PONE-D-19-32702

Clinically significant acute pain disturbs motor cortex intracortical inhibition and facilitation in orthopedic trauma patients: A TMS study

PLOS ONE

Dear Dr De Beaumont,

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.

As you will see below, the two Reviewers have expressed several concerns regarding the methodological approach. In particular, the Reviewers were concerned by the validity of the comparison between groups and possible interactions with drugs. Also, the Reviewers point to potential issues with the way the statistical analysis was carried out, notably for post-hoc comparisons. Finally, Reviewer 1 has several suggestions to improve the overall quality of the manuscript.  Please make sure that all significant issues and concerns are adequately addressed in the revised version. 

We would appreciate receiving your revised manuscript by Feb 10 2020 11:59PM. When you are 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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François Tremblay, PhD

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: Partly

Reviewer #2: Yes

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

Reviewer #1: No

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: 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: The study by Jodoin and colleagues used single- and paired-pulse transcranial magnetic stimulation (TMS) to investigate changes in motor cortical excitability following isolated upper limb fracture. Several measures of intracortical function were applied in the acute injury phase, with the patient population stratified in to two groups based on reporting either mild or moderate-severe levels of injury-related pain. Relative to a healthy control group, the authors report that only measures of SICI were altered in patients with moderate-severe levels of pain. This change was interpreted as a specific effect of injury on GABAA-mediated circuits in primary motor cortex. Some specific comments about this study are listed below:

Major

1. The introduction is very long, including a lot of detail that could perhaps be left to the discussion. Please adopt a more concise approach.

2. The authors state that standard exclusion criteria were used for TMS, but I can’t see any mention of exclusion due to drugs; were participants excluded due to prescription drug use? Also, it seems likely that patients would have been using some kind of pain management during this early period – was this the case? If so, how could this have influenced the study findings?

3. I appreciate the effort that the authors have made to demonstrate that the mixed handedness of the patient group is not of importance. However, it seems like this issue could have been overcome by matching handedness between patients and controls. Why was this not done?

4. A conditioning intensity of 0.8RMT was used for SICI, with an ISI of 3 ms. As this conditioning intensity approximates 100%AMT (Garry et al., 2009), it’s possible that measures of SICI were contaminated by SICF (i.e., Peurala et al., 2008). This point should be addressed.

5. The authors make no comment about the normality of their data. Was this assessed? Were measures taken to adjust for non-normal data?

6. Several of the ANOVAs failed to indicate an effect of group, yet post hoc comparisons were still performed between groups (i.e., measures of RMT, ICF and LICI). This is not appropriate, and these comparisons should be removed from the manuscript.

7. It doesn’t appear that the authors included any corrections for multiple comparisons in their post hoc tests. Please include an appropriate measure where necessary.

8. Please report information about the response to test alone stimulation. Where the MEPs comparable between groups?

9. Individual panels of the same figure should be grouped together as s single image. In addition, as the post hoc statistics are reported in the text, it is not necessary to repeat them in each panel; please remove these from all figures.

10. At several points in the manuscript, the authors refer to ‘clinically significant’ pain. Can they provide some information and references on how they define pain as clinically significant?

11. LICI is expressed as a ratio, whereas all other paired-pulse measures are expressed as a percentage; why the difference between measures?

12. Did the authors investigate relationships between neurophysiological measures and outcomes of the DASH? This analysis would be of interest and should be reported.

13. The authors state that changes in intracortical inhibition may reflect plasticity processes as a direct response to injury. However, can they provide any evidence to show that changes in use of the limb (i.e., a secondary effect of injury) weren’t responsible for the observed neurophysiological changes?

14. It is unclear how the neurophysiological alterations observe in the acute phase support high initial pain as a predictor for chronic pain, or how the reported results demonstrate that changes in M1 lead to pain chronification (lines 422-425)? Can the authors please clarify how they reached this conclusion based on the empirical information they report?

15. I agree that these findings may indicate the investigation of rTMS for normalising neurophysiological changes in acute pain. However, the authors statement that this approach is ‘particularly promising’ (line 455) for ‘providing analgesic effects’ (line 455) is probably overzealous. Please tone down these kinds of comments.

Minor

1. Please reword the methods section of the abstract for clarity.

2. Line 136, Typo – Wee

3. Line 206 – please clarify the use of the term ‘vertex’ in this context. Are the authors suggesting that stimulation was applied to the vertex?

4. Line 213 – please clarify RMT criteria; the standard approach recommended by the most recent IFCN guidelines is a 0.05 mV MEP in at least 5/10 stimuli. The authors erroneously state that 0.5 mV in 6/10 stimuli.

