PONE-D-19-28981

Effect of transcranial direct current stimulation on cognitive function in stroke patients: a systematic review and meta-analysis

PLOS ONE

Dear Dr. Liu,

Thank you for submitting your manuscript to PLOS ONE. Your paper was reviewed by two experts on the brain stimulation field, both of them found that the aim of the study has high relevance, however, they have also indicated that the present version of the paper suffers from many shortcomings, mainly related to the interpretation of the results. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the all points raised during the review process.

We would appreciate receiving your revised manuscript by 19th of January, 2020. When you are ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file.

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Andrea Antal, PhD

Academic Editor

PLOS ONE

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Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #1: No

Reviewer #2: Partly

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2. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: No

Reviewer #2: Yes

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3. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: Yes

Reviewer #2: Yes

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4. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #1: No

Reviewer #2: No

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5. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: General assessment:

The article fits the scope of the journal. The research is novel. The title is representative of the articles contents. The abstract summarises the contents clearly. The state-of-the-art is well described in the knowledge gap defined. The objectives are well articulated. The applied research methodology is solid, but the comparator as a covariate in the included studies should be taken into account to a greater extent. The review has been registered retrospectively. The results are reliable, but of limited validity and the objectives have partly been reached. Important limitations arising from the choice of comparators should correctly be mentioned. The conclusions are at the moment not justified.

Detailed assessment (the pagination refers to the PDF-preprint):

your work examines the effects of anodal tDCS on cognition after stroke. To make this clear to the reader, I suggest to every time referred to „anodal tDCS“ throughout the manuscript, where appropriate. I would also recommend to check for language errors once again.

Page nine: the Prospero-ID presented in the abstract is wrong and refers to another publication. Please correct.

Page 9: you state, that tDCS was firstly developed in 1992. Please provide the corresponding citation for that.

Page 11: the term used for describing the comparator „passive stimulus“ seems to be a bit ambiguous, here. Apparently, you subsumed no additional intervention and sham tDCS under this term (as can be seen from table 1) and I would suggest to describe this here, also.

Page 12: please check the last sentence of the last paragraph in „outcome measures“, there seems to be a word missing.

Page 13: please cite the computer program review manager 5.3, as requested in the programme.

Page 13: „The publication bias was unable to be assessed due to a small number of studies included.“ I would regard this sentence as a part of the discussion section and hereby recommend to move it there.

Page 13: there seems to be a typo: „we determined that 15 studies with 16 trails“, shouldn‘t it be „trials“ here?

Figure 1: you excluded 33 studies, but the reasons are only given for 15. Moreover, you screened 49 full text articles and excluded 33 studies and this resulted in 15 included studies, but 49-33 should be 16. Please clarify. If the difference is due to an inequality of the number of fulltext publications, I would recommend to explain this to the reader with a comment in the figure caption.

Page 14: in the last sentence, after CNT and LOTCA, are these signs, commata? Please check.

Table 1: in Park 2013 there seems to be a typo (CPR instead of CRP).

Page 17: in the risk of bias section, you stated all trials reported complete outcome data and there were no selective reporting among the studies. I am a bit curious, how you did proof for complete report of outcome data, has there been an a priori published trial protocol for every single included study and you have checked it and there was no deviation? If no, I would disagree with your risk of bias rating and personally would rate it at least as unclear.

Table S3: blinding of participants and personnel - there are only five studies, who used sham tDCS as an adequate method of blinding of participants. I would disagree with your risk of bias rating in the studies which did not use sham tDCS and not rated as high risk of bias in this regard, since this might have introduced superior performance bias because of the absence of a placebo effect. Please check.

Page 11, Analysis: in order to reduce bias, introduced by analysing studies with different comparators (sham tDCS versus no sham tDCS) I would recommend to restructure the results section as follows (after having a look at the interventions listed in table 1):

analysis one: active tDCS versus sham tDCS

analysis tool: active tDCS versus no intervention

for reasons of simplicity, you may want to combine results MMSE and MoCA, if you regard both outcome measures measuring the same outcome.

Page 11: in the analysis corresponding to figure 2, you have calculated SMD on the basis of change scores (Park 2013) and total values. However, there is is mathematically not allowed. You can have a look into the Cochrane Handbook for further instruction.

Figure 3: in this subgroup analysis, the study „Tong 2018“ suddenly has got a different sample size and different means and standard deviations when compared to the analyses of figure 2, but shouldn‘t it be the same question please check.

Page 18: „Specialized in attention function“ I would recommend to rename this outcome into „attention“ for „attention function“ or something similar, since otherwise it may be hard for the reader to understand meaning.

Page 19: in the discussion section, you interpret the SMDs of your analyses in units of the underlying outcome measure „The improvement was around 1.01 points for the MMSE and 3.18 points for the MoCA.“ This is wrong. Please interpreted it in units of standard deviations or back transform it to the original outcome measure (the Cochrane Handbook gives advice on this).

