction time (RT), 13,14 and pinch strength (PS). 13,14 Clinical data on the effectiveness of the application of tdcs on upper limb motor function have varied, with four studies showing small to moderate effects of tdcs on upper limb motor function in stroke patients. 9e11,15 One limitation of the studies with limited effect may have been their small sample sizes. In such circumstances, a metaanalysis should be able to quantify a pooled measure of effect from the existing studies, allowing for a better overall estimate of the population parameter (i.e., change in functional outcome). 16 Essentially, by standardizing the outcome data by effect size (ES), a group of similar studies may be compared in a more objective and quantifiable manner. A previous systematic review and meta-analysis on the effects of a-tdcs have demonstrated the effectiveness of a-tdcs on modulating corticomotor excitability and motor function in healthy individuals and subjects with stroke. 17 Preepost tdcs corticomotor excitability measures revealed a small but significant ES (0.31 [0.14, 0.48], p ¼ ) in healthy subjects and a moderate but significant ES (0.59 [0.24, 0.93], p ¼ 0.001) in favor of a-tdcs in stroke survivors. Similarly, data on upper limb motor function demonstrated a small and nonsignificant effect (0.39 [ 0.17, 0.94], p ¼ 0.17) in subjects with stroke and a large but nonsignificant effect (0.92 [ 1.02, 2.87], p ¼ 0.35) in healthy subjects in favor of improvement in motor function. 17 The previous meta-analysis included data from four trials on stroke survivors that were available as of October 2010, which found small to moderate effects of a-tdcs on upper limb motor function in stroke patients. 9e11,15 By including additional studies (for a total of eight), our systematic review will be able to quantify a pooled measure of effect from a larger group of existing studies. In addition, previous analyses focused on posttreatment functional improvement compared with baseline levels of function, without comparing treatment with a control. The present study will include a preepost intervention comparison analysis as well as the contrast of sham-controlled groups to a-tdcs group. Failure to observe a significant effect of a-tdcs on upper limb impairment measures in subjects with chronic stroke in previous meta-analyses should not be overlooked; recent studies present strong evidence of improved motor function after application of a- tdcs. These results have led us to further explore the effect of a- tdcs using a larger sample of studies and to compare a-tdcs with sham stimulation. The purpose of this review was to perform an analysis to determine whether a-tdcs has any effect on stroke patients functional outcome compared with 1) their baseline measurements and 2) sham stimulation. The results of this analysis will provide further evidence of the utility of a-tdcs as a component of upper extremity interventions in patients with motor impairment after stroke. Table 1 Inclusion and exclusion criteria for included studies Participants Intervention Comparison Outcomes impairments, motor, recovery, motor recovery, motor rehabilitation, upper extremity, upper, and rehabilitation. Five reviewers (KG, KH, DM, EO, and MS) independently screened the title and abstract of publications identified in the initial search strategy against the inclusion criteria (Table 1). A total of 13 potential articles were retrieved from the database searches 9e15,18e23 (Figure 1). Selection criteria Inclusion Exclusion Stroke as a primary diagnosis; Healthy people; patients with hemorrhage or infarct; no aphasia or cognitive location specificity or chronicity impairments; history of other limits neurologic diagnosis; nonhuman studies a-tdcs stimulation to motor area (M1); stimulation with non-pharmacologic intervention Studies in which the comparison of interest was no treatment, sham treatment, or placebo control c-tdcs; simultaneous a-tdcs and c-tdcs (bihemispheric); stimulation with pharmacologic intervention Any other control group Functional tests such as time All other outcome measures taken to finish a functional task (i.e., attention tasks, cognition, (i.e., JebseneTaylor Hand fmri, etc.) Function Test) Trial design Randomized control trials; controlled clinical trials; pre epost trials Type of Published in peer-reviewed publication journal; English publications Review articles and case reports Non-English articles a-tdcs ¼ anodal transcranial direct current stimulation; c-tdcs ¼ cathodal transcranial direct current stimulation; fmri ¼ functional magnetic resonance imaging. Reviewers selected the eight articles included in this metaanalysis by applying the specific inclusion and exclusion criteria (Table 1) to the initial list of 13 articles. 9e15,18e23 The inclusion criteria were 1) studies that involved stroke patients with Methods The methods and definitions used in the present meta-analysis were broadly similar to those used in a previous meta-analysis. 17 Literature search The aim was to identify all trials, published or otherwise, that were available by May 2012 and compare the effects of a-tdcs both pre- and poststimulation and with a control, using functional outcome measures. An extensive literature search was performed using the following databases: PubMed, EMBASE, Cochrane, Web of Science, and Ovid. The following 12 keywords were used in various combinations during the search process: tdcs, transcranial direct current stimulation, direct current stimulation, stroke, motor Fig. 1. A flow diagram of the number of studies identified, the number excluded and the reason for exclusion, and the final number of studies included in the systematic review and meta-analysis.

