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PONE-D-21-30462The optimum parameters and neuroimaging alteration in DMN, DAN, CEN of rTMS to PSCI patients, a protocol of an orthogonally-designed triple-blind RCTPLOS ONE

Dear Dr. LI,

Thank you for submitting your manuscript to PLOS ONE. 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 points raised during the review process.

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This work was supported by the Post-Doctor Research Project, West China Hospital, Sichuan University (No. 2020HXBH018); the Chengdu Science and Technology Bureau (No. 2019-YF05-00061-SN); and the Health Department of Sichuan Province (No. S15063). The funders played no role in the design, conduct, or reporting of this study.

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The Post-Doctor Research Project, West China Hospital, Sichuan University (2020HXBH018); the Chengdu Science and Technology Bureau (No. 2019-YF05-00061-SN); and the Health Department of Sichuan Province (No. S15063) funded this research.

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Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. Does the manuscript provide a valid rationale for the proposed study, with clearly identified and justified research questions?

The research question outlined is expected to address a valid academic problem or topic and contribute to the base of knowledge in the field.

Reviewer #1: Yes

Reviewer #2: Yes

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2. Is the protocol technically sound and planned in a manner that will lead to a meaningful outcome and allow testing the stated hypotheses?

The manuscript should describe the methods in sufficient detail to prevent undisclosed flexibility in the experimental procedure or analysis pipeline, including sufficient outcome-neutral conditions (e.g. necessary controls, absence of floor or ceiling effects) to test the proposed hypotheses and a statistical power analysis where applicable. As there may be aspects of the methodology and analysis which can only be refined once the work is undertaken, authors should outline potential assumptions and explicitly describe what aspects of the proposed analyses, if any, are exploratory.

Reviewer #1: Yes

Reviewer #2: Partly

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3. Is the methodology feasible and described in sufficient detail to allow the work to be replicable?

Descriptions of methods and materials in the protocol should be reported in sufficient detail for another researcher to reproduce all experiments and analyses. The protocol should describe the appropriate controls, sample size calculations, and replication needed to ensure that the data are robust and reproducible.

Reviewer #1: Yes

Reviewer #2: No

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4. Have the authors described where all data underlying the findings will be made available when the study is complete?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception, at the time of publication. 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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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: No

Reviewer #2: No

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6. Review Comments to the Author

Please use the space provided to explain your answers to the questions above and, if applicable, provide comments about issues authors must address before this protocol can be accepted for publication. You may also include additional comments for the author, including concerns about research or publication ethics.

You may also provide optional suggestions and comments to authors that they might find helpful in planning their study.

(Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: The authors deal with a relevant and timely topic, i.e., the optimum parameters and neuroimaging alteration in default mode network (DMN), dorsal attention network (DAN), and central executive network, (CEN) of repetitive transcranial magnetic stimulation (rTMS) in patients with post-stroke cognitive impairment (PSCI). To this end, they proposed a single-center, orthogonally-designed, triple-blind randomized controlled trial in 45 patients, who will be randomly assigned to one of 9 active rTMS groups based on four stimulation paraments: stimulating site, frequency, intensity, and pulse number. Neuropsychological, activities of daily living, quality of life, and functional neuroimaging evaluations will be also performed at baseline, post-rTMS, and 3 months after rTMS. The authors concluded that this study will evaluate the optimum parameters of rTMS for PSCI patients with and will explore the alteration of neural function in DMN, DAN, and CEN brain network. This would facilitate the standardized application of rTMS in cognition impairment rehabilitation.

Overall, the protocol is nicely conceived and designed; the methods are sufficiently described and might disclose useful translational data. I have some comments, especially in the Introduction and in the Discussion. Moreover, language should be edited by a native-English speaker.

Title: please reduce or spell out the use of abbreviation.

Abstract: please include a brief rationale of the protocol; the abbreviation PSCI should be spelled out.

Introduction: please provide a short overview on the pathophysiology and neurobiology of PSCI and, more in general, of vascular cognitive impairment (for a recent comprehensive review, see PMID: 32340195). In particular, the exact relationships between vascular lesion, cognition, and neuroplasticity are not completely understood, although converging findings point out the possibility to identify a panel of markers able to predict cognitive deterioration in the so-called "brain at risk" for vascular or mixed dementia. This will be of pivotal importance when designing trials of disease-modifying drugs or non-pharmacological approaches, such as non-invasive neuromodulatory techniques (including rTMS) in dementia, as very recently reviewed (PMID: 34482205).

Introduction: please state the experimental hypothesis: what did the authors expect? Why and how?

Methods: did the authors include in the protocol also a sham (fictitious) stimulation procedure?

