Dear Dr. Demina,

Please submit your revised manuscript by Jul 24 2025 11:59PM. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at plosone@plos.org . When you're 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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We look forward to receiving your revised manuscript.

Kind regards,

Sandra Carvalho, Ph.D.

Academic Editor

PLOS ONE

Journal Requirements:

When submitting your revision, we need you to address these additional requirements.

1. Please ensure that your manuscript meets PLOS ONE's style requirements, including those for file naming. The PLOS ONE style templates can be found at

https://journals.plos.org/plosone/s/file?id=wjVg/PLOSOne_formatting_sample_main_body.pdf and

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2. Your ethics statement should only appear in the Methods section of your manuscript. If your ethics statement is written in any section besides the Methods, please delete it from any other sectio

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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?

Reviewer #1: Yes

Reviewer #2: Partly

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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??>

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??>

Reviewer #1: Yes

Reviewer #2: Yes

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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

Reviewer #1: Yes

Reviewer #2: Yes

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

Reviewer #1: Yes

Reviewer #2: Yes

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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.

Reviewer #1: This study aimed to conduct a systematic review and network meta-analysis to simultaneously compare different non-invasive brain stimulation strategies for alcohol use disorder. The strength of this study was to conduct analysis using a rigorous method of systematic reviews. However, there were some concerns in this study.

First, the authors had better add the limitations of this study in the discussion.

Second, they had better describe a new limitation in the discussion that they did not use Psychological Index Terms in the PsycINFO search strategy.

Reviewer #2: The protocol is reasonably designed, but it is necessary to refine the decision basis of methodology and strengthen the transparency of statistical analysis and processes to enhance scientificity and reproducibility. The specific opinions are as follows:

1. Inclusion and exclusion criteria for research subjects

The criterion of excluding patients with comorbidities such as depression or post-traumatic stress disorder may lead to a deviation between the research sample and clinical practice, as patients with AUD often have comorbidities in clinical settings.

It is recommended to supplement the scientific basis for excluding patients with comorbidities, or consider setting up subgroup analyses to explore the impact of comorbidities on the results.

2. Description of intervention measures

The inclusion criteria for NIBS intervention parameters (such as stimulation intensity, frequency, and treatment course) are too broad, which may lead to excessive heterogeneity of interventions and affect the comparability of network Meta-analysis.

It is recommended to stratify according to stimulation techniques (such as tDCS, rTMS) and parameters, and set subgroup nodes in the network Meta-analysis.

3. Issues in defining primary outcomes

In the alcohol consumption reduction trial, the primary outcomes are "total alcohol consumption and heavy drinking days after 3-6 months", but the evaluation time points of different studies (such as 3 months vs. 6 months) may lead to data heterogeneity.

In the definition of relapse rate, the operational criteria for "relapse" (such as drinking for 2 consecutive days or cumulative alcohol consumption ≥ a certain threshold) are not clarified.

It is recommended to unify the evaluation time windows of primary outcomes as "3 months" and "6 months" after intervention, and conduct subgroup analyses respectively. Clarify the definition of relapse.

4. Lack of heterogeneity assessment methods

Only "net heat plot for inconsistency evaluation" is mentioned, but how to quantify heterogeneity (such as using I² statistic) is not explained, making it impossible to judge the degree of variation between studies.

The specific implementation methods of "sensitivity analysis" (such as excluding low-quality studies or stratifying by region) are not clarified, resulting in non-reproducible methods.

5. Please supplement the GRADE. GRADE (Grading of Recommendations Assessment, Development and Evaluation) is a widely used systematic approach for grading the quality of evidence and strength of recommendations in clinical guidelines and systematic reviews.

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Reviewer #1: Yes:  Masahiro Banno, MD, PhD

Reviewer #2: No

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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 PLOS at figures@plos.org . Please note that Supporting Information files do not need this step.

Non-invasive brain stimulation paradigms in treatment of alcohol use disorder: systematic review and network meta-analysis protocol

PLOS ONE

Dear Dr. Demina,

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.