3 164 A.J. Butler et al. / Journal of Hand Therapy 26 (2013) 162e171 hemorrhagic lesions or infarctions with upper extremity motor impairment without location specificity or chronicity limits; 2) patients who received a-tdcs stimulation to the primary motor cortex (M1) along with non-pharmacologic intervention; 3) use of functional measures such as time taken to finish a functional task; 4) comparison of interest was no treatment, sham treatment, or placebo treatment; 5) randomized controlled trials (RCTs), controlled clinical trials, and preepost trials; and 6) articles published in English in peer-reviewed journals. Studies that involved healthy subjects, participants with aphasia, cognitive impairments, or any other neurologic diagnoses were excluded from the study. Case studies and reviews were also excluded. In addition, studies using rtms (repetitive transcranial magnetic stimulation), cathodal tdcs, simultaneous a-tdcs and cathodal tdcs, or tdcs in conjunction with pharmacologic interventions were also excluded. Additional studies were excluded because the reviewers were unable to find full texts of articles, articles were ahead of print, or the articles were unavailable in English text. Data extraction For each study, three authors (KG, KH, and DM) independently selected the outcome measures that have been shown to be valid and reliable for the assessment of clinical impairment of the upper limb. For those studies that reported multiple outcomes, the most conservative measure of treatment response was selected, based on group consensus. Two other individuals independently extracted the numerical data (EO and MS). Selected articles from all searches were grouped according to 1) outcome measures and a-tdcs parameters, 2) demographic and stroke characteristics of participants, and 3) mean standard deviation (SD) of motor function outcome for the experimental and control groups. Outcome measures All studies included in the meta-analysis contained retrospective data. The following measures of upper limb motor impairment were used: JTT, 24 FM Test, 25 PS, BBT, 26 RT, and grip strength (GS). The JTT is an objective and standardized test that evaluates the broad range of hand function used during daily activities 24 and includes a range of seven subsets of fine motor, weighted, and nonweighted hand function activities. The FM Test is a stroke-specific, performance-based impairment index designed to assess motor functioning, balance, sensation, and joint functioning in hemiplegic post-stroke patients. 25 The motor domain of the FM Test includes items measuring movement, coordination, and reflex action of the shoulder, elbow, forearm, wrist, hand, hip, knee, and ankle. The motor score ranges from 0 (hemiplegia) to 66 points (normal motor performance) for the upper extremity. 27 Pinch strength of the impaired hand was measured with a force transducer or pinchometer and recorded in newtons, with higher pinch forces indicating stronger PS. The BBT is a timed motor test of unimanual dexterity that was also used. 26 The test involves grasping and moving 1-inch square wooden blocks from one side of an 8-inch square box to the other, passing them over a wooden partition 5 inches high, using one hand. Each hand was tested separately. The patient was scored according to the number of blocks passed from one side to the other in 1 minute, with lower scores corresponding to greater upper extremity impairment. Reaction time, measured in milliseconds, was also used to assess motor performance. For this test, increased time corresponds to greater upper extremity impairment. Finally, GS was assessed by having subjects grip a dynamometer as strongly as possible for 3 seconds with their affected hand. Data analysis Effect size is referred to as the standard mean difference (SMD), which provides the measurement of differences in the mean outcome after the intervention. 28 The ES was used to determine the effect a-tdcs had on improving motor function in the upper extremity. Data collected from the above studies were entered into the ES calculator using review manager (RevMan version 5) software. 29 The data entered into RevMan to determine the ES included the number of participants from each group (n), their mean response (mean), and SD of their response (Tables 2 and 3). RevMan calculates the statistical significance of the difference between the means and 95% confidence intervals (CIs) for the mean difference. RevMan uses Hedges adjusted g, which is similar to Cohen s d but includes an adjustment for small sample bias 29 of RCTs (Tables 2 and 3). These controlled ESs may be conservatively interpreted with Cohen s convention of small (0.2), medium (0.5), and large (0.8) effects. 30 Table 2 Fixed-effects meta-analysis of eight studies that examined the PreePost effects of anodal tdcs on motor function in stroke survivors Included studies Outcome measure Baseline measure Post-measure Weight (%) Standard mean difference Mean SD Total (n) Mean SD Total (n) IV, Fixed (95% CI) Boggio et al. 9 JTT ( 1.12, 1.68) Fregni et al. 10 JTT ( 0.90, 1.37) Hummel, 2005 JTT (0.21, 2.94) Hummel et al. 13 RT (0.20, 2.02) Hummel et al. 13 PS ( 0.59, 1.09) Kim et al. 11 BBT ( 0.52, 1.26) Kim et al. 12 FM Test ( 0.12, 2.40) Mahmoudi et al. 22 JTT ( 0.72, 1.03) Stagg et al. 14 RT ( 0.60, 0.94) Stagg et al. 14 GS ( 0.85, 0.69) Total (0.10, 0.70) tdcs ¼ transcranial direct current stimulation; SD ¼ standard deviation; IV ¼ independent variable; CI ¼ confidence interval; JTT ¼ JebseneTaylor Hand Function Test; RT ¼ reaction time; PS ¼ pinch strength; BBT ¼ Box and Block Test; FM ¼ FugleMeyer Test; GS ¼ grip strength. Green square represents the effect size for each individual trial, horizontal line represents 95% confidence interval, and black diamond represents pooled effect size for all trials. The SMD for pinch strength, 13 grip strength, 14 BBT, 11 and FM 12 were multiplied by 1 to ensure that all scales point in the same direction. Heterogeneity: c 2 ¼ 8.86, df ¼ 9 (p ¼ 0.45); I 2 ¼ 0%. Test for overall effect: Z ¼ 2.59 (p ¼ 0.010).

4 A.J. Butler et al. / Journal of Hand Therapy 26 (2013) 162e Table 3 Fixed-effects meta-analysis of seven studies that examined the effects of anodal tdcs vs. sham stimulation on motor function in stroke survivors Included studies Outcome measure Sham a-tdcs Weight (%) Standard mean difference Mean SD Total (n) Mean SD Total (n) IV, Fixed (95% CI) Boggio et al. 9 JTT ( 0.97, 1.87) Fregni et al. 10 JTT ( 0.83, 1.46) Hummel, 2005 JTT (0.17, 2.88) Hummel et al. 13 RT (0.63, 2.60) Hummel et al. 13 PS ( 0.26, 1.45) Kim et al. 11 BBT ( 0.63, 1.13) Mahmoudi et al. 22 JTT ( 0.78, 0.97) Stagg et al. 14 RT ( 0.43, 1.12) Stagg et al. 14 GS ( 0.89, 0.65) Total (0.18, 0.81) tdcs ¼ transcranial direct current stimulation; SD ¼ standard deviation; a-tdcs ¼ anodal transcranial direct current stimulation; CI ¼ confidence interval; JTT ¼ JebseneTaylor Hand Function Test; RT ¼ reaction time; PS ¼ pinch strength; BBT ¼ Box and Block Test; GS ¼ grip strength. Green square represents the effect size for each individual trial, horizontal line represents 95% confidence interval, and black diamond represents pooled effect size for all trials. The SMD for pinch strength, 13 grip strength, 14 and BBT, 11 were multiplied by 1 to ensure that all scales point in the same direction. The study by Kim et al. 12 was excluded in this statistical analysis (see Methods). Heterogeneity: c 2 ¼ 10.92, df ¼ 8(p¼ 0.21); I 2 ¼ 27%. Test for overall effect: Z ¼ 2.82 (p ¼ 0.005). Effect size estimates were combined across studies to obtain a summary statistic. We adopted fixed-effects models instead of random-effects models in the current analysis because no statistical heterogeneity was detected between trials. Under the fixedeffects model, we assume that there is one true ES, which is shared by all the included studies. Consequently, the combined effect of all included studies is our estimate of this common ES. 31,32 We calculated ES estimates between pre-intervention (control group) and post-intervention scores (experimental group) for a- tdcs stimulation. Separate ES estimates were calculated for scores after a-tdcs stimulation and sham stimulation at a single postintervention time point. Slowly ramping down initial current intensity after a minimal interval of stimulation is the de facto standard for sham stimulation in transcranial electrical stimulation research. 33 Data from Kim et al. 12 were excluded because of the significant difference between group outcome scores at baseline. ESs were calculated for all data for preepost and shamea-tdcs analyses in Tables 2 and 3, respectively. In studies where the mean and SD for a given outcome measure were not stated by the authors or accessible from the tables and figures, an was sent to the corresponding author asking for that information. In some cases, data were retrieved from figures using Java plot digitizer 34 to determine the pre- and post-intervention data and standard error. Effect size calculations were adjusted depending on the outcome measure. For outcome measures in which decreased time during a motor task demonstrates improved function, we entered the data in preepost fashion, with pre-intervention data as the control group and post-intervention data as the experimental group. For Hummel et al. 13 (PS), Kim et al. 11 (BBT), Kim et al. 12 (FM Test), and Stagg et al. 14 (GS), higher scores during a motor task demonstrate improved function. Based on the organization of data in the RevMan, this resulted in a negative ES after statistical analysis. Consequently, multiplication of the SMD of these outcomes by 1 ensured that all ESs were displayed in a positive direction. Note: The data from Stagg et al. 14 showed a decrease in GS from preto post-intervention and between sham and a-tdcs, resulting in the negative ES value after correction. Meta-analyses were performed to calculate a weighted intervention effect across all trials using a fixed-effect model; results were expressed as an SMD with a 95% CI. Statistical heterogeneity was assessed using I I 2 values of less than 80% preclude the use of meta-analyses (the studies findings must be summarized separately), whereas values more than 80% support the use of meta-analytic comparisons. We present two fixed-effects metaanalyses on the effectiveness of a-tdcs for all included trials. One analysis determines pre- vs. postea-tdcs effects, and the other determines the effect of sham stimulation vs. a-tdcs. Quality assessment Study quality was assessed using the Physiotherapy Evidence Database (PEDro) scale 36,37 (Table 4). The PEDro scale includes 11 specific criteria, in which the first item assesses the external validity and the remaining ten items assess the internal validity. The PEDro scale is scored out of 10; the higher the PEDro score, the higher the assumed quality of the trial. The following cutoff points, defined by Foley et al., 38 are used to assess the quality of each trial: 9e10, excellent; 6e8, good; 4e5, fair; and below 4, poor. Publication bias was assessed using funnel plots (Figures 2 and 3). Results Identification and selection of studies Figure 1 shows the flowchart for the selection of studies. The literature search of online databases identified a total of 96 studies. After removal of duplicates (32) and titles or abstracts not pertaining to the research purpose (51), 13 potentially relevant articles were identified. From these 13 studies, eight matched the inclusion and exclusion criteria seen in Table 1, yielding the eight studies included in this meta-analysis. Table 4 PEDro scale results for quality assessment of articles Included studies PEDro Boggio et al. 9 7 Fregni et al Hummel, Hummel et al Hummel et al Kim et al Mahmoudi et al Stagg et al PEDro ¼ Physiotherapy Evidence Database.

