Article summary
Transcranial Direct Current Stimulation vs Sham Stimulation to Treat Aphasia After Stroke A Randomized Clinical Trial Julius Fridriksson, PhD; Chris Rorden, PhD; Jordan Elm, PhD; Souvik Sen, MD; Mark S. George, MD; Leonardo Bonilha, MD, PhD
IMPORTANCE Aphasia is a debilitating language disorder for which behavioral speech therapy is the most efficient treatment, but therapy outcomes are variable and full recovery is not always achieved. It remains unclear if adjunctive brain stimulation (anodal transcranial direct current stimulation [A-tDCS]) applied during aphasia therapy can improve outcomes.
OBJECTIVE To examine the futility of studying A-tDCS as an adjunctive intervention during speech therapy to improve speech production (naming) for individuals with long-term poststroke aphasia.
DESIGN, SETTING, AND PARTICIPANTS Double-blinded, prospective randomized clinical trial using a futility design to test adjunctive A-tDCS during speech therapy. The setting was an outpatient clinic. Enrollment of individuals began in August 2012 and was completed in March 2017, and the duration of follow-up was 6 months. Analyses began in April 2017. The study recruited from a volunteer sample, and 89 patients were screened. Patients with long-term (>6 months) aphasia due to 1 previous left hemisphere stroke were enrolled. In comparing A-tDCS and sham tDCS, patients were matched based on site (University of South Carolina or Medical University of South Carolina), baseline age, type of aphasia, and aphasia severity.
INTERVENTIONS Outpatient speech therapy for 3 weeks (15 sessions, 45 minutes each) combined with either A-tDCS vs sham tDCS applied to preserved left temporal lobe regions.
MAIN OUTCOMES AND MEASURES The primary outcome was the ability to name common objects, assessed twice before and after therapy.
RESULTS A total of 74 patients were enrolled. Participants had a mean (SD) age of 60 (10) years, had 15 (2) years of education, and were 44 (40) months from stroke onset. There were 52 men (70%) and 62 non-Hispanic white individuals (84%). Most were retired or not employed (59 [80%]). Broca aphasia was the most common aphasia type (39 [52.7%]). The adjusted mean (SE) change from pretreatment baseline in correct naming was 13.9 (2.4) words (95% CI, 9.0-18.7) for A-tDCS and 8.2 (2.2) words (95% CI, 3.8-12.6) for sham tDCS, with mean (SE) A-tDCS difference of 5.7 (3.3) words (95% CI, −0.9 to 12.3), indicating a relative 70% increase in correct naming for A-tDCS relative to sham. The futility hypothesis P value was .90, indicating failure to reject the null hypothesis and, therefore, providing no evidence that further study of A-tDCS is futile. No serious adverse events were associated with A-tDCS.
CONCLUSIONS AND RELEVANCE Our findings provide motivation to proceed with another trial to study the effect of A-tDCS on the outcome of aphasia treatment in individuals poststroke. Anodal tDCS during speech therapy is feasible and potentially transformative for aphasia treatment and should be further studied.
TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT01686373.
JAMA Neurol. doi:10.1001/jamaneurol.2018.2287 Published online August 20, 2018.
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Author Affiliations: Department of Communication Sciences & Disorders, University of South Carolina, Columbia (Fridriksson); Department of Psychology, University of South Carolina, Columbia (Rorden); Department of Public Health Sciences, The Medical University of South Carolina, Charleston (Elm); Department of Neurology, University of South Carolina, Columbia (Sen); Department of Psychiatry, The Medical University of South Carolina, Charleston (George); Department of Neurology, The Medical University of South Carolina, Charleston (George, Bonilha); Ralph H. Johnson VA Medical Center, Charleston, South Carolina (George).
Corresponding Author: Julius Fridriksson, PhD, Department of Communication Sciences & Disorders, Arnold School of Public Health, University of South Carolina, 915 Greene St, Discovery I, Columbia, SC 29208 (jfridrik@sc.edu).
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T he National Institute on Deafness and Other Commu-nication Disorders estimates that at least 1 million peopleexperience poststroke aphasia in the United States.1 Con- siderable evidence suggests behavioral aphasia treatment is effective in improving communication and quality of life in in- dividuals with long-term aphasia.2-4 Nevertheless, even with therapy, aphasia recovery is often minimal.5
During the past decade, several pilot studies have indi- cated adjunctive transcranial direct current stimulation (tDCS) may improve the effects of aphasia treatment.6-9 Transcra- nial direct current stimulation is a noninvasive method that uses an electrical current (1-2 mA) typically induced between 2 electrodes placed on the scalp. The specific neural mecha- nism underlying tDCS modulation is not completely under- stood, but anodal tDCS (A-tDCS) has been shown to generally enhance cortical activity, whereas cathodal stimulation usu- ally has the opposite effect.10
Based on promising pilot data,6,7 we carried out a double- blinded randomized clinical trial to test whether further in- vestigation of the efficacy of adjunctive A-tDCS combined with aphasia therapy to manage long-term poststroke aphasia is futile. We used a futility design in which the null hypothesis assumed a benefit of A-tDCS compared with sham tDCS (S-tDCS), and the alternative hypothesis assumed no differ- ence between A-tDCS and S-tDCS.11-13 Instead of demonstrat- ing efficacy, the futility design permits the identification of treatments that do not warrant further investigation, demon- strating a lack of superiority. Treatments for which a lack of superiority cannot be demonstrated are then suitable candi- dates for further investigation with traditional superiority trial designs.
Methods Patients The trial protocol is available in Supplement 1. Patients were enrolled from August 2012 to March 2017, and analyses be- gan in April 2017. Patient inclusion criteria was single-event ischemic stroke in the left hemisphere, longer than 6 months poststroke, between the ages of 25 and 80 years, previously right-handed, aphasia as confirmed using the Western Apha- sia Battery-Revised (WAB-R14), no magnetic resonance imaging (MRI) contraindications, and able to achieve at least 65% ac- curacy on a screening version of the aphasia treatment task (see details in the section titled Aphasia Treatment). The correla- tion between performance on the screening version of the aphasia treatment task and overall aphasia severity, mea- sured as the Aphasia Quotient (AQ; a 100-point scale) on the WAB-R, was r = 0.27, P = .02. Exclusion criteria was history of brain surgery, seizures during the previous 12 months, sensi- tive scalp (per patient report), more than 80% naming accu- racy on the Philadelphia Naming Test (PNT),15 and unable to overtly name at least 5 of 80 items during pretreatment func- tional MRI (fMRI) sessions. The study was approved by the in- stitutional review boards at the University of South Carolina and the Medical University of South Carolina, where all data collection occurred. All participants provided written con-
sent for study inclusion. An independent data safety moni- toring board assessed safety and quality of the study.
Randomization and Blinding Eligible individuals were randomized to either A-tDCS or S-tDCS coupled with a computerized behavioral treatment of anomia.16 The Biostatistics Core at the Data Coordination Unit (located at Medical University of South Carolina) pro- grammed the randomization algorithm, which used the minimal sufficient balancing method to prevent imbalances in site, baseline age, aphasia type, and aphasia severity.17 Study participants and all members of the study team (the speech lan- guage pathologists [SLPs] who administered clinical testing and treatment, study coordinators, and principal and coinvestiga- tors) were blinded to the intervention assignment.
