-->PONE-D-26-07973-->-->Synergistic Effect of tDCS and Neuromotor Recruitment on Functional Recovery in Chronic Paraplegia: A Randomized Controlled Trial-->-->PLOS One

Dear Dr. Rifai Sarraj,

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.

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We look forward to receiving your revised manuscript.

Kind regards,

Mohammad Sidiq, PhD Physiotherapy, FAIMER Fellow

Academic Editor

PLOS One

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Additional Editor Comments (if provided):

The article is an interesting and clinically relevant randomized controlled trial that presents the answer to a particular question in the field of neurorehabilitation. Although the topic is quite timely and the results can make a difference, there are some issues connected to clarity of the methodology, transparency of reporting, and following the journal rules. As it stands, the publication needs significant revision before it can be accepted to the standards of scientific rigor in various aspects, including consistency in the study design, statistical presentation, and availability of data. The response to such issues will enhance the validity and interpretability of findings and enhance the overall quality of the manuscript.

Here are my comments apart from the reviewer observations as under

1. Registration and clarification of the study.

The manuscript mentions the trial registration (NCT04790149), but it appears to be post hoc to the start of the study. The Method section must explain the delay (not just the cover letter) and confirm that there were no protocol changes after registration.

2. Blinding Inconsistency

It is referred to as "single-blind" (Abstract) and "double-blind" (Methods). Inconsistency means that something went wrong here; please clarify who was blinded.

3. Data Availability Statement - non-simultaneous.

The existing statement (available upon request) is against journal policy. Authors are required to save data in an open-source repository, or informative restrictions need to be explained.

4. Sample Size Justification

Although it is stated that a priori power analysis was conducted, no specifications (effect size, power, or alpha) are provided. Kindly provide complete parameters and assumptions.

5. Control Group Description

The intervention of the "reference group” is in need of a more detailed explanation. Discuss the reason this is normal care and whether or not intensity/dosage can be equated with intervention arms.

6. Statistical Reporting Issues

P-values and other statistics are not fully worked out or formatted wrongly (e.g., an empty value in Results).

Always report F-values, degrees of freedom, exact p-values, and sizes of effects.

7. Outcome Measures - Validity and Novelty.

The AMA scale should have better validation or citation support, as it does not seem as standardized as ISNCSCI/LEMS.

8. Short Intervention Duration

Chronic SCI has a fairly low intervention duration of 10 days/3 weeks. Clinical relevance should be better justified by the authors, and effects on sustainability should be discussed.

9. Mechanistic Claims Overstated

The mentioning of the so-called Hebbian plasticity or the top-down and bottom-up mechanisms are both speculative statements. Be less conclusive or provide more supporting evidence.

10. Figures and Reporting

Figures (graphical abstract, Figures 1-3) are mentioned but not wholly incorporated and discussed in the descriptive details.

ensure that figures are of journal quality and are labeled.

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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: No

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

Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: No

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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

Reviewer #3: 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

Reviewer #3: 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: Overview and general recommendation:

Thank you for giving me the opportunity to review the manuscript entitled “Synergistic Effect of tDCS and Neuromotor Recruitment on Functional Recovery in Chronic Paraplegia: A Randomized Controlled Trial”. The findings of this study are expected to contribute meaningfully to the body of knowledge in the field and support the development of more effective treatment strategies for this population. The study is very well described, following CONSORT guidelines. The research proposal is relevant and aligns with the journal’s scope.

Minor Comments

The description of the Assessment of Movement Attempt (AMA) Scale is entirely in bold. Please correct this.

Was the treatment protocol designed based on a previous study? If so, it would be helpful to clarify.

Did the authors plan analyses according to the intention-to-treat principle? Was there no sample loss?

Reviewer #2: The study addresses an important clinical question and contributes to neurorehabilitation literature.

Study Design and Methodology

The manuscript inconsistently reports the study as single-blind (Abstract) and double-blind (Methods), which creates confusion. Clarification is essential.

The control group size (n=10) is considerably smaller than intervention groups (n=20 each), raising concerns about statistical power and group comparability.

Although randomization is described, allocation concealment details remain insufficient, particularly regarding implementation and sequence security.

No sample size calculation or power analysis details are clearly described in the manuscript body, which is a critical requirement for RCTs.

The NEUROM protocol is described in detail; however:

The standardization and reproducibility of sensory stimulation and therapist-dependent techniques are unclear.

There is no mention of treatment fidelity assessment or inter-therapist reliability.

The tDCS protocol lacks justification (e.g., rationale for 1 mA intensity, bilateral stimulation, duration).

The selected outcomes (LEMS, sensory scores, AMA) are appropriate; The AMA scale lacks sufficient validation details and references for clinical applicability. No primary vs. secondary outcome distinction is explicitly stated.

The significance level (alpha) is missing in the statistical section.

Effect sizes and confidence intervals are not consistently reported.

There is no mention of handling missing data, although authors claim no loss to follow-up.

The use of multiple comparisons correction needs clearer justification and reporting.

The authors claim a “synergistic effect”, but: The absence of a tDCS-only group limits the ability to conclude synergy definitively. The conclusion about “top-down vs. bottom-up mechanisms” is interesting but appears overstated and speculative given the data. Clinical significance (not just statistical significance) is insufficiently discussed.

The Data Availability Statement is non-compliant with PLOS guidelines, as “available upon request” contradicts journal policy.

Trial registration is provided; It is unclear whether the trial was prospectively registered.

Abstract

Overly interpretative (mechanistic conclusions should be toned down).

Include confidence intervals and clarify primary outcomes.

Introduction

Provides good background, but:Some references are outdated.

The research gap and novelty could be more explicitly stated.

Methods Minor grammatical and formatting issues present.

Clarify: Inclusion criteria (e.g., chronicity threshold inconsistencies: >3 months vs. mean 15 months).

Intervention duration inconsistency (10 days vs. 3 weeks mentioned).

Results

Should include effect sizes (optional ) and CI.

Figures (e.g., CONSORT diagram) are referenced but not fully presented in the text.

Discussion

Strength: Integrates neuroplasticity concepts well.

Limitations: Needs more critical appraisal of limitations, especