PONE-D-22-26079Effects of integrated hospital treatment on the default mode, salience, and frontal-parietal networks in anorexia nervosa: A longitudinal resting-state functional magnetic resonance imaging studyPLOS ONE

Dear Dr. Gondo,

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 two reviewers addressed several major and minor concerns about your manuscript. Please revise your manuscript according to reviewer's comments.

Please submit your revised manuscript by Dec 15 2022 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,

Kenji Hashimoto, PhD

Section 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. You indicated that you had ethical approval for your study. In your Methods section, please ensure you have also stated whether you obtained consent from parents or guardians of the minors included in the study or whether the research ethics committee or IRB specifically waived the need for their consent.

3. We note that the grant information you provided in the ‘Funding Information’ and ‘Financial Disclosure’ sections do not match. 

When you resubmit, please ensure that you provide the correct grant numbers for the awards you received for your study in the ‘Funding Information’ section.

4. In your Data Availability statement, you have not specified where the minimal data set underlying the results described in your manuscript can be found. PLOS defines a study's minimal data set as the underlying data used to reach the conclusions drawn in the manuscript and any additional data required to replicate the reported study findings in their entirety. All PLOS journals require that the minimal data set be made fully available. For more information about our data policy, please see http://journals.plos.org/plosone/s/data-availability.

Upon re-submitting your revised manuscript, please upload your study’s minimal underlying data set as either Supporting Information files or to a stable, public repository and include the relevant URLs, DOIs, or accession numbers within your revised cover letter. For a list of acceptable repositories, please see http://journals.plos.org/plosone/s/data-availability#loc-recommended-repositories. Any potentially identifying patient information must be fully anonymized.

Important: If there are ethical or legal restrictions to sharing your data publicly, please explain these restrictions in detail. Please see our guidelines for more information on what we consider unacceptable restrictions to publicly sharing data: http://journals.plos.org/plosone/s/data-availability#loc-unacceptable-data-access-restrictions. Note that it is not acceptable for the authors to be the sole named individuals responsible for ensuring data access.

We will update your Data Availability statement to reflect the information you provide in your cover letter.

[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: Partly

**********

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

Reviewer #1: Yes

Reviewer #2: No

**********

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: No

Reviewer #2: 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

**********

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: This study investigated abnormalities of the resting-state functional connectivity in the default mode network, salience, and frontal-parietal networks in the patients with anorexia nervosa. The functional connectivity in these three networks were evaluated cross-sectionally and longitudinally. This is very interesting study, there are however some issues to be mentioned.

1) The authors conducted many analyses and obtained many results. However, the manuscript seems to be redundant.

2) In the Ethics section, the authors wrote ‘The current study was approved by the human research ethics committee at our hospital.’ What was ‘our hospital’?

3) In addition, the authors wrote ‘Written informed consent was obtained from all participants.’ Was this informed consent for the neuroimaging studies or/and cognitive behavioral approach with behavioral limitation?

4) In the Participants section, the authors wrote ‘All AN and HC participants were right-handed and aged between 15 and 50 years old.’ However, there was no description about parental consent for the adolescent participants in the Ethics section. This is a critical issue.

5) ‘patients with severe depression, suicidal risk, personality disorders, schizophrenia, or alcohol dependence were excluded’ in this study. How about the obsessive-compulsive disorder that often comorbid with anorexia nervosa?

6) How many numbers of male and female participants are there in each of the AN and HC group?

7) The author should write age range in both the AN and HC groups in the Table2.

8) Information of benzodiazepine should be written in the Table2.

9) I could not understand the meaning of ‘AN-specific changes’ that the authors used. What the ‘AN-specific’ mean in this manuscript?

10) Even though the AN patients received treatments, their mean BMI was 16.0, still small, and the mean total score of the EDI was 45.8, still high. Severity of the AN was changed from severe to mild, but the patients were not recovered. This is one of limitation in this study.

Reviewer #2: Remarks to the authors:

In the present study, the authors measured resting-state functional magnetic resonance images (MRi) from 18 patients with anorexia nervosa (AN) and 18 healthy subjects before and after integrated hospital treatment to examine hypotheses that the resting-state brain networks might be altered in such patients, and that treatment might normalize neural functional connectivity. (nourishment and psychological therapy). They showed that AN of post intervention exhibited higher functional connectivity (FC) in default mode network (DMN) and also higher FC in salience network (SN). The authors concluded results might reflect trait neural pathology regarding abnormal somatic perception, difficulty in socio-emotional processing, and excessive cognitive control in patients with AN. The manuscript is well written, and proposes interesting results in general. What follows are critical concerns and some suggestions to improve the manuscript.