Page 20: last sentence of comparing with others studies - but there is not a univocal corpus of evidence, that tDCS is beneficial… For a comprehensive overview of current reviews on this topic, you may have a look into the published Cochrane reviews of this or a related topic or into the tDCS guideline of Lefaucheur et al. (2017).

Page 20: strengths and limitations: I would add here the threat publication of bias and the comparator issue (sham tDCS versus no intervention), if appropriate.

Page 21, implications for research: you state, that „intensity (≥1.8 Ma or ≤1.5 Ma)“, but shouldn‘t it be „intensity (≥1.5 mA or ≤1.5 mA)“ instead? Please check.

Overall, a well written review with some methodological flaws in an emerging topic with very recent evidence.

Reviewer #2: In the paper, the authors aim to present a systematic review of the effects of transcranial stimulation on cognitive function in stroke patients. They also provide a meta analysis combining results from several reports that have evaluated the effects of this therapeutic technique after stroke; specifically, in cognitive function.

As the authors state, the effects of transcranial stimulation after stroke have been mainly focused on motor or speech ability, however, many of these patients have cognitive deficits that can represent important impairments in their quality of life. Rigorous systematic reviews about the effectiveness of tDCS in healthy individuals regarding cognitive function, have shown little-to-no reliable neurophysiologic and cognitive effects (Horvath et al., 2015). However, some researchers argue that the effects of tDCS in cognitive function might be more evident after cognitive disfunction. Therefore, evaluating if transcranial stimulation results in cognitive improvements after stroke, could be of significant value, considering the low cost and invasiveness of transcranial stimulation.

The review is generally sound in its methodology by having two reviewers that independently screened the studies, extracted the data, and evaluated the quality of included studies using the Cochrane Collaboration Risk of Bias Tool. I consider, that as a generality the inclusion criteria is adequate. However, when measuring the effects of tDCS after stroke, many other criteria comes in to play, making it difficult to assess the real effectiveness of the technique. For example, the study does not consider dividing results by the affected area, the extent of infarct, and the post-stroke time-line from treatment. They do present some information about such factors, but it needs a much stronger discussion and clarification on how these differences in population and methodologies may affect the results.

In general, I consider that although the study is methodologically valid, the language is unclear, making it difficult to follow. The authors should revise the language to improve readability. Additionally, I consider that there needs to be a more critical discussion of the results in order to consider the real state of the contribution of tDCS to cognitive function after stroke. Taking into consideration that this is a systematic review, the discussion is not very clear or needs further and more critical explorations. I think this could be resolved only with structural changes to the manuscript and noting that the availability of studies (due to variability of methods and populations) can not derive a reliable conclusion on the effects of tDCS in cognitive processes. The evidence shown by the authors, does point to some cognitive improvements, but there might be many considerations before arriving to a strong conclusion; the paper needs to have such discussion.

Some specific points of improvement are the following:

1. The reference in the following sentence does not reflect the information contained in authors’ statements that: “Stroke ranks No. 5 among all causes of death and is a leading cause of long-term disability in the world, which produces a major burden to society [1].”

[1] Burke JF, Lisabeth LD, Brown DL, Reeves MJ, Morgenstern LB. Determining stroke's rank as a

cause of death using multicause mortality data. Stroke. 2012;43(8):2207-11.

2. The authors claim that: “As a neuromodulatory approach, tDCS works by depolarizing or hyperpolarizing neuronal membrane potentials through the activation of sodium- and calcium-dependent channels and NMDA receptor activity, thereby modulating neuronal excitability”. However, no references are provided to support the claim.

3. Authors state “…and some preliminary studies also shown beneficial effects of tDCS on cognitive functions both in healthy subjects and stroke patients [9,10]”. However, authors cite:

Webster B, Celnik P, Cohen L. Noninvasive Brain Stimulation in Stroke Rehabilitation.

Fregni F, Boggio PS, Mansur CG, Wagner T, Ferreira MJL, Lima MC, et al. Transcranial direct current stimulation of the…

Please cite specific effects and studies.

4. On the results section the authors state that: “The results of subgroup analysis suggested that the effectiveness of tDCS seems to be slightly better for ischemic stroke than hemorrhagic stroke, but there was not significant difference.” However, in their conclusions they state: "tDCS is likely to be effective for patients with cognitive impairment after stroke, and the effect might be different among hemorrhagic and ischemic stroke". This conclusion doesn’t seem to be based on facts, at least from their own results.

5. Please consider revising the language specifically of the following paragraphs, in order to be able to follow the study properly:

“Except for high morbidity and mortality, the burden of stroke related-disability is another big problem in survivors, of which, the incidence of poststroke cognitive impairment (PSCI) is ranging from 22% to 47% in different studies [3-5], it has had a serious impact on both the economic and the quality of life.”

“Transcranial direct current stimulation (tDCS) was firstly developed in 1992 for

clinical purposes; nowadays, tDCS constitutes as a promising method in neurological

condition regulating.”

“Specifically, some other measurements are used for the evaluation of

attention and memory ability separately, including Computerized Neuropsychological

Test (CNT), Loewenstein occupational therapy cognitive assessment (LOTCA) and

various other forms of testing used in clinical.”

“Seven trials included two stroke types, seven studies focused on ischemic stroke and one studies on hemorrhagic stroke alone.”

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Reviewer #1: Yes: Bernhard Elsner

Reviewer #2: No

[NOTE: If reviewer comments were submitted as an attachment file, they will be attached to this email and accessible via the submission site. Please log into your account, locate the manuscript record, and check for the action link "View Attachments". If this link does not appear, there are no attachment files to be viewed.]

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PONE-D-19-28981R1

Effect of transcranial direct current stimulation on cognitive function in stroke patients: a systematic review and meta-analysis

PLOS ONE

Dear Dr. Liu,

Thank you for submitting your manuscript to PLOS ONE. Your paper was reevaluated by the same reviewers. Both of them indicated that the paper has improved a lot, however, there are still critical points that should be clarified. Therfore, after careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses all points raised during the review process.

We would appreciate receiving your revised manuscript by 11th of May, 2020. When you are ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file.

If you would like to make changes to your financial disclosure, please include your updated statement in your cover letter.

To enhance the reproducibility of your results, we recommend that if applicable you deposit your laboratory protocols in protocols.io, where a protocol can be assigned its own identifier (DOI) such that it can be cited independently in the future. For instructions see: http://journals.plos.org/plosone/s/submission-guidelines#loc-laboratory-protocols

Please include the following items when submitting your revised manuscript:

• A rebuttal letter that responds to each point raised by the academic editor and reviewer(s). This letter should be uploaded as separate file and labeled 'Response to Reviewers'.
• A marked-up copy of your manuscript that highlights changes made to the original version. This file should be uploaded as separate file and labeled 'Revised Manuscript with Track Changes'.
• An unmarked version of your revised paper without tracked changes. This file should be uploaded as separate file and labeled 'Manuscript'.

Please note while forming your response, if your article is accepted, you may have the opportunity to make the peer review history publicly available. The record will include editor decision letters (with reviews) and your responses to reviewer comments. If eligible, we will contact you to opt in or out.

We look forward to receiving your revised manuscript.

Kind regards,

Andrea Antal, PhD

Academic Editor

PLOS ONE

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Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation.

Reviewer #1: (No Response)

Reviewer #2: All comments have been addressed

**********

2. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #1: Partly

Reviewer #2: Yes

**********

3. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: No

Reviewer #2: Yes

**********

4. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: Yes

Reviewer #2: Yes

**********

5. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #1: Yes

Reviewer #2: Yes

**********

6. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: The authors address most of the comments very well, but a still would like to bring up a few points:

-Since you changed the term "anodal tDCS" from the original version of the manuscript to "active tDCS" is now unclear to the reader, which type of tDCS has been provided in the included studies. I therefore suggest to add the missing information in table 1 (maybe in the "intervention"column), since I regarded as crucial for the reader to exactly know, to what type of tDCS you refer your analysis)

- you state that "tDCS was first developed for clinical purposes in 1992" [6]. I am not sure, if reference [6] supports this. Maybe the authors would like to refer to PMID 10990547, which is a widely accepted reference in this regard.

- Please cite review manager 5.3 in the following way, which is shown in the programme under "help_>about"

- @Risk of bias within the studies: Here you refer the corresponding biases, which I regard as discussion and would recommend to move it to the discussion section to "strength and weaknesses"

- @synthesis of results: "Thirteen studies..." I would recommend to also state the number of participants included in these 13 studies.

- @General cognitive function: you have combined MMSE points together with MoCA points in a mean difference (MD) analysis. As far as I know, this is not allowed, since these are different outcome measures for the same outcome. I therefore recommend to recalculate these analyses and all corresponding subgroup analysis as well as the assessment of publication bias with standardised mean difference (SMD) analysis. I am not sure if this will substantially affect the magnitude and direction of effect, but it would be correct.

-@Subgroup analysis: when reporting the results of subgroup analysis I would recommend to also report the results of the Chi² test for subgroup differences at the very bottom of the forest plots.

-@ summary of the evidence: you state, that there were 14 RCTs included, but shouldn't it be either 15 (for qualitative analysis) or 13 (for quantitative synthesis) as presented in figure 1? Please check.

