PONE-D-24-39635Novel brain biomarkers of obesity based on statistical measurements of white matter tractsPLOS ONE

Dear Dr. de Celis-Alonso,

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.

ACADEMIC EDITOR:

Based on the reviewers’ comments, the manuscript requires extensive revision to meet the publication standards of PLOS ONE . Below is an outline of the required changes for acceptance, recommended improvements, and additional feedback, structured to address any conflicting advice and enhance clarity on the actions needed.

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<h3>Required Changes for Acceptance</h3>

1. Clarification and Definition of Acronyms
   
   • Required Change : Define acronyms (e.g., NW for Normal Weight, OB for Obese) upon first use in the text (line 132), not after (line 136). Clear terminology improves readability and consistency for the reader.
2. Consistency in Software Use and Image Orientation
   
   • Required Change : Address potential inconsistencies caused by using two different software tools (MRtrix3 and FSL). Perform a validation check as outlined by Reviewer 2 by testing the analysis with one subject, verifying that the gradient table and image orientations (Left-Right, Anterior-Posterior, Superior-Inferior) are consistent across all data processing steps. This is critical to ensure reliability in results and should be reported in the manuscript.
   • Conflict Resolution : If following only one software is not feasible, explicitly state the reasons and provide detailed explanations on how consistency across outputs was maintained and validated.
3. Hypothesis Specification
   
   • Required Change : Clarify the hypotheses regarding which white matter tracts may be associated with obesity and justify these choices based on relevant literature. The current “shotgun” approach should be refined to a more targeted hypothesis that strengthens the theoretical basis of the study.
   • Conflict Resolution : Align the hypothesis with the stated goal of understanding the relationship between specific white matter tracts and obesity.
4. Sample Generalizability
   
   • Required Change : Explicitly discuss the limitations of the sample (i.e., young, healthy females aged 19-26) and address how these constraints affect generalizability. Include a more precise description of how this sample is representative (or not) and clarify that the findings are specific to this demographic subset.
   • Conflict Resolution : Ensure that any generalization to broader populations is cautious and adequately qualified to avoid overstatement.
5. Neuroplasticity Discussion
   
   • Required Change : Avoid broad statements about neuroplasticity being “rampant” and instead provide a more detailed analysis of why only certain white matter tracts might be associated with obesity. This analysis should align with the specific tracts examined and avoid implying unsupported causation.
   • Conflict Resolution : Ensure statements about neuroplasticity are focused on observed associations within the study’s constraints and are not overly generalized.
6. Language and Consistency
   
   • Required Change : Address the manuscript’s language issues, including grammar, spelling, tense consistency, and voice. Ensure the manuscript is written in either first-person or passive voice consistently, not a mix of both.
   • Conflict Resolution : This is a crucial change for clarity and professionalism, as inconsistent language can undermine the study’s perceived rigor and readability.

<h3>Recommended Improvements (Not Required for Acceptance)</h3>

1. Data on Eddy Current Distortion Management
   
   • Recommended Improvement : Detail how high signals from eddy current distortions were managed in the FA images (e.g., removing bright voxels at the edges of the brain). While not critical, explaining these steps will enhance the transparency and quality of data processing.
2. Refining the Neuroplasticity Interpretation
   
   • Recommended Improvement : Provide a more nuanced discussion of neuroplasticity to address why only specific tracts may be associated with obesity, rather than assuming associations are widespread. This will improve the discussion’s scientific precision.
3. Spelling and Grammar in Depth
   
   • Recommended Improvement : Conduct an additional layer of proofreading focused on minor language issues (e.g., typos, tense inconsistencies). This will improve readability but is supplementary to the broader language consistency required above.

<h3>Specific Feedback on Manuscript Sections</h3>

1. Abstract and Introduction
   
   • Ensure hypotheses are clearly stated and aligned with the study objectives. Define abbreviations when first used to enhance clarity.
2. Methods
   
   • Provide a thorough description of all software used, including validation of consistency in data processing steps if using multiple software tools.
   • Specify how high-signal voxels from eddy current distortions were handled.
   • Detail the justification for specific white matter tracts examined based on theoretical or empirical grounding to align with the study’s objectives.
3. Results
   
   • Ensure all results reported strictly relate to the statistical analyses stated in the Methods section.
   • Clarify the rationale for significant differences across white matter tracts and link these findings back to the hypotheses.
4. Discussion
   
   • Ensure the neuroplasticity findings are discussed with nuance, avoiding generalizations across the brain and focusing instead on specific tracts related to obesity.
   • Discuss the limitations of the study sample in terms of generalizability, clearly outlining how these limitations may affect broader applications of the findings.
   • Ensure that interpretation statements, especially on neuroplasticity, are well-supported by the study’s data.
5. Conclusion
   
   • Avoid overstating the findings’ generalizability to broader populations or implying causation where only associations were observed.

Please submit your revised manuscript by Dec 12 2024 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,

Maryam Bemanalizadeh

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: Yes

Reviewer #2: Partly

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

Reviewer #1: I Don't Know

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: Yes

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: Quite well written, interesting study on the use of FA to detect and predict obesity. However, several comments for either validating and/or improving the results:

1. In line 132, the comment was "I’m confused..! These acronyms (NW and OB) were not defined earlier. I assume they mean (normal weight and obese). Just define them". Later they were defined in line 136. Define them in line 132 instead.

2. In line 182, Using two softwares (MRtrix3 and FSL) may create multiple issues with your data (especially image header files). Make sure to check the gradient table as well as the image orientations (Left-Right, Anterior-Posterior, Superior-Inferior). I have a concern that the results may got affected and are misleading. You can test it by using only one subject to perform all analysis and track defined voxels (e.g. as a mask with a letter "R" in the right side of the image) + check all inputs and outputs (especially gradient table) and ensure that they are literally the same. In order to fully understand my point, please check this paper https://doi.org/10.1016/j.media.2014.05.012.

3. In section 2.1.3, How did you manage the high signals around the edges of the brain that resulted from eddy current distortions? The bright voxels surrounding the FA images that results from eddy current distortions should be removed before the alignment.

Reviewer #2: The overall premise of the study is quite intriguing. The relationship between neural connectivity and overall metabolic health is an important field of study.

Unfortunately, the stated hypotheses do not address the overall goal of the study. The approach is a "shotgun" method of searching for white matter tracts that may be associated with obesity. Which white matter tracts would the authors hypothesize to be associated with obesity and why?

Additionally, and as acknowledged by the authors in the Limitations section, the study sample is constrained to include only healthy females between 19-26 years old. This sample disallows generalizability to males, anyone older than mid-20s, and anyone considered "not healthy." Along the same line, the authors state that the study sample is representative of the general population within those demographics, but many factors lead to obesity that may lead someone to be described as unhealthy. Thus, it is unclear what group these subjects are actually representative of.

The authors repeatedly point out that their findings suggest there is neuroplasticity in these white matter tracts. I don't believe any recent work has suggested that neuroplasticity is not rampant across the brain for many reasons. Why would the findings of specific white matter tracts having an association with obesity, as opposed to all white matter tracts being associated, be the case? The authors rightly acknowledge they have found association and not causation, but they do pose any testable hypotheses that may explain their findings.

Finally, the manuscript is in significant need of editing for grammar, spelling, typos, and tense. Every paragraph has at least one error. Some of the manuscript is written in the first-person plural while other parts are in passive tense.

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Reviewer #1: No

Reviewer #2: No

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Novel brain biomarkers of obesity in young adult women based on statistical measurements of white matter tracts

PONE-D-24-39635R1

Dear Dr. de Celis-Alonso,

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,

Maryam Bemanalizadeh

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

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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

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

Reviewer #1: I Don't Know

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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

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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: Yes

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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)

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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: No

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