5 166 A.J. Butler et al. / Journal of Hand Therapy 26 (2013) 162e171 following a-tdcs. 9e15,22 The pooled SMD was 0.40 (95% CI ¼ 0.10e 0.70, z ¼ 2.59, p ¼ 0.010) (Table 2), and heterogeneity was low (I 2 ¼ 0%). The pooled ES of 0.40 suggests that a-tdcs has a small to moderate effect in improving motor function of the contralateral upper limb between pre- and postea-tdcs measurements in stroke patients. 39 These data provide evidence that the application of a- tdcs may contribute to enhanced motor outcomes in the upper extremity of stroke survivors compared with baseline. Change in motor function in stroke patients: a-tdcs vs. Sham a-tdcs Fig. 2. Funnel plot to explore publication bias in eight trials of preepost effects of anodal transcranial direct current stimulation on motor function in subjects with stroke. The funnel plot was roughly symmetrical about the SMD (vertical line), indicating no publication bias. 57 The open squares correspond to the treatment effects from individual trials, and the dashed lines show the expected 95% confidence intervals around the SMD. The effect size is depicted on the x-axis and SE on the y-axis. SE ¼ standard error. Overview of trials All demographic information and stroke characteristics are presented in Table 5. A total of 64 subjects with a stroke received a- tdcs as an intervention to facilitate improvement in motor function outcome measures. Average age of the subjects ranged from 53.7 to 66.4 years. Most subjects suffered an ischemic stroke, with very few having suffered a hemorrhagic stroke. Stroke duration ranged from 34 days to 44.3 months. All studies examined the effect of a-tdcs had on upper extremity motor function. Mean muscle strength, according to the Medical Research Council (MRC) scale (from 0 to 5, with 5 being normal muscle strength), ranged from 2.7 to 4.8 9,10,12,13,15 and 3 but <5. 11 The MRC score was not available for two studies. 14,22 Change in motor function in stroke patients: PreePost a-tdcs Forest plots for the standard mean difference in JTT, RT, PS, BBT, FM Test, and GS following a-tdcs, with 95% CIs, are presented in Figure 1. A pooled analysis of the eight studies showed an overall significant increase in the level of motor function in stroke patients As with preepost measures, functional outcome scores also differed after a-tdcs stimulation and sham stimulation at a single post-intervention time point, with generally improved motor function in the a-tdcs group as compared with sham. Postea-tDCS and sham data were compared for all studies, with the exception of Kim et al. 12 The pooled results of these studies 9e11,13e15,22 showed a significant effect of treatment over placebo on motor function (0.49 [0.18, 0.81], z ¼ 2.82, p ¼ 0.005, I 2 ¼ 27%) (Table 3). The pooled ES of 0.49 suggests that a-tdcs has a small to moderate effect in improving motor function of the contralateral upper limb as compared with sham treatment. 39 Electric field orientation, current density, and duration of a-tdcs The orientation and placement of electrodes for all subjects were similar for all included studies, with the anode placed on the scalp overlying the affected M1. Important parameters for tdcs application were current density, size of the electrode, and intensity and duration of stimulation (Table 6). Of the included studies, seven of eight used an intensity of 1 ma, 9e11,13e15,22 with only one study 12 using an intensity of 2 ma. Current density (the product of stimulation intensity and electrode size) varied slightly between studies, ranging from to The smallest current density was applied through a 35-cm 2 electrode, with an intensity of 1mA, 9,10,14,22 whereas the highest current density was applied through a 25-cm 2 electrode, with an intensity of 2 ma. 12 In all included studies, the duration of a-tdcs stimulation was 20 minutes. 9e15,22 Method of quality assessment and publication bias The results of the quality assessment using the PEDro scale are shown in Table 4. All studies achieved a score of 7 or higher, with a mean score of 8. According to Foley et al., 38 a mean score of 8 denotes that all studies were of good to excellent quality. Additionally, publication bias was assessed with funnel plots and heterogeneity testing (Figures 2 and 3). The funnel plot for the eight studies comparing preepost measures revealed a roughly symmetrical distribution about the SMD (vertical line), with all studies falling within the 95% CI. These results allow us to conclude that there was no publication bias involved in the analysis. For the a-tdcs vs. sham comparison, the funnel plot again revealed a lack of publication bias for the seven studies involved. Discussion Fig. 3. Funnel plot to explore publication bias in six trials for the effects of anodal transcranial direct current stimulation vs. sham stimulation on motor function in subjects with stroke. No evidence of publication bias was shown. The open squares correspond to the treatment effects from individual trials, and the dashed lines show the expected 95% confidence intervals around the summary estimate. The effect size is depicted on the x-axis and SE on the y-axis. SE ¼ standard error. Although many studies have described improved upper limb motor function after the application of a-tdcs, the value of applying a-tdcs as a therapeutic intervention for upper limb stroke rehabilitation remains uncertain. Our meta-analysis of eight RCTs demonstrated that the application of a-tdcs over the affected M1 is associated with a small to moderate change in function when outcome scores were compared between baseline and end of study.

6 A.J. Butler et al. / Journal of Hand Therapy 26 (2013) 162e Table 5 Demographic and stroke characteristics of participants Included studies Sample size (n) Cause of stroke Mean time duration after stroke Mean muscle strength (MRC Scale) Mean age (yr) Boggio et al. 9 4 Infarction 40.9 mo Fregni et al Infarction 27.1 mo Hummel, Infarction 44.3 mo Hummel et al Infarction 41.8 mo Kim et al Eight infarction and two hemorrhagic 6.4 wk 3 but < Kim et al Infarction 34.0 d Mahmoudi et al Infarction 8.3 mo na 60.8 Stagg et al infarction and one hemorrhagic 40.2 mo na 66.4 MRC¼ Medical Research Council; na ¼ data not available. These results support the findings of a previous meta-analysis. 17 In addition, we provide new evidence that suggests that a-tdcs stimulation has a small to moderate effect in improving motor function of the contralateral upper limb when compared with sham stimulation. These findings are significant in that they lend further support to the amassing evidence that the application of a-tdcs as part of a poststroke upper limb intervention protocol may lead to motor recovery. Indeed, the current results extend the findings of Bastani and Jaberzadeh 17 who reported a small and nonsignificant effect (0.39 [ 0.17, 0.94], p ¼ 0.17) of a-tdcs on motor function in subjects with stroke. Specifically, while utilizing similar a-tdcs protocols to Bastani and Jaberzadeh, the current analysis identified two significant ESs (SMD, 0.40 preepost and 0.49 a-tdcs vs. sham). The current meta-analysis also included four additional studies not cited by Bastani and Jaberzadeh, as well as an a-tdcs vs. sham comparison. As a result, the present findings may be taken as incremental evidence that previous tentative conclusions still hold, even when considering more studies and comparisons. The present analysis identified two statistically significant ESs. Conceptually, the ES reflects the difference between the average patient receiving a-tdcs and the average control patient (i.e., baseline or sham), expressed in SD units. Therefore, the ES of 0.40 for the preepost comparison implies that the score of a person after application of a-tdcs is 0.40 SDs above the average baseline and hence exceeds the average baseline score by 67%. Similarly, an ES of 0.49 for the a-tdcsesham comparison indicates that the a-tdcs group exceeds the score of 68% of the patients in the sham group. For both comparisons, it should be noted that two studies yielded significantly higher SMDs, with 95% CIs that did not cross 0 13,15 (Tables 2 and 3). In examining study parameters, the duration of stimulation, current, and type of stroke were the same or similar to the other studies. Apparent difference between the studies by Hummel et al. and the others includes the current density (0.04 ma/cm 2 ), the time after stroke, and baseline level of function. According to previous research, higher current densities are associated with stronger effects of tdcs, which may have influenced the Table 6 a-tdcs parameters Included studies Size of reference electrode (cm 2 ) Intensity (ma) Current density (ma/cm 2 ) Boggio et al Fregni et al Hummel, Hummel et al Kim et al Kim et al Mahmoudi et al Stagg et al a-tdcs ¼ anodal transcranial direct current stimulation. Time (min) results, 6,40 but there is a need for further study in this area to determine if there is a doseeresponse effect. Recent literature 41 has examined the effect of time since stroke on functional outcomes, but again, more evidence is needed before definite conclusions can be drawn. In addition to the above factors, it is possible that other subject characteristics may affect the impact of tdcs. It has been shown that the location of stroke and brain structure involved may affect the impact of tdcs. 42,43 Some of the studies reported the specific lesion locations for their subjects, whereas other studies failed to report this information. In addition, we only included studies that applied a-tdcs over M1. The primary motor cortex is an essential component of the motor pathway; however, additional research is needed to determine optimum stimulation sites and their subsequent behavioral sequelae. The present analysis included only a-tdcs studies. Future analyses are needed to determine if other stimulation techniques (i.e., cathodal or bihemispheric stimulation) could yield similar results. Although all polarities of applied currents have been backed by research, 12,44,45 it has been shown that a-tdcs may be the most effective polarity in chronic stroke. 46 For example, several functional magnetic resonance imaging studies 47e50 have shown that overactivity in the unaffected hemisphere is correlated with impaired recovery of the affected hand in the subacute phase of stroke. However, in the chronic phase after stroke, neural overactivity in the unaffected motor areas has been demonstrated to have the opposite effect, with beneficial effects on the motor function of the affected hand. 48,50 The most likely explanation for this apparent contradiction is that in the chronic phase of stroke recovery, the unaffected hemisphere has begun to compensate for the functional impairments of the affected hemisphere. 46 As a result, facilitation of the affected hemisphere, rather than inhibition of the unaffected, may be a more useful approach to enhance motor function of the affected hand. Publication bias and study quality We conducted a fixed-effects model meta-analysis and calculated standard mean differences based on the inverse variance weighting method. Although random-effects models are appropriate when the aim is to generalize beyond the observed studies, 31 the meta-analysis in the present study was performed using fixedeffects analysis because no statistical heterogeneity was detected between trials. The low level of heterogeneity among the studies suggests no major clinical (i.e., participant and outcome) or methodical (i.e., study design or risk of bias) difference between them. 51 Funnel plots show symmetry about the mean with all studies falling inside the 95% CI, allowing for greater confidence that the selected studies were chosen in an unbiased fashion. In addition, the PEDro scores of each study were 8 or higher, indicating good methodical quality.

