PONE-D-24-27267Hemodynamics in chronic pain: A pathway to multi-modal health risksPLOS ONE

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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: Yes

Reviewer #3: Yes

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

Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: 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: No

Reviewer #3: No

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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: Yes

Reviewer #3: Yes

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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: This research article investigates hemodynamic and cardiovascular (CV) mechanisms in response to clino-orthostatic challenges in a population of fibromyalgia patients and compared it to a group of healthy controls. The novelty of the study stems in the implementation of non-linear models to capture the interactions between the distinct yet interconnected hemodynamic processes in the CV system, which cannot be captured using linear models. The authors seek to advance the CV ‘pain-o-meter’ hypothesis that aims to objectively assess chronic pain conditions based on measured CV mechanics. Overall, the paper is well written.

The reviewer would like the following points to be addressed:

- In the introduction, the authors claim that linear statistical methods were a limitation for analyzing the hemodynamic and CV reactions. As the methodological novelty of this paper originates from implementing non-linear models, it would be beneficial to expand on the current contributions of linear statistical models and where these have resulted in limited or erroneous understanding of hemodynamic processes.

- The statistical test performed and reported table 1 is not mentioned in the text. Please add a description of what has been performed and reported.

- The results of the administered questionnaires are presented in table 1, yet the description of these tests is described later in the manuscript. I suggest the authors consider reorganizing the flow.

- In the calculation of the systemic vascular resistance, how did the authors measure or estimate the central venous pressure?

- The paper would benefit from a more detailed description of the statistical models presented on page 17. In the equation, clearly define and reference all variables used within.

- The results section presents what appear to be the results of F-tests. This procedure should be described in the method’s section.

- The results section report the fluctuation of the hemodynamic and CV measures as measured with the “edf” values. The significance of this measurement was not clearly apparent from the discussion section, as it appeared that mainly steady-state values and transitions were of interest. What conclusions are drawn from the “edf” values? Also, hemodynamic and CV measures are known to fluctuate with the breathing, could this have played a role in the observed fluctuations?

- The statement “Previous research suggests that these lifestyle factors do not significantly alter the fundamental relationship between mechanisms governing CV processes and pain mechanisms.” requires citations.

- In the figures, the dashed vertical lines, which are used to delineate periods in that mark a significant between group differences, are hard to follows in some instances. The reviewer suggests modifying the graphical method used to highlight this difference.

- In the Supplemental Materials, the authors show figures comparing the Session 1 and Session 2 hemodynamic and CV measures. Certain measures, such as CO and SVR, show noticeable differences in overall magnitude, shapes, and effective degrees of freedom. Could the authors further comment on this.

Reviewer #2: I thank the authors for their very interesting contribution on a very practical topic for patients: studying the relationship between hemodynamic/cardiovascular mechanisms and chronic pain in search of CV-related 'pain-o-metric' indicators. The study utilizes patients with fibromyalgia as the diseased (in-pain) group and healthy individuals as control, recruiting an adequate number of patients for each (albeit homogeneous---which was nicely addressed in the limitations subsection). The entirely data-driven approach studies differences related to lying and standing (clinostatic and orthostatic challenges) between the groups in terms of SV, HR, CO, PEP, SVR, SBP, and DBP, highlighting between-group differences as a function of time during the challenges, and providing both basic/linear as well as covariate-adjusted results. A particular novelty here is in the use of non-linear statistical methods, which appears to provide a lot more insight than a standard linear data-driven approach (whose results the authors also provide for comparison). The results are convincing: there are clear differences between the FM and control groups, and the possible explanations in the discussion are credible in my opinion.

The paper is well-organized and excellently written (the English is nearly perfect, save for some typos I mention below), with a lot of comprehensive results and discussion. The latter, in particular, is relatively deep, with additional (alternative) arguments and discussions to be found in Supplementary Material. I also appreciate the unusually long "limitations" part of the discussion, which is very detailed.

I recommend this paper for publication so long as the following questions/comments/concerns are addressed. In particular, the methodology can get confusing and a bit vague, with not enough details/references.

(I'm sorry, but without line numbers, which I suggest you use next time, I can only give page numbers to direct you)

(these are in order of page number; the first few appear minor with copy edits, but eventually there are content-related questions/concerns in what follows)

1) Abstract: a couple of minor suggestions: "sec-by-sec" might be replaced by "second-by-second" (avoiding abbreviations in an abstract); "the chronic disease" might be replaced by "chronic disease" (no article); "enabled the identification" might be replaced by "enables..." (in order to be consistent with the present tense, and to respect that the methodology you are proposing is applicable beyond your work).

2) Intro, first paragraph, page 3: "World" should not be capitalized.

3) Table 1: there is no explanation, neither in the caption, nor in the text, of "t-\\chi" or "p-value" before the table appears. someone working in data-driven statistical approaches can guess easily, but for completeness, the former, at least, should be explained somewhere in text or caption.

4) Page 9: the title "Procedure, and clinical and psychological testing instruments" is a bit awkward; consider rephrasing to remove the second "and" (maybe: "Procedure and clinical/psychological testing instruments)

5) Page 12, bottom of the page: "respective data-driven adaptive techniques were used to take into account..." When someone reads this, they expect a list of the techniques, or more description. if you are referring to the rest of the "statistical metrics" section, then you should mention here ("as detailed in what follows")

6) Page 13, "hence, this non-linear methodology aimed to overcome..." It is not clear that your methodology is non-linear at this point. Also, the definition of "non-linear" versus "linear" is not mathematical here (I don't think), and so some phrases must be included in order to explain what exactly you mean by non-linear vs. linear. is non-linear just regressions that are co-variate adjusted?

7) Page 13, "because of this, a special non-parametric approximation technique..." What is the technique? Why is it special? Can you add some references? How do they accommodate non-linear effects?

8) Page 15, "fixed in 240" should be "fixed to 240"

9) On page 15, you italicize (correctly) "p" for p-value. elsewhere in the manuscript, it is no longer italisized (e.g. bottom of page 17). please correct throughout and make it consistent.

10) a number of metrics are used without citation...BIC, AIC. similarly, for bootstrapping discussion, please provide references and/or a description of what it exactly is for those who are less informed. in fact, a lot of the statistical methods section does not include references to the methods you are using. I know some are quite standard, but it would be useful for a reader to quickly refer to a paper for a description of the analysis metric you are using (i.e., to see the formulas, etc.)

11) "Supplementary materials" is sometimes lower case on the second word, sometimes upper case. Please correct throguhout.

12) It is unusual for someone to call Supplementary Materials Davydov (i.e., using their last name in the title). it's confusing. Please just use "Supplementary Materials" throughout the manuscript and in the supplement itself (i.e., remove your name from the section calls).

13) Page 17" "non-standardized (B) regression coefficients" ... shouldn't this "B" be lowercase to comply with convention?

14) in line with comment 9, perhaps consider italicizing (as is common) all the statistical variables (e.g., those that start on Page 18 results...b,t,p, etc.). it will make it easier to see these values embedded in such dense text.

15) Figures 1-7: since in a number of subfigures (particularly (B) and (C)) have teh exact same axes, a title might be useful to help people see right away that one plot is unadjusted and the other is adjusted. in fact, you may benefit from putting titles on all the figures (i.e., "Before adjustment of BMI", "After adjustment of BMI", etc.) In some cases it's (a) and (b), i.e., Figure 2. I think the specific co-variate considered (which varies between your figures/metrics) should be included in the figure titles.

16) Page 21: "with high, low, and very low HR frequency fluctuations" ...these are only two figures (2A) and (2B) corresponding to high and low fluctuations. please correct.

17) Figure 2, caption: I think there is a typo. in the last line, it should be "fast (C) and slow (D)" and not "fast (B) and slow (C)".

18) All figures: the grey dotted lines are not mentioned in any of the captions (as to what they demarcate). in the text they are not mentioned either, but we can easily infer that it's the intervals you are referring to. please metnion the dotted lines so people know what they mean more easily.

19) following 18), what do the dotted lines correspond to in Figure 2D? for other figures, you at least mention some of the intervals, or that you are showing locations of max deviation. but for 3D, I don't understand at all what the dotted lines are supposed to represent in the curves...

20) page 23, "very short random periods of significant differences": please revise. how do you define "significant difference" here, and "random periods"? i don't quite see that in the figure (the overall trend shows differences are high throughout...)

21) page 29, "after a common rapid SVR drops" should be "after a common rapid SVR drop" (singular)

22) figures 6 and 7: these appear to be the only two metrics (DBP and SBP) where, after co-variate adjustment, the differences betweem FM and CT become smaller. can you discuss/explain?

Reviewer #3: The manuscript presents an interesting and relevant investigation into the hemodynamic responses of fibromyalgia patients during clino-orthostatic challenges, which has important implications for understanding chronic pain and cardiovascular health. The use of a non-linear, data-driven technique seems a novel approach, and the study could potentially contribute valuable insights. However, I have some concerns that need to be addressed:

1- Many sentences specially in Introduction are overly long, which detracts from their clarity. I suggest revising these sentences to focus on one idea at a time. I suggest breaking up these sentences and focusing on presenting one idea at a time.

2- Please be consistent for the word “nonlinear” or “non-linear”. Choose one for the entire manuscript.

3- While the exclusion criteria are comprehensive, it would be helpful to provide more information on the specific FM-related medications allowed in the study. It would be important to clarify how the authors managed potential effects.How were their potential effects on cardiovascular outcomes accounted for?

4- The control group is described as being similar in age, nationality, civil status, and education level. However, it is not clear whether matching was done precisely or if this was achieved through random sampling. A more detailed explanation of the matching process would strengthen the methodological rigor of this section. For example, were controls individually matched to patients?

5- The exclusion criteria are well-detailed, but it would be beneficial to explain whether any additional steps were taken to control for confounding factors such as BMI, physical activity levels, or psychosocial stress, as these can influence cardiovascular and pain-related outcomes. Please update study limitations if needed.

6- A brief mention of how the sample size was determined or whether a power analysis was conducted would strengthen the validity of the study. Was the sample size based on previous studies in fibromyalgia, or calculated to ensure sufficient statistical power for the planned analyses?

7- It would be useful to specify if the tests were performed in the morning, afternoon, or at random times. Time of day can influence cardiovascular metrics, and standardizing test timing would reduce variability.

8- While participants were instructed to refrain from alcohol, smoking, caffeine, and exercise for three hours, three hours may be too short a time to eliminate the potential effects of these factors, especially caffeine. It would be beneficial to clarify whether this time period was based on previous studies or other justifications. Please update study limitations if needed.

9- Please mention whether potential confounders like sleep quality or daily pain fluctuations were considered when scheduling participants' appointments. Since FM patients often experience fluctuating symptoms, were steps taken to control for the time of day or participant-specific variability in pain levels? This could improve the consistency of physiological and psychological measurements.

10- The electrode placements for ECG and ICG are described in good detail, but providing a visual or diagram in the supplemental materials would help, particularly for those less familiar with these measurement techniques.

11- It would be useful to elaborate on the clinical implications of these findings. For example, how might these differences in SV response influence the management of FM patients in clinical settings?

12- The limitations of the study are well-addressed, but it could be useful to discuss any potential strategies for mitigating these limitations in future research.

13- Which cardiovascular metric you found most affected by pain? In total? In lying? And in Standing? Why do you think that metric is most affected?

14- Authors mentioned “Data supporting this study are not currently publicly available due to its farther use by the research team.”. At least, the data used for the plots in this study should be presented in Supplement I believe.

15- Could you explicitly indicate what is the novelty of this paper? Has any other study in the literature shown this novelty before? Please highlight the potential clinical significance of the key differences found in this study?

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Reviewer #1: No

Reviewer #2: No

Reviewer #3: Yes: Rashid Alavi

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Hemodynamics in chronic pain: A pathway to multi-modal health risks

PONE-D-24-27267R1

Dear Dr. Davydov,

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,

Niema M. Pahlevan, PhD

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

Reviewer #3: 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

Reviewer #3: Yes

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

Reviewer #1: Yes

Reviewer #3: Yes

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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

Reviewer #3: No

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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

Reviewer #3: 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 has adequately addressed all of the comments from the previous round of revision. This reviewer has no further comments.

Reviewer #3: All my comments have been addressed, no more comments. The manuscript looks good to me now.Thank you!

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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

Reviewer #3: Yes: Rashid Alavi

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