- "Furthermore, active tDCS was beneficial for attention specifically but not for memory specifically." I would recommend to move this sentence exactly one sentence downwards in order to make clear, the following sentence about the subgroup analysis refers only to the outcome general cognitive function.

-"In addition, the other two studies excluded from the statistical pooling both reported evidence of effects in favor of active tDCS regarding measures of cognitive function." I would recommend to move this sentence to the results section, because I I would regard them as a result, which should first be presented and second be discussed.

-@Comparison with other studies: "Moreover, in 2007, the evidence-based tDCS guidelines" shouldn't it be 2017? Please check.

-@Strengths and limitations: I think a considerable strength of your work is that you have searched specifically Chinese databases and that you have got included several RCTs from China, which the authors of comparable reviews have not. Maybe you would like to state that? I think this also contributes to defect, that source 38 only has identified only one RCT regarding to your research question.

-@Implications for practice: "are most likely to benefit from transcranial" One of the weaknesses of your work is the risk of bias rating of included studies, meaning that it is likely that your effects may be biased or overestimated. Therefore I would suggest to change, i.e. to downgrade your statement a bit and mention the considerable risk of bias in the included studies

-@implications for practice:"(ischemic MD = 3.67; hemorrhagic MD = 3.12) and shorter disease duration (< 30 days MD = 3.68;

30 days -50 days MD =3.10; = 50 days MD = 1.95);" I would recommend not to state the effect sizes here in the discussion section, since I think it will confuse the reader. I think it would be better to describe it and to refer to the corresponding subgroup analysis.

-"In addition, we made an effort to divide the results by stimulation parameters, including intensity, the number of sessions and duration" Please move to the results section since these results were not presented before discussion.

-"Despite the substantial cognitive effects of active" I would downgrade this sentence in regard to the risk of bias issues, is already commented above.

-@Conclusions:What about demanding for more high-quality studies like you did in the abstract? I would support this.

Reviewer #2: I consider that the authors addressed reviewers comments appropriately. The manuscript now is written in a clear language and reflects more accurately their scientific findings.

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7. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

If you choose “no”, your identity will remain anonymous but your review may still be made public.

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Reviewer #1: Yes: Bernhard Elsner

Reviewer #2: Yes: Andrea G.P. Schjetnan

[NOTE: If reviewer comments were submitted as an attachment file, they will be attached to this email and accessible via the submission site. Please log into your account, locate the manuscript record, and check for the action link "View Attachments". If this link does not appear, there are no attachment files to be viewed.]

While revising your submission, please upload your figure files to the Preflight Analysis and Conversion Engine (PACE) digital diagnostic tool, https://pacev2.apexcovantage.com/. PACE helps ensure that figures meet PLOS requirements. To use PACE, you must first register as a user. Registration is free. Then, login and navigate to the UPLOAD tab, where you will find detailed instructions on how to use the tool. If you encounter any issues or have any questions when using PACE, please email us at figures@plos.org. Please note that Supporting Information files do not need this step.

Effect of transcranial direct current stimulation on cognitive function in stroke patients: a systematic review and meta-analysis

PONE-D-19-28981R2

Dear Dr. Liu,

We are pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it complies with all outstanding technical requirements.

Within one week, you will receive an e-mail containing information on the amendments required prior to publication. When all required modifications have been addressed, you will receive a formal acceptance letter and your manuscript will proceed to our production department and be scheduled for publication.

Shortly after the formal acceptance letter is sent, an invoice for payment will follow. To ensure an efficient production and billing process, please log into Editorial Manager at https://www.editorialmanager.com/pone/, click the "Update My Information" link at the top of the page, and update your user information. If you have any billing related questions, please contact our Author Billing department directly at authorbilling@plos.org.

If your institution or institutions have a press office, please notify them about your upcoming paper to enable them to help maximize its impact. If they will be preparing press materials for this manuscript, you must inform our press team as soon as possible and no later than 48 hours after receiving the formal acceptance. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information, please contact onepress@plos.org.

With kind regards,

Andrea Antal, PhD

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation.

Reviewer #1: All comments have been addressed

Reviewer #2: All comments have been addressed

**********

2. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #1: Yes

Reviewer #2: Yes

**********

3. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: Yes

Reviewer #2: Yes

**********

4. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: Yes

Reviewer #2: Yes

**********

5. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #1: Yes

Reviewer #2: Yes

**********

6. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: (No Response)

Reviewer #2: I consider that the authors addressed the valuable suggestions of Reviewer #1 appropriately. I think this has improved the article significantly and, in my view is ready to be accepted.

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7. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

If you choose “no”, your identity will remain anonymous but your review may still be made public.

Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.

Reviewer #1: Yes: Bernhard Elsner

Reviewer #2: Yes: Andrea Gomez Palacio Schjetnan