7 168 A.J. Butler et al. / Journal of Hand Therapy 26 (2013) 162e171 Effect size and sample size Of the eight included trials, three found an ES of 0.5 or greater, whereas the remaining five studies found ESs smaller than 0.5. However, none of the studies were adequately powered to detect this ES. Whether a study is able to statistically detect a difference between groups depends on the magnitude of the ES and the sample size. The effect of sample size on significance can best be visualized using the 95% CI, as wide intervals arise from small studies and the effect does not reach statistical significance when the interval includes the null value. The trials included in this systematic review had sample sizes ranging from 4 to 13 per group. For a trial with two independent samples, with alpha set to 0.05 and 80% power, the sample size required to detect a large ES (0.8) is 26 persons per group, a moderate ES (0.5) is 64 per group, and a small ES (0.2) is 394 per group. Therefore, in order for us to accurately assess the effects of existing a-tdcs interventions on upper limb motor impairment, we need more studies that have an appropriate statistical power to detect the minimum clinically important difference. Future studies should target common upper limb motor impairment measures as a primary end point and have performed appropriate power analyses for those measures. By the same token, if upper limb motor impairment is assessed as a secondary end point, we need studies that are adequately powered overall to detect a significant effect in these secondary outcomes. With these needs in mind, this meta-analysis provides estimates of ESs for minimum sample size considerations in future trials. Studies that involve a-tdcs interventions and examine preepost effects for JTT (SMD ¼ 0.44) require 43 persons per group for an alpha set to 0.05 and 80% power. Those that involve RT (SMD ¼ 0.56), PS (SMD ¼ 0.25), BBT (SMD ¼ 0.37), and FM Test (SMD ¼ 1.14) require 28, 128, 60, and nine persons per group, respectively. Furthermore, trials that are concerned with a-tdcs vs. sham effects need 76 (JTT), 24 (RT), 47 (PS), and 506 (BBT) persons per group. These sample size estimates represent the minimum number of subjects required to be sensitive relative to our computed ESs. One must take into account possible error in the ES estimates (not computation error but random statistical fluctuations) plus the error intrinsic to any study. Attention to subject attrition in multiple observation experimental protocols should also be taken into consideration when deciding on sample sizes for future studies. Limitations Despite promising results from this meta-analysis, the following limitations should be considered when interpreting their significance. First and foremost, the small number of studies (eight RCTs) limits the interpretation of efficacy data. Only the articles in English language published in peer-reviewed journals were included, which may have excluded some relevant articles and further limited our study numbers. Also, although the findings of statistically significant small to moderate treatment effects are encouraging, the current results must be explored in larger, more adequately powered trials. When compared with other meta-analyses using various treatment forms known to elicit upper extremity recovery after stroke, our results demonstrate promising effects of a-tdcs on upper limb recovery. A structured review and meta-analysis examining the effects of bilateral movement training yielded a large and significant ES of 0.73 for bilateral movement training in stroke patients. 52 The study incorporated similar outcome measures to the present analysis, including the BBT, RT, and FM Test. In addition, a recent meta-analysis examining the effect of constraint-induced movement therapy (CIMT) in stroke reported a moderate ES of 0.46 for the Wolf Motor Function Test. 53 Although our calculated ESs for a-tdcs are slightly lower than those for bilateral training and for Constraint-Induced Therapy, we must consider the limited number of RCTs for a-tdcs. The authors included 30 reports of 27 RCTs involving CIMT or modified CIMT. Seventeen of 25 total comparisons were RCTs in the bilateral movement training analysis. The analysis included a mix of impairment and functional outcome measures (JTT, pinch force, RT, FM Test, BBT, and GS) rather than one uniform measure. These outcomes measure different domains as defined within the International Classification of Functioning, Disability and Health framework for measuring health and disability. 54 It is widely recognized that dissimilar dependent measures may have different reliability and sensitivities to change and may therefore lead to different conclusions about the efficacy of various therapies under investigation. That said, all outcomes used in the current analyses are standard, functional outcome measures, standardized to the same scale by calculating the pooled SMD. By standardizing the data to an SMD, it is then possible to make comparisons between studies and determine the overall effect. Most studies reviewed suffered from methodological deficiencies beyond the type of design as randomized, quasiexperimental or observational. For example, insufficient consideration was given to participant dropout rate, the use of other concurrent interventions during the a-tdcs period, therapist adherence to the intervention program, evaluation of application of a-tdcs and competence of the interventionalist. Other methodological deficiencies included lack of a description of a-tdcs application, inadequate statistical power to calculate intervention effects, and the clinical relevance of results. Finally, many of the trials that were reviewed included combined treatment conditions, such as a-tdcs in conjunction with pharmacotherapy or a combination of a-tdcs and robotic therapy. These conditions were not included in the present analysis because the objective of this study was to examine the isolated effect of a- tdcs as a monotherapy as compared with placebo as monotherapy, without any other interventions to confound the effects. Based on the principles of Hebbian learning, 55 it is possible that combining the electrical stimulation of M1 with functional tasks may help to reinforce the involved motor pathways at the synaptic level and thus enhance functional performance over time. Areas for future research This meta-analysis is not definitive with respect to the clinical use of a-tdcs as a therapeutic modality. Although the present analysis has provided evidence for the benefit of a-tdcs in terms of functional outcomes for individuals after stroke, there are still a number of questions that remain unanswered. For example, it remains unclear if the type or location of stroke as well as the time since stroke are significant variables affecting post-tdcs results. Although a recent study demonstrates that a-tdcs does not improve clinical outcomes for acute stroke patients, and current research supports the use of a-tdcs for chronic stroke, the exact period to apply tdcs requires further exploration. 41 Due to the limited number of investigations with comparable follow-up data, the meta-analysis was restricted to data obtained immediately or very soon after the a-tdcs intervention. Therefore, although several investigations do point to long-term benefits of a-tdcs, 12 much additional research is required to confirm such benefits. It is also possible that prolonged application over multiple sessions may yield enhanced effects.