Methods: although a total of 45 patients is acceptable, 5 subjects per group is a rather small sample size.

Discussion: in the context of the proposed protocol, it should be mentioned that, in some patients plasticity may be considered as an adaptive response to disease progression (thus allowing the preservation of motor programming and execution) but a maladaptive response in others. Please also mention the involvement of metaplasticity in neurological and neuropsychiatric disorders, including stroke and PSCI (PMID: 34276553).

Discussion: pitfalls and limitations of both protocol and technique should be included, together with possible solutions and future research agenda (for some suggestions, please see PMID: 33193753).

Reviewer #2: Dear Editor,

Thank you for the opportunity to provide a review of Manuscript PONE-D-21-30462 entitled "The optimum parameters and neuroimaging alteration in DMN, DAN, CEN of rTMS to PSCI patients, a protocol of an orthogonally-designed triple-blind RCT". My comments relate primarily to the adequacy of the implementation and reporting of epidemiologic and statistical procedures.

The quality of the technical English is inconsistent. There are grammatical errors scattered throughout the text. The authors need to perform a thorough round of copyediting to correct these. Nevertheless, these did not affect my evaluation of the manuscript.

# Major Issues

Page 10: "active rTMS groups in 1:1 ratio". This ratio is wrong since there are nine treatment groups, not two.

Page 10: "This trial will be conducted in line with the consolidated standards of reporting trials (CONSORT) statement...". CONSORT should NOT be used to guide the conduct of trials. These are REPORTING standards. CONSORT does not tell you how to conduct a study. They tell you how to describe it in a consistent fashion. Please change this statement.

Page 11: "No severe aphasia". How will aphasia be assessed and what is the criteria for severe aphasia used here?

Page 12: "informed consent". In this study where patients are cognitively impaired, how will the capacity to understand the study and to give proper informed consent be assessed?

Page 12: The description of the sample size calculations is inappropriate and cannot be confirmed because there is no replicable information provided by the authors. This must be corrected.

Page 19: The use of one-way ANOVA to analyse paired data (MRI ALFF and ACD) is highly inappropriate. This must be changed.

Page 19: The level of significance must be stated.

*IMPORTANT* There is no assessment of safety. This is a major oversight and needs to be added. This is non-negotiable.

*IMPORTANT* Why is there no sham group?

# Recommendation

I am unable to support the approval of this manuscript for publication in the journal until these issues are considered.

Thank you.

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Reviewer #1: No

Reviewer #2: No

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The optimum parameters and neuroimaging mechanism of repetitive transcranial magnetic stimulation to post-stroke cognitive impairment, a protocol of an orthogonally-designed randomized controlled trial

PONE-D-21-30462R1

Dear Dr. LI,

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

Within one week, you’ll receive an e-mail detailing the required amendments. When these have been addressed, you’ll receive a formal acceptance letter and your manuscript will be scheduled for publication.

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Kind regards,

Giuseppe Lanza, M.D., Ph.D.

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. Does the manuscript provide a valid rationale for the proposed study, with clearly identified and justified research questions?

The research question outlined is expected to address a valid academic problem or topic and contribute to the base of knowledge in the field.

Reviewer #2: Yes

**********

2. Is the protocol technically sound and planned in a manner that will lead to a meaningful outcome and allow testing the stated hypotheses?

The manuscript should describe the methods in sufficient detail to prevent undisclosed flexibility in the experimental procedure or analysis pipeline, including sufficient outcome-neutral conditions (e.g. necessary controls, absence of floor or ceiling effects) to test the proposed hypotheses and a statistical power analysis where applicable. As there may be aspects of the methodology and analysis which can only be refined once the work is undertaken, authors should outline potential assumptions and explicitly describe what aspects of the proposed analyses, if any, are exploratory.

Reviewer #2: Yes

**********

3. Is the methodology feasible and described in sufficient detail to allow the work to be replicable?

Descriptions of methods and materials in the protocol should be reported in sufficient detail for another researcher to reproduce all experiments and analyses. The protocol should describe the appropriate controls, sample size calculations, and replication needed to ensure that the data are robust and reproducible.

Reviewer #2: Yes

**********

4. Have the authors described where all data underlying the findings will be made available when the study is complete?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception, at the time of publication. 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 #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 #2: Yes

**********

6. Review Comments to the Author

Please use the space provided to explain your answers to the questions above and, if applicable, provide comments about issues authors must address before this protocol can be accepted for publication. You may also include additional comments for the author, including concerns about research or publication ethics.

You may also provide optional suggestions and comments to authors that they might find helpful in planning their study.

(Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #2: I am satisfied that the authors have addressed all the issues previously identified. I am happy to support the acceptance of this manuscript.

**********

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 #2: No

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