The revised protocol is methodologically sound, addresses the reviewers’ concerns appropriately, and adheres to PLOS ONE’s standards for systematic review protocols involving network meta-analyses. Before proceeding to final acceptance, I kindly ask for clarification on a few minor scientific points that could further enhance the transparency and reproducibility of the work. Specifically, while you mention harmonizing relapse definitions across studies, please consider specifying the preferred operational criteria (such as heavy drinking days or cumulative consumption thresholds) that will guide data extraction and harmonization. In addition, it would be helpful to clarify how multi-arm studies will be handled in the network meta-analysis—for example, whether you intend to split shared comparator groups or adjust for correlation between arms using specific statistical methods within the netmeta package. Lastly, a brief explanation of how the risk of bias assessments (RoB 2) will be integrated into the CINeMA framework for confidence evaluation would improve methodological transparency. These are minor suggestions aimed at strengthening the clarity and scientific rigor of the protocol. I look forward to receiving your final version.

Please submit your revised manuscript by Sep 20 2025 11:59PM. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at plosone@plos.org . When you're 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.

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

If you would like to make changes to your financial disclosure, please include your updated statement in your cover letter. Guidelines for resubmitting your figure files are available below the reviewer comments at the end of this letter.

If applicable, we recommend that you deposit your laboratory protocols in protocols.io to enhance the reproducibility of your results. Protocols.io assigns your protocol its own identifier (DOI) so that it can be cited independently in the future. For instructions see: https://journals.plos.org/plosone/s/submission-guidelines#loc-laboratory-protocols . Additionally, PLOS ONE offers an option for publishing peer-reviewed Lab Protocol articles, which describe protocols hosted on protocols.io. Read more information on sharing protocols at https://plos.org/protocols?utm_medium=editorial-email&utm_source=authorletters&utm_campaign=protocols .

We look forward to receiving your revised manuscript.

Kind regards,

Sandra Carvalho, Ph.D.

Academic Editor

PLOS ONE

Journal Requirements:

If the reviewer comments include a recommendation to cite specific previously published works, please review and evaluate these publications to determine whether they are relevant and should be cited. There is no requirement to cite these works unless the editor has indicated otherwise. 

Please review your reference list to ensure that it is complete and correct. If you have cited papers that have been retracted, please include the rationale for doing so in the manuscript text, or remove these references and replace them with relevant current references. Any changes to the reference list should be mentioned in the rebuttal letter that accompanies your revised manuscript. If you need to cite a retracted article, indicate the article’s retracted status in the References list and also include a citation and full reference for the retraction notice.

Additional Editor Comments:

Thank you for your careful and thoughtful responses to the reviewers’ comments.

The revised protocol is methodologically sound, addresses the reviewers’ concerns appropriately, and adheres to PLOS ONE’s standards for systematic review protocols involving network meta-analyses. Before proceeding to final acceptance, I kindly ask for clarification on a few minor scientific points that could further enhance the transparency and reproducibility of the work. Specifically, while you mention harmonizing relapse definitions across studies, please consider specifying the preferred operational criteria (such as heavy drinking days or cumulative consumption thresholds) that will guide data extraction and harmonization. In addition, it would be helpful to clarify how multi-arm studies will be handled in the network meta-analysis. For example, whether you intend to split shared comparator groups or adjust for correlation between arms using specific statistical methods within the netmeta package. Lastly, a brief explanation of how the risk of bias assessments (RoB 2) will be integrated into the CINeMA framework for confidence evaluation would improve methodological transparency.

These are minor suggestions aimed at strengthening the clarity and scientific rigor of the protocol.

I look forward to receiving your final version.

[Note: HTML markup is below. Please do not edit.]

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 PLOS at figures@plos.org . Please note that Supporting Information files do not need this step.

Non-invasive brain stimulation paradigms in treatment of alcohol use disorder: systematic review and network meta-analysis protocol

PONE-D-24-54144R2

Dear Dr. Demina,

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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If your institution or institutions have a press office, please notify them about your upcoming paper to help maximize its impact. If they’ll be preparing press materials, please inform our press team as soon as possible -- 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.

Kind regards,

Sandra Carvalho, Ph.D.

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

Dear authors,

Thank you for submitting the revised version of your manuscript “Non-invasive brain stimulation paradigms in treatment of alcohol use disorder: systematic review and network meta-analysis protocol” (PONE-D-24-54144).

I am pleased to inform you that your manuscript is now accepted for publication in PLOS ONE. The revisions have addressed the earlier comments, and the protocol is well structured, transparent, and appropriately registered.

Congratulations on your work, and thank you for choosing PLOS ONE as the venue for your research.