Major Concerns:

1. It is strongly required for the authors to describe adopted denoising methods of their raw imaging data including motion correction and its exclusion criterion, which is currently obligatory for research of resting state functional MRI.

2. It is not popular to define the posterior insula as a part of default mode network, although these misleading findings could be found in results of an exploratory analysis of brain functional networks. It is highly recommended for the authors to interpret results based on understanding shared with those who are expertized in MRI studies, and to adopt appropriate expression to avoid misunderstanding of readers.

Minor Concerns

1. The study design of the current study cannot also distinguish influence of intervention from change of body weight, in the other words malnourished state. The authors should discuss the point in the limitation section.

2. In the introduction part (page 5, line 104), the authors stated that the previous studies showed inconsistent results. However, it is understandable that remitted AN exhibits different state from current AN (ie. ‘State or trait’ issue).

3. The authors should refer reasons why they adopt random effect model and its details, possibly with some previous references.

4. If some “sleep scale” was measured after resting state functional MRI to confirm participants were awake, it should be referred in the method section.

5. The authors should precisely explain what component contribution values are (page 15, line 315). Do they stand for the strengths of within-network connectivity, or those of network connectivity to whole brain?

6. The authors stated that comparison of SDS between pre- and post-intervention was performed among 12 AN participants, but in the section “Relationship of RSN FC in ROIs to psychometric measurements” of page 15, the number of participants is 15 there.

7. As for AN-specific ROIs, it is preferable for authors to carefully describe why they used the sphere mask from the peak voxel, instead of the mask of the region detected in the previous analyses.

8. Just out of my curiosity, it would be welcomed if the authors show correlation between FC and body weight change, if possible. If no correlation was detected in that, it could be indirectly assumed that the FC change between pre- and post- was related to some effect of intervention.

**********

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: 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.

PONE-D-22-26079R1Effects of integrated hospital treatment on the default mode, salience, and frontal-parietal networks in anorexia nervosa: A longitudinal resting-state functional magnetic resonance imaging studyPLOS ONE

Dear Dr. Gondo,

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 reviewer #2 addressed additional comments about your manuscript. Please revise your manuscript again. I will make the final decision after you submit to the journal.

Please submit your revised manuscript by Mar 05 2023 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,

Kenji Hashimoto, PhD

Section Editor

PLOS ONE

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

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: (No Response)

**********

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: Partly

**********

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: This study investigated abnormalities of the resting-state functional connectivity in the default mode network, salience, and frontal-parietal networks in the patients with anorexia nervosa. The functional connectivity in these three networks were evaluated cross-sectionally and longitudinally. This is a valuable study. In the revised manuscripts, the authors have adequately addressed your comments.

Reviewer #2: Remarks to the authors:

The authors have precisely approached all my comments and questions, and the manuscript has been considerably improved. What follows are suggestion to improve the manuscript.

Concerns:

1. In page 19 line 308, it is not assumed that the posterior insula might be detected in the group comparison, if the mask of default mode network (DMN) were appropriately applied. Careful interpretation and handling of this point would be recommended.

2. In page 19 line 316, it should be clarified whether a repeated measures ANOVA was adopted (recommended).

3. In page 20 line 332, the use of sphere-shaped ROI has the risk that regions with different brain functions can be included. The authors should consider to cite an appropriate reference that shows validity of the method in analyzing resting state functional MRI instead they use labels that include peak voxels.

4. In page 20 line 335-337, were mean values of the spheres calculated in these analyses?

5. In page 22 line 364, just asking for confirmation purpose, was multiple comparison correction performed for 5 ROIs?

6. In page 27, the authors mentioned that posterior insula was detected especially in AN. Does it mean that it was visually obvious? It is a bit difficult for readers to understand, and the author should explain its implication.

7. Still concerns in handling of posterior insula as if a part of DMN. The related expression in the discussion section should be carefully amended.

**********

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: 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.

Effects of integrated hospital treatment on the default mode, salience, and frontal-parietal networks in anorexia nervosa: A longitudinal resting-state functional magnetic resonance imaging study

PONE-D-22-26079R2

Dear Dr. Gondo,

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 for payment will follow shortly after the formal acceptance. To ensure an efficient process, please log into Editorial Manager at http://www.editorialmanager.com/pone/, click the 'Update My Information' link at the top of the page, and double check that your user information is up-to-date. 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 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,

Kenji Hashimoto, PhD

Section Editor

PLOS ONE

Additional Editor Comments (optional):

Reviewers' comments: