PONE-D-25-24743 Reward network mechanism in anhedonia and depression PLOS ONE

Dear Dr. Dai,

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.

Please submit your revised manuscript by Aug 23 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.

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). 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,

Rosemary Bassey, 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

https://journals.plos.org/plosone/s/file?id=ba62/PLOSOne_formatting_sample_title_authors_affiliations.pdf

2. Please describe in your methods section how capacity to provide consent was determined for the participants in this study. Please also state whether your ethics committee or IRB approved this consent procedure. If you did not assess capacity to consent please briefly outline why this was not necessary in this case.

3. In the online submission form, you indicated that The data that support the findings of this study are available from the corresponding author upon reasonable request.].

All PLOS journals now require all data underlying the findings described in their manuscript to be freely available to other researchers, either 1. In a public repository, 2. Within the manuscript itself, or 3. Uploaded as supplementary information.

This policy applies to all data except where public deposition would breach compliance with the protocol approved by your research ethics board. If your data cannot be made publicly available for ethical or legal reasons (e.g., public availability would compromise patient privacy), please explain your reasons on resubmission and your exemption request will be escalated for approval.

4. Thank you for stating the following financial disclosure: [Doctor Dai claimed that this work was supported by the key project of natural science foundation of Chongqing (cstc2020jcyj-zdxmX0009), the Key project and innovation project of People's Liberation Army of China (2021HL003).]. 

Please state what role the funders took in the study.  If the funders had no role, please state: ""The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.""

If this statement is not correct you must amend it as needed.

Please include this amended Role of Funder statement in your cover letter; we will change the online submission form on your behalf.

5. Thank you for stating the following in the Competing Interests section: [Authors claimed receiving research funding from key project of nature science foundation of Chongqing (cstc2020jcyj-zdxmX0009), the Key project and innovation project of People's Liberation Army of China (2021HL003).Other authors report no biomedical financial interests or potential conflicts of interest.

All authors state that the content has not been published or submitted for publication elsewhere.].

Please confirm that this does not alter your adherence to all PLOS ONE policies on sharing data and materials, by including the following statement: ""This does not alter our adherence to  PLOS ONE policies on sharing data and materials.” (as detailed online in our guide for authors http://journals.plos.org/plosone/s/competing-interests).  If there are restrictions on sharing of data and/or materials, please state these. Please note that we cannot proceed with consideration of your article until this information has been declared.

Please include your updated Competing Interests statement in your cover letter; we will change the online submission form on your behalf.

6. Thank you for stating the following in the Acknowledgments Section of your manuscript: [Authorsclaimed that this study was supported by key project of nature science foundation of Chongqing (cstc2020jcyj-zdxmX0009), the Key project and innovation project of People's Liberation Army of China (2021HL003). The authors thank clinical doctors who devote to patients recruitment, including Dr. Dr. L. D. Hu from Geleshan Psychiatry Hospital, Dr. X. Y. Zhou from Psychiatry center of Chongqing, Dr.Y.He from 324 Hospital of Chong Qing. We appreciate the endeavor of all graduate students who participated this study as research assistants. We also thank all subjects who took part in this study, especially the clinical patients.]

We note that you have provided funding information that is not currently declared in your Funding Statement. However, funding information should not appear in the Acknowledgments section or other areas of your manuscript. We will only publish funding information present in the Funding Statement section of the online submission form.

Please remove any funding-related text from the manuscript and let us know how you would like to update your Funding Statement. Currently, your Funding Statement reads as follows: [Doctor Dai claimed that this work was supported by the key project of natural science foundation of Chongqing (cstc2020jcyj-zdxmX0009), the Key project and innovation project of People's Liberation Army of China (2021HL003).]. 

Please include your amended statements within your cover letter; we will change the online submission form on your behalf.

7. 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 move it to the Methods section and delete it from any other section. Please ensure that your ethics statement is included in your manuscript, as the ethics statement entered into the online submission form will not be published alongside your manuscript.

8. We notice that your supplementary figures are uploaded with the file type 'Figure'. Please amend the file type to 'Supporting Information'. Please ensure that each Supporting Information file has a legend listed in the manuscript after the references list.

9. We notice that your supplementary figures are included in the manuscript file. Please remove them and upload them with the file type 'Supporting Information'. Please ensure that each Supporting Information file has a legend listed in the manuscript after the references list.

10. 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.

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

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: Yes

Reviewer #2: Yes

Reviewer #3: Yes

**********

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

Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: Yes

**********

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

Reviewer #3: Yes

**********

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: Yes

Reviewer #2: Yes

Reviewer #3: Yes

**********

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: The manuscript by Sun D.X. and co-authors analyses the clinical data on anhedonia and depression from the side of reward network mechanism.