5. Line 408 – please correct spelling of dextromethorphan

6. Line 449-450 - please provide refs for statements that SAI and LAI reflect GABAA and GABAB mediated neurotransmission, respectively.

Reviewer #2: PONE-D-19-32702: Clinically significant acute pain disturbs motor cortex intracortical inhibition and facilitation in orthopedic trauma patients: A TMS study

In the present study, the authors investigated M1 area excitability in patients with acute pain due to isolated upper limb fracture. It is shown that SICI and ICF are reduced in patients with moderate to severe pain, while they were similar to those of healthy controls in patients with mild pain. The authors suggest that the present results may represent a conceptual background for the therapeutic use of TMS in acute pain.

The study is well conducted and the results are discussed correctly.

I have some points:

1) How can the authors exclude that the abnormal M1 excitability is due to the lower use of the painful upper limb? Patients with higher pain are supposed to use their painful upper limb less than those with lower pain and control subjects. Immobilization is known to lead to M1 excitability changes (Viaro et al., J Physiol 2014).

2) As for the effect on ICF, ANOVA was not significant. Are the authors allowed to perform post-hoc analysis?

3) Could the authors exclude any pharmacological effect? In other words, was the last assumption of analgesic drugs before the neurophysiological investigation checked?

4) In the Introduction, the pioneering papers by Valeriani et al. (Clin Neurophysiol 1999, Exp Brain Res 2001) on the M1 area inhibition after experimental phasic pain should be quoted.

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Reviewer #1: No

Reviewer #2: Yes: Massimiliano Valeriani

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PONE-D-19-32702R1

Moderate to severe acute pain disturbs motor cortex intracortical inhibition and facilitation in orthopedic trauma patients: A TMS study

PLOS ONE

Dear Dr De Beaumont,

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.

Your revised manuscript was received favourably by the Reviewers. While Reviewer #1 was mostly satisfied, there are few remaining minor issues for you to address (e.g., interpretation of modulation in SICI). I am sure that you can address these issues promptly and hope to get a revised version shortly.

We would appreciate receiving your revised manuscript by Apr 11 2020 11:59PM. When you are 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.

If you would like to make changes to your financial disclosure, please include your updated statement in your cover letter.

To enhance the reproducibility of your results, we recommend that if applicable you deposit your laboratory protocols in protocols.io, where a protocol can be assigned its own identifier (DOI) such that it can be cited independently in the future. For instructions see: http://journals.plos.org/plosone/s/submission-guidelines#loc-laboratory-protocols

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). This letter should be uploaded as separate file and labeled 'Response to Reviewers'.
• A marked-up copy of your manuscript that highlights changes made to the original version. This file should be uploaded as separate file and labeled 'Revised Manuscript with Track Changes'.
• An unmarked version of your revised paper without tracked changes. This file should be uploaded as separate file and labeled 'Manuscript'.

Please note while forming your response, if your article is accepted, you may have the opportunity to make the peer review history publicly available. The record will include editor decision letters (with reviews) and your responses to reviewer comments. If eligible, we will contact you to opt in or out.

We look forward to receiving your revised manuscript.

Kind regards,

François Tremblay, PhD

Academic Editor

PLOS ONE rega

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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: (No Response)

Reviewer #2: 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 #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: 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

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: While the authors have addressed most of my concerns, a few issues remain:

1. In regards to contamination of SICI by SICF, I was not suggesting to use AMT. The issue could have been accounted for by using a lower %RMT conditioning stimulus. I understand why the authors would want to include the intensity commonly tested within the existing literature, but inclusion of an additional, lower intensity, conditioning stimulus would have been very feasible. At the very least, the possibility of SICF contamination should be addressed to some degree in the discussion.

2. The authors did not address why they elected to retain outcomes of all post-hoc comparisons in the figures, despite the fact that they’re reported in the text (see comment 9).

3. Typos on line 224 (RMT criteria still refer to 0.5mV MEP, which should be 0.05mv) and 243 (LICI stimuli referred to as subthreshold, should be suprathreshold).

Reviewer #2: (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.

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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: Massimiliano Valeriani

[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 to be viewed.]

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

Moderate to severe acute pain disturbs motor cortex intracortical inhibition and facilitation in orthopedic trauma patients: A TMS study

PONE-D-19-32702R2

Dear Dr. De Beaumont,

We are pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it complies with all outstanding technical requirements.

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With kind regards,

François Tremblay, 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

**********

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

**********

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

Reviewer #1: 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

**********

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

**********

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: Just one minor typo in the new text addressing SICF - you've listed short afferent cortical facilitation, which should be short interval.

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Reviewer #1: Yes: George Opie