Transcranial Direct Current Stimulation Brain stimulation relied on a constant current stimulator (Pho- resor II PM850; Iomed Inc) that provided 1 mA of A-tDCS stimu- lation induced between two 5 × 5 cm saline-soaked sponges (electrodes). The selection of 1 mA current was consistent with our previous pilot studies and our in-house data suggesting that 1 mA is less likely to induce scalp pain compared with 2 mA, a current strength also commonly used in the literature. The an- ode electrode was placed on the left scalp over a targeted cor- tical region and the cathode electrode was placed on the con- tralateral supraorbital frontal scalp region (above the right eyebrow). All participants completed 2 MRI sessions at base- line, which included T1- and T2-weighted structural MRI and a picture naming fMRI protocol. As our goal was to stimulate surviving eloquent tissue, the anodal electrode was placed over the temporal lobe region with the highest naming related ac- tivation on the fMRI (for more details on the fMRI setup, see the study by Fridriksson5). Each individual’s fMRI data were coregistered w ith their T1 sc an, and a magnetic position tracker (Ascension Technology flock-of-birds) in combination with MRIreg (http://people.cas.sc.edu/rorden /mricro/mrireg/index.html) was used to coregister each individual's scalp coordinates with their T1 scan. Using this setup, the desired cortic al region was loc ated and demarcated on a latex cap worn by the patient. This cap was
Key Points Question For individuals with long-term poststroke aphasia undergoing speech therapy, is it futile to conduct further research to evaluate the treatment efficacy of brain stimulation (anodal transcranial direct current stimulation [tDCS]) as an adjunctive intervention to improve speech production (naming)?
Findings This randomized clinical trial used a futility design to test adjunctive anodal tDCS during speech therapy among 74 patients with long-term aphasia who received 3 weeks of therapy coupled with either anodal tDCS or sham tDCS. The magnitude of pretreatment to posttreatment improvement using anodal tDCS compared with sham did not find evidence that further investigation of anodal tDCS was futile.
Meaning Anodal tDCS during speech therapy should be further assessed for treatment of patients with aphasia.
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carefully fitted on the patient prior to the start of each tDCS administration to accurately position the anode electrode in the same area from one day to the next. Following positioning, the cap was removed and the electrodes were held in place with self-adhesive bandages. The scalp coordinates where the left hemisphere electrode was placed for each participant can be seen in eFigure in Supplement 2. The A-tDCS stimulation was started at the beginning of the behavioral treatment sessions and remained active during the first 20 minutes of the 45- minute treatment session. The 20-minute stimulation period was chosen based on our preliminary studies that suggested it was well tolerated by participants and was not associated with serious adverse events. Typically, participants in tDCS studies report itching or tingling sensation under the electrodes during the first 15 to 20 seconds of stimulation; however, this sensation is transient.10 To blind patients as to whether they were receiving active or sham tDCS, the same scalp sensation was induced during the start of the S-tDCS sessions when the tDCS stimulation was applied to the scalp for 30 seconds but then the current was gradually decreased over 15 seconds as the current was shunted to a load resistor. In-house hardware was used to mask treatment type (A-tDCS vs S-tDCS) for both patients as well as the SLPs. The described randomization scheme directed an independent technician to set the position of an internal switch on the sham controller. Neither the patient nor SLP was aware of the position and the SLP did not know which switch position (X or Y) was the sham position. Treatment type was encoded in the software so the SLP only needed to enter a patient and session number to start stimulation without knowing whether those specific numbers were assigned to A-tDCS or S-tDCS. Following each individual’s treatment, a technician validated whether the tDCS device was delivering anodal or sham stimulation.
Aphasia Treatment The aphasia treatment was performed through a computer- ized task that involved matching pictures depicting common ob- jects with words that were heard (via headphones) and seen (the face of the speaker below the nose is shown on the computer screen).7,16 Patients were instructed to press a green response button if the picture and spoken word matched and a red re- sponse button if they did not. Incorrect matches included a se- mantic foil, a phonological, or an unrelated word. Half of the pairs represented a correct match. Immediate feedback was pro- vided following each response, and task accuracy was dis- played on the computer screen at the end of each session to allow patients to monitor their progress. A total of 160 low-, me- dium-, and high-frequency words not included on the PNT were targeted in the computerized treatment task. Most partici- pants completed treatment in clinics, whereas a few received treatment at their place of residence.