8 A.J. Butler et al. / Journal of Hand Therapy 26 (2013) 162e The mechanism of a-tdcs itself, although central to all interventions, was only rarely discussed in the included studies. It is assumed that the primary effects of a-tdcs are achieved by increasing corticomotor excitability within the stimulated regions 6 while decreasing the total local GABAergic interneuronal pool as a result of the stimulation. 14 Future animal and pharmacologic studies are needed to test the mechanism of a-tdcs modulation. Finally, it is important to note that a-tdcs should not be accepted as a neurotherapeutic panacea for upper limb motor recovery. It is likely that some clients may recover function without a-tdcs. Others may not be appropriate for this form of therapy and may in fact benefit more from alternative interventions such as CIMT, bilateral arm training, or others. Further, general questions about matching patient characteristics to therapeutic models should be investigated within the neurorehabilitation approach. For instance, it has been argued that the presence of finger extension and shoulder abduction within 72 hours after stroke predicts functional recovery. 56 This and other potential moderators should be assessed with respect to the effect of noninvasive stimulation. With the establishment of a highly effective form of therapy, researchers can begin to address the question of whom it will and will not benefit. Conclusion There is considerable room for improvement in future clinical trial design, including the use of common outcome measures and appropriate sample size, before definitive conclusions can be drawn on the use of this technique for the rehabilitation of patients with stroke. However, despite the weaknesses, our meta-analysis of eight randomized placebo-controlled trials provides further evidence that a-tdcs may help to improve motor function of the paretic upper limb in patients suffering from chronic stroke. Acknowledgments This work was supported by grants R21 AT from the National Institutes of Health (NIH) and B4657P from the Department of Veterans Affairs (VA). The authors certify that no party having a direct interest in the results of the research supporting this article has or will confer a benefit on them or on any organization with which the authors are associated, and, if applicable, the authors certify that all financial and material support for this research (e.g., NIH, VA, or National Health Service grants) and work are clearly identified in the manuscript. References 1. Adamson J, Beswick A, Ebrahim S. Is stroke the most common cause of disability? J Stroke Cerebrovasc Dis. 2004;13(4):171e Lo AC, Guarino PD, Richards LG, et al. Robot-assisted therapy for long-term upper-limb impairment after stroke. N Engl J Med. 2010;362:1772e Hendricks HT, van Limbeek J, Geurts AC, Zwarts MJ. Motor recovery after stroke: a systematic review of the literature. Arch Phys Med Rehabil. 2002;83: 1629e Schaechter JD. Motor rehabilitation and brain plasticity after hemiparetic stroke. Prog Neurobiol. 2004;73(1):61e Barreca S, Wolf SL, Fasoli S, Bohannon R. Treatment interventions for the paretic upper limb of stroke survivors: a critical review. Neurorehabil Neural Repair. 2003;17(4):220e Nitsche MA, Paulus W. Excitability changes induced in the human motor cortex by weak transcranial direct current stimulation. J Physiol. 2000;527(pt 3):633e Edwards DJ, Krebs HI, Rykman A, et al. Raised corticomotor excitability of M1 forearm area following anodal tdcs is sustained during robotic wrist therapy in chronic stroke. Restor Neurol Neurosci. 2009;27(3):199e Nitsche MA, Fricke K, Henschke U, et al. Pharmacological modulation of cortical excitability shifts induced by transcranial direct current stimulation in humans. J Physiol. 2003;553(pt 1):293e BoggioPS, Nunes A, Rigonatti SP, Nitsche MA, Pascual-Leone A, Fregni F. Repeated sessions of noninvasive brain DC stimulation is associated with motor function improvement in stroke patients. Restor Neurol Neurosci. 2007;25(2):123e Fregni F, Boggio PS, Mansur CG, et al. Transcranial direct current stimulation of the unaffected hemisphere in stroke patients. Neuroreport. 2005;16(14):1551e Kim DY, Ohn SH, Yang EJ, Park CI, Jung KJ. Enhancing motor performance by anodal transcranial direct current stimulation in subacute stroke patients. Am J Phys Med Rehabil. 2009;88:829e Kim DY, Lim JY, Kang EK, et al. Effect of transcranial direct current stimulation on motor recovery in patients with subacute stroke. Am J Phys Med Rehabil. 2010;89:879e Hummel FC, Voller B, Celnik P, et al. Effects of brain polarization on reaction times and pinch force in chronic stroke. BMC Neurosci. 2006;7: Stagg CJ, Bachtiar V, O Shea J, et al. Cortical activation changes underlying stimulation-induced behavioural gains in chronic stroke. Brain. 2012;135:276e Hummel F, Celnik P, Giraux P, et al. Effects of non-invasive cortical stimulation on skilled motor function in chronic stroke. Brain. 2005;128:490e Portney LG, Watkins MP. Chapter 16. Systematic Reviews and Meta-analysis. Foundations of Clinical Research: Applications to Practice. Upper Saddle River, NJ: Pearson Prentice Hall; e Bastani A, Jaberzadeh S. Does anodal transcranial direct current stimulation enhance excitability of the motor cortex and motor function in healthy individuals and subjects with stroke: a systematic review and meta-analysis. Clin Neurophysiol. 2012;123:644e Harvey RL, Stinear JW. Cortical stimulation as an adjuvant to upper limb rehabilitation after stroke. PMR. 2010;2(12 suppl 2):S269eS Hodics T, Upreti B, Alex A, et al. Transcranial direct current stimulation (tdcs) enhanced stroke recovery and cortical reorganizationdan ongoing clinical trial. Eur J Neurol. 2011;18(suppl 2): Hummel F, Cohen LG. Improvement of motor function with noninvasive cortical stimulation in a patient with chronic stroke. Neurorehabil Neural Repair. 2005;19(1):14e Kandel M, Beis JM, Ganis V, Prestini M, Paysant J, Jacquin-Courtois S. Transcranial direct current stimulation associated with physical therapy after stroke: feasibility of a prospective, randomised, double blinded, sham controlled study. Ann Phys Rehabil Med. 2011;54(suppl 1):e Mahmoudi H, Haghighi AB, Petramfar P, Jahanshahi S, Salehi Z, Fregni F. Transcranial direct current stimulation: electrode montage in stroke. Disabil Rehabil. 2011;33(15e16):1383e Polanowska K, Seniow J, Czlonkowska A Rules of application and mode of action of transcranial direct current stimulation in neurorehabilitation: primary motor cortex. Neurol Neurochir Pol. 2010;44(2):172e180. [Polish]. 24. Jebsen RH, Taylor N, Trieschmann RB, Trotter MJ, Howard LA. An objective and standardized test of hand function. Arch Phys Med Rehabil. 1969;50:311e Fugl-Meyer AR, Jaasko L, Leyman I, Olsson S, Steglind S. The post-stroke hemiplegic patient. 1. A method for evaluation of physical performance. Scand J Rehabil Med. 1975;7(1):13e Mathiowetz V, Volland G, Kashman N, Weber K. Adult norms for the Box and Block Test of manual dexterity. Am J Occup Ther. 1985;39(6):386e Gladstone DJ, Danells CJ, Black SE. The fugl-meyer assessment of motor recovery after stroke: a critical review of its measurement properties. Neurorehabil Neural Repair. 2002;16(3):232e Slade SC, Keating JL. Unloaded movement facilitation exercise compared to no exercise or alternative therapy on outcomes for people with nonspecific chronic low back pain: a systematic review. J Manipulative Physiol Ther. 2007;30(4):301e Deeks J, Higgins J. Statistical algorithms in Review Manager ; Available at: RevMan-5.pdf. Accessed May 1, Cohen J. Statistical Power Analysis for the Behavioral Sciences. 2nd ed. Hillsdale, NJ: Lawrence Erlbaum Publishers; Hedges LV, Vevea JL. Fixed- and random-effects models in meta-analysis. Psychol Methods. 1998;3(4):486e DerSimonian R, Laird N. Meta-analysis in clinical trials. Control Clin Trials. 1986;7:177e Ambrus GG, Al-Moyed H, Chaieb L, Sarp L, Antal A, Paulus W. The fadeindshort stimulationdfade out approach to sham tdcsdreliable at 1 ma for naive and experienced subjects, but not investigators. Brain Stimul; [Epub ahead of press]. 34. Joseph AH. Plot Digitizer ; Available at: get/multimedia/graphic/graphic-others/plot-digitizer.shtml. 35. Higgins JP, Thompson SG, Deeks JJ, Altman DG. Measuring inconsistency in meta-analyses. BMJ. 2003;327:557e Moseley AM, Herbert RD, Sherrington C, Maher CG. Evidence for physiotherapy practice: a survey of the Physiotherapy Evidence Database (PEDro). Aust J Physiother. 2002;48(1):43e Maher CG, Sherrington C, Herbert RD, Moseley AM, Elkins M. Reliability of the PEDro scale for rating quality of randomized controlled trials. Phys Ther. 2003;83:713e Foley N, Teasell R, Bhogal S, Speechley M. Stroke rehabilitation evidence-based review: methodology. Top Stroke Rehabil. 2002;10:1e Higgins JPT, Green S, eds. Cochrane Handbook for Systematic Reviews of Interventions: The Cochrane Collaboration. Hoboken, NJ: Wiley-Blackwell; 2011.