The manuscript is well-prepared, gives enough data to confirm the author's statements and claims.

With this in mind, presented manuscript is a good work that may be published in PLOS One journal.

Per contrary, it has several important points I would like to address to the authors and I expect they will correct them:

1. Please discuss the recent data on brain structures (that you study in your work) interactions in regulation of anhedonia and depression. I suppose there are a lot of new experimental articles that show how these brain regions interact with each other in controlling behavior employing cell and tissue histology and physiology methods.

2. The references list is very old. Two articles published on 2020 and 2021 are the newest ones in this manuscript. The authors should update the references list by adding the newer publications.

3. In addition to the study limitations, the authors should also include the perspectives subsection, where they should write in details on how potentially this work and the data may be used in further research.

4. Sometimes the English usage appears strange, please check the spelling.

Reviewer #2: This study is an interesting research topic that has demonstrated the different reward network involvement of anhedonia and depression. However, in order to increase readers' understanding, it seems necessary to revise the following parts.

1. Throughout the manuscript, certain words (aka. correlate) are repeated too much, and the fact that it is unnecessarily the first study is used repeatedly for discussion. English correction is needed throughout the paper.

2. With this study alone, it seems unreasonable for the reward network to evaluate which of the state or trace markers will be suitable. Nevertheless, if the authors describe it as suitable as a trace marker, the evidence for this should be described.

3. In the introduction, authors argued that anhedonia is a core symptom of depression, and MDD and anhedonia may have different natural mechanisms. Could you explain this issue more detail in evidence?

4. pp. 42-44. When describing the conflicting results of previous studies on decreased depression, hyperactivation was described before without mentioning a specific brain region, and hypoactivation was described later in putamen and caudate. The authors should specify the specific brain region that is hyperactivated.

5. In the last part of the introduction, the authors established two hypotheses, talking about the purpose of the study. The authors should further describe the scientific basis for this hypothesis.

6. In Figures 1-5, specific positions with the annotation (A,B,C) should be established and specify each figure location in the manuscript.

Reviewer #3: This is an observational study with a cross-sectional design that employed resting-state functional magnetic resonance imaging (rs-fMRI) to investigate patterns of functional brain connectivity. The primary objective was to compare connectivity differences across three groups: individuals with remitted depression, individuals currently experiencing a depressive episode, and individuals with no history of psychiatric disorders. The methodology was clearly described, utilizing standardized and validated instruments appropriate for the target population and suitable for the collection and analysis of neurofunctional data.

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

Although the sample size is relatively small, the study presents valuable contributions to the theoretical understanding of depression, as well as to the development of clinical management strategies. It highlights promising directions for relapse prevention and the personalization of treatment approaches.

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

Yes. The statistical analysis was appropriately conducted and allowed for the exploration of the data in line with the study’s objectives.

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

Yes, the authors have made all relevant data available.

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

Yes, the manuscript is clearly written and presented in standard academic English.

5. Additional Comments to the Author

The topic addressed in this manuscript is highly relevant in the fields of neuroscience and psychiatry, offering important insights into the neurobiological mechanisms underlying depression. Notably, the identification of alterations in functional brain connectivity across different phases of the disorder contributes to the growing understanding of its pathophysiology.

A key strength of the study lies in its potential to identify neural biomarkers of depression. The detection of distinct connectivity patterns among the groups studied may support the development of diagnostic and prognostic markers related to the presence, absence, or remission of the disorder. Furthermore, these findings provide a foundation for more individualized therapeutic interventions, such as neuromodulation techniques or psychotherapeutic approaches targeting specific neural circuits.

Recommendation: The manuscript is of scientific merit and relevance. It is therefore recommended for publication.

**********

6. 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: No

Reviewer #2: Yes: Jae Yong Choi

Reviewer #3: 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.]

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.

Reward network mechanism in anhedonia and depression

PONE-D-25-24743R1

Dear Dr. Qin Dai,

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.

An invoice will be generated when your article is formally accepted. Please note, if your institution has a publishing partnership with PLOS and your article meets the relevant criteria, all or part of your publication costs will be covered. Please make sure your user information is up-to-date by logging into Editorial Manager at Editorial Manager® and clicking the ‘Update My Information' link at the top of the page. For questions related to billing, please contact billing support.

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,

Rosemary Bassey, Ph.D.

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

Reviewer #1:

Reviewer #2:

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: No

**********

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 have cleared all the points and answered all my questions. The manuscript may now be accepted for publication.

Reviewer #2: Thank you very much. All comments made by reviewers were properly reflected in the revised 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 #1: No

Reviewer #2: Yes: Jae Yong Choi

**********