Procedures The initial screening visit occurred over 2 days. Participants underwent a medical history and comprehensive neurologic, language, and cognitive testing using the following tests: Na- tional Institutes of Health Stroke Scale,18 WAB-R, the Boston Naming Test–Second Edition,19 the Pyramids and Palm Trees
Test,20 the Apraxia of Speech Rating Scale,21 and the matrix reasoning subtest of the Wechsler Adult Intelligence Scale, Third Edition.22 Consistent with what is a typical dose of out- patient therapy for long-term aphasia in the United States,23
both study arms received 3 weeks of the computerized ano- mia treatment (15 sessions within 21 days, 45-minute ses- sions). Patients were assessed at the end of each treatment session for adverse events, vital signs, and discomfort ratings (for potential scalp sensations associated with tDCS) using the Wong-Baker FACES Pain Rating Scale.24 Treatment fidelity was monitored through periodic observations of assessment and treatment sessions by the principal investigator (J.F.) and the lead clinician in charge of the study.
Outcomes The primary end point was the change in the number of cor- rectly named common objects at 1 week posttreatment, mea- sured using a portion (Naming 80) of the trained items from the treatment plus the PNT. Only some treatment items were selected to decrease assessment time at each time. The PNT is commonly used in research studies to assess anomia and in- cludes 175 pic tures depic ting mid-f requenc y to high- frequency nouns, which patients are instructed to name 1 item at a time. Naming accuracy was scored based on PNT scoring guidelines.15
The pretreatment to posttreatment change was com- puted as the difference between the mean of the 2 pretreat- ment assessments and the mean of the 2 posttreatment ses- sions. Secondary outcomes included change in the number of correctly named items at 4 and 24 weeks posttreatment.
Statistical Analysis The primary null hypothesis assumed A-tDCS would lead to at least a 1.5-item greater improvement in correct naming compared with S-tDCS. The alternative hypothesis assumed no difference between the 2 conditions. The statistic al hypotheses were H0: μA − μS ≥ 1.5 vs HA: μA − μS <1.5, in which μA was the expected change (pretreatment and 1-week post- treatment) in the number of correctly named items in the A-tDCS group and μS was the expected change in the S-tDCS group. If the null hypothesis was rejected at a 1-sided signifi- cance level of .10, then A-tDCS would be unlikely to be effec- tive for aphasia management, and further study of A-tDCS would be considered futile.
In preliminary studies with 5 treatment sessions, the mean difference between the A-tDCS and S-tDCS groups in naming accuracy was 2.5 words (change from baseline; pooled SD 2.6), and the S-tDCS group mean change was 4.0.6,7 To estimate the sample size, we assumed the mean change from baseline to 1-week posttesting for the A-tDCS group under the null hy- pothesis of nonfutility to be μA = μS + 1.5 = 4 + 1.5 = 5.5. Un- der these assumptions (H0: μA = 5.5 and HA: μA = 4) with 33 in- dividuals per group, a 2-sample t test with a .10 1-sided significance level will have 85% power to reject the null hy- pothesis that the A-tDCS treatment is 1.5 points better than S-tDCS and declare futility when the A-tDCS treatment comes from a distribution with mean change of 4 (assuming the pooled SD is 2.6). Assuming a dropout rate of 5%, the
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required sample size was inflated from 33 to 37 per group to account for the effect of the dropouts in the intent-to-treat analysis using an inflation factor.25
The primary analysis was an intent-to-treat analysis and was adjusted for enrolling site and baseline aphasia severity measured as the AQ from the WAB-R. Missing data (for 1 pa- tient) were imputed using multiple imputation, assuming a monotone missing mechanism, missing at random, and used 10 imputed data sets (SAS PROC MI and MIANALYZE). All analy- ses were conducted in SAS version 9.3 (SAS Institute Inc).
Results Between August 2012 and April 2017, 89 patients were screened, and 74 patients (83%) were enrolled (Figure 1). Thirty- four individuals (41%) were randomized to receive A-tDCS, and 40 (48%) were randomized to receive S-tDCS. The last indi- vidual was randomized during April 2017. On May 25, 2017, the study database was partially locked, up to and including the 1-week posttreatment visits. Once all follow-up visits were com- pleted, the database was locked on November 8, 2017. One in- dividual withdrew consent after completing posttreatment as- sessments, and 1 individual was lost to follow-up after the 11th treatment session. Therefore, the primary outcome was miss- ing for only 1 individual.
Two individuals who had hemorrhagic stroke rather than ischemic stroke were erroneously enrolled, both in the S- tDCS group. As this was an intent-to-treat trial, their data were included in the primary analyses. Baseline demographic and clinical characteristics were similar between the 2 treatment arms (Table 1). The enrolled individuals had a mean (SD) age of 60 (10) years, had 15 (2) years of education, and were 44 (40) months from stroke onset. There were 52 men (70%) and 62
non-Hispanic white individuals (84%). Most were retired or not employed (59 [80%]). Broca aphasia was the most common aphasia type (39 [52.7%]). Several of the clinical characteris- tics were somewhat higher on average at baseline in the A- tDCS group, although not statistically significantly different from the S-tDCS group. eTable in Supplement 2 compares the distribution of aphasia types and severity in the current trial with a large national cohort of patients with long-term apha- sia (AphasiaBank26). Overall, the current trial included more severe aphasia than the AphasiaBank cohort as indicated by a lower WAB-R AQ and has greater rate of Broca aphasia and fewer participants with anomic aphasia. To ensure proper blinding, each patient and clinician was asked to guess the stimulation type at the end of their treatment phase. Pa- tients’ guessing accuracy was 47.9% and clinicians’ guessing accuracy was 54.2%, meaning that each group’s accuracy was essentially at chance guessing. All but 1 participant improved on the treatment task as suggested by greater task accuracy on
Figure 1. Participant Flow Diagram
89 Participants screened
15 Excluded (not eligible)
74 Randomized
34 Allocated to A-tDCS
33 Received 15 treatment sessions of A-tDCS
3 Lost to follow-up 1 Lost after the 11th treatment
session 2 Participants after the week-4
posttreatment sessions
40 Allocated to S-tDCS
34 Included in primary analysis 40 Included in primary analysis
39 Received 15 treatment sessions of S-tDCS
0 Lost to follow-up 1 Withdrew consent after
posttreatment sessions 1 Discontinued treatment sessions
owing to adverse events
A-tDCS indicates anodal transcranial direct current stimulation; S-tDCS, sham transcranial direct current stimulation.
Table 1. Baseline Demographics and Clinical Characteristicsa
Variable
Mean (SD)
A-tDCS (n = 34) S-tDCS (n = 40) Age, y 60 (11) 60 (10)
Men, No. (%) 24 (70.5) 28 (70)
Non-Hispanic white, No. (%) 27 (79.4) 35 (88)
Education, y 15 (3) 14 (2)
Time since stroke onset, mo 44 (45) 40 (35)
Picture word matching screen accuracy, %
76 (13) 73 (14)
WAB-R aphasia quotient 60 (19) 56 (20)
BNT total No. correct 22 (19) 17 (16)
PPTT total 46 (4) 46 (4)
Matrix reasoning-WAIS III 12 (6) 11 (5)
ASRSb 3 (2) 3 (2)
NIH Stroke Scale scoreb 5 (3) 5 (3)
PNT correct 62 (45) 55 (41)
Naming 80 correct 21 (18) 16 (16)
History, No. (%)
Diabetes 5 (14.7) 6 (15)
Depression 4 (11.7) 9 (22.5)
Aphasia type, No. (%)
Global 1 (2.9) 2 (5.0)
Broca aphasia 18 (52.9) 21 (52.5)
Transcortical motor 1 (2.9) 0 (0.0)
Wernicke aphasia 3 (8.8) 2 (5.0)
Transcortical sensory 0 (0.0) 0 (0.0)
Conduction 6 (17.6) 9 (22.5)
Anomic 5 (14.7) 6 (15.0)
Abbreviations: ASRS, Apraxia of Speech Rating Scale; A-tDCS, anodal transcranial direct current stimulation; BNT, Boston Naming Test; NIH, National Institutes of Health; PNT, Philadelphia Naming Test; PPTT, Pyramids and Palm Trees Test; S-tDCS, sham transcranial direct current stimulation; WAB-R, Western Aphasia Battery-Revised; WAIS III, Wechsler Adult Intelligence Scale. a No statistically significant differences between groups were detected at
baseline (P > .05). b Higher scores indicate that they were worse.
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the last treatment session compared with the first treatment session (overall mean [SD] change in accuracy was 10.3 [7.9]), suggesting that patients were actively participating in the apha- sia therapy and were compliant with the task.
Table 2 demonstrates the results from the primary analy- sis, which is based on the intent-to-treat sample (n = 74). The P value of .90 indicates a failure to reject the null hypothesis, and there is no evidence that further investigation of A-tDCS would be futile as an adjunctive treatment for poststroke apha- sia. Baseline aphasia severity (AQ) was correlated with the over- all improvement in naming at 1 week posttreatment (Pearson ρ = 0.29, P = .01). The adjusted mean (SE) 1-week posttreat- ment change was an increase in 13.9 (2.4) (95% CI, 9.0-18.7) items correctly named for the A-tDCS group and 8.2 (2.2) (95% CI, 3.8-12.6) for the S-tDCS group (mean [SE] difference of 5.7 [3.3]; 95% CI, −0.9 to 12.3; Figure 2). The results of an unad- justed, completers-only analysis excluding the 2 ineligible patients with hemorrhagic stroke (n = 71) of the primary out- come were consistent with the primary analysis of the intent- to-treat sample (test of H0: μA − μS ≥ 1.5; t statistic, 1.35; 1-sided P = .91). Because of an imbalance at baseline on the primary outcome, a sensitivity analysis was conducted and the pri- mary outcome was adjusted for baseline PNT + Naming 80 score, treatment site, and baseline AQ; the results were con-
sistent with the primary analysis (test of H0: μA − μS ≥ 1.5; t sta- tistic, 1.2; 1-sided P = .89). At 4 weeks posttreatment, the ad- justed mean (SE) change from baseline in correct naming was an increase in 16.8 (2.8) correctly named (95% CI, 11.3-22.4) for A-tDCS and 9.4 (2.5) (95% CI,4.4-14.5) for S-tDCS (intent-to- treat sample, adjusted for site and baseline aphasia severity) (test of μA−μS ≥ 1.5, 1-sided P = .94). At 24 weeks posttreat- ment, the adjusted mean (SE) change from baseline in correct naming was 14.9 (3.7) (95% CI, 8.8-21.1) for A-tDCS and 7.1 (3.3) (95% CI, 1.59-12.0) for S-tDCS (intent-to-treat sample, ad- justed for site and baseline AQ) (test of H0: μA−μS ≥ 1.5, 1-sided P = .90).
The treatment sessions were well tolerated. There were 2 enrolled individuals (3%) who did not receive all 15 treatment sessions (1 A-tDCS individual and 1 S-tDCS individual). The A-tDCS individual dropped out after treatment session 11. The S-tDCS individual experienced a seizure during the course of the trial, and treatment sessions were subsequently discontin- ued. Importantly, the individual who experienced the seizure was in the S-tDCS group, thus receiving sham stimulation.
There were 8 mild, nonserious adverse events (Table 3), and there were no statistically significant differences be- tween treatment groups for number of adverse events. Two individuals (6%) in the A-tDCS group experienced transient scalp redness/irritation (erythema) compared with none in the S-tDCS group. On the Wong-Baker FACES Pain Rating Scale, most often individuals reported no hurt: 94% (n = 476) in A-tDCS vs 86% (n = 511) in S-tDCS. The highest pain rating reported was 3 (indicating “hurts even more”), which was reported 4 times by 2 individuals (3%), both in the S-tDCS group. Vital signs were similar between groups for all treat- ment sessions.
Discussion This study found no evidence that further study of adjunc- tive A-tDCS would be futile when combined with behavioral aphasia treatment. Given that we failed to reject the null hy- pothesis, that A-tDCS results in better treatment outcome than S-tDCS, the results suggest a larger trial may be warranted to further evaluate the effects of A-tDCS on aphasia treatment. The current results, along with our previous smaller pilot studies6,7 lend support to the underlying scientific hypoth-
Figure 2. Mean (SE) Change in Correct Naming by Treatment Group
25
20
15
10
5
0
Ch an
ge F
ro m
B as
el in
e in
C or
re ct
N am
in g
Time Posttreatment, wk 1 4 24
A-tDCS S-tDCS
A-tDCS indicates anodal transcranial direct current stimulation; S-tDCS, sham transcranial direct current stimulation.
Table 2. Primary Outcome: Change in Correct Naming on Philadelphia Naming Test and 80 Trained Items at 1-Week Posttreatment Period
Variable Mean (95% CI) H0: μA−μS ≥ 1.5 t Statistic P Value (1-sided)
Intent-to-Treat Sample, Adjusted Means A-tDCS (n = 34) 13.9 (9.0 to 18.7)
1.27a .896S-tDCS (n = 40) 8.2 (3.8 to 12.6)
Difference 5.7 (−0.9 to 12.3)
Completers Only Sample, Unadjusted Means A-tDCS (n = 33) 14.0 (7.7 to 20.4)
1.35b .909S-tDCS (n = 38) 7.8 (4.3 to 11.4)
Difference 6.2 (−0.7 to 13.2)
Abbreviations: A-tDCS, anodal transcranial direct current stimulation; NA, not applicable; S-tDCS, sham transcranial direct current stimulation. a Adjusted for site and baseline
aphasia quotient. b Unadjusted.
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esis that adjunctive A-tDCS improves the outcomes of long- term aphasia treatment among individuals with poststroke aphasia, although further research is needed to test this definitively.
Breitensten and colleagues2 found that baseline stroke severity was associated with aphasia treatment outcome in which patients with more severe aphasia were less likely to re- spond. In the current trial, stroke severity, as assessed by the National Institutes of Health Stroke Scale, and the distribu- tion of aphasia types, was comparable across the 2 study arms. However, there were several numerical differences in aphasia severity at baseline, all of which were not statisti- cally significant, but the A-tDCS group was nominally better at baseline. However, the difference in the primary outcome remained even after adjusting for baseline differences in apha- sia severity; thus, the observed difference is unlikely to be due to differences in baseline status.
Naming was chosen as the primary outcome because ano- mia is present in all types of aphasia regardless of severity, and naming is commonly targeted in aphasia treatment to im- prove word retrieval and speech production. Although nam- ing is not synonymous with speech production, naming im- pairment is directly associated with poor quality of life in patients with aphasia.27 Yet, other pilot studies have also sug- gested adjunctive A-tDCS during aphasia treatment can re- sult in greater improvements in functional communication abilities.28 Whereas the standard of care for aphasia is behav- ioral speech therapy,29 a minimal clinically important differ- ence in naming accuracy has not been established for English- speaking patients. Specifically, it is not clear what amount of improvement in language processing patients would con- sider as enhancement of daily functioning, although we be- lieve that even 1 to 2 words’ improvement could be meaning- ful to some patients who have very limited speech output. At all 3 times posttreatment, the change from baseline in A-tDCS was nearly twice as large as that of the S-tDCS group, an ef-
fect that is likely to be meaningful. Nevertheless, based on the current data, we cannot assume the treatment effect demon- strated here would generalize to functional communication abilities.
The treatment task used here emphasizes lexical-semantic processing and was selected because it has been shown to im- prove naming in persons with aphasia.6,7,16 Most importantly, it enabled controlling of equal treatment time and intensity across the 2 study arms. There are other forms of aphasia therapy that are probably equally or more effective for improving naming, and the purpose of the current trial was not to confirm the effective- ness of aphasia therapy but to assess the adjuvant benefit of A- tDCS when combined with a proven form of aphasia therapy. Based on first principles, we can see no reason why the effect of A-tDCS should be treatment-type–specific suggesting that an effect of A-tDCS would likely generalize to other kinds of apha- sia treatment approaches. However, this may need to be veri- fied in future studies. It is also important that future studies as- sess factors such as the length of the aphasia treatment session in relation to the optimal tDCS duration and intensity as we do not know whether and how much the current results are spe- cific to the current study protocol.
Given that the total number of A-tDCS sessions adminis- trated here was more than 500, the rate of adverse events shown in this study would have to be considered very low. Erythema on the scalp occurred exclusively in the A-tDCS group (6% of in- dividuals) but was mild and resolved within 1 to 2 days. These data suggest A-tDCS administered at 1 mA for 20 minutes is safe and has minimal adverse effects. A recent Cochrane review of tDCS studies in aphasia also reported no serious adverse events for any studies included in the review.30
Limitations The current study was not powered for superiority analyses to compare A-tDCS with S-tDCS. Therefore, we cannot con- clude that A-tDCS is effective for boosting the effect of apha- sia even though the magnitude of naming improvement was numerically greater with A-tDCS compared with S-tDCS. It is also a limitation that we cannot definitively determine that the naming improvements translate to improvements in quality of life.
Conclusions The results reported here suggest that adjunctive A-tDCS is wor- thy of further study in a randomized clinical trial as an option to enhance the effect of behavioral treatment of aphasia in stroke. They provide the necessary basis to inform a defini- tive trial to assess A-tDCS as a treatment option for aphasia.
ARTICLE INFORMATION
Accepted for Publication: May 17, 2018.
Published Online: August 20, 2018. doi:10.1001/jamaneurol.2018.2287
Author Contributions: Drs Fridriksson and Elm had full access to all of the data in the study and take
responsibility for the integrity of the data and the accuracy of the data analysis. Concept and design: Fridriksson, Rorden, Elm, George, Bonilha. Acquisition, analysis, or interpretation of data: All authors. Drafting of the manuscript: Fridriksson, Elm, Bonilha.
Critical revision of the manuscript for important intellectual content: All authors. Statistical analysis: Fridriksson, Rorden, Elm, Bonilha. Obtained funding: Fridriksson, George. Administrative, technical, or material support: Fridriksson, Rorden, George, Bonilha. Supervision: Fridriksson, George, Bonilha.
Table 3. Adverse Eventsa
Adverse Event
Treatment, No. (%) of Patients
A-tDCS (n = 34) S-tDCS (n = 40) Headache 0 (0) 2 (5)
Dizziness 1 (3) 2 (5)
Erythema 2 (6) 0 (0)
Convulsion 0 (0) 1 (2.5)
Hypertension 0 (0) 1 (2.5)
Abbreviations: A-tDCS, anodal transcranial direct current stimulation; S-tDCS, sham transcranial direct current stimulation. a No statistically significant differences between treatment groups were
detected (Fisher exact test, 2-sided P > .20).
Research Original Investigation Transcranial Direct Current Stimulation to Treat Aphasia After Stroke
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Conflict of Interest Disclosures: None reported.
Funding/Support: This research was funded by the National Institute on Deafness and Other Communication Disorders (grant DC011739).
Role of the Funder/Sponsor: The funder had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.
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Transcranial Direct Current Stimulation to Treat Aphasia After Stroke Original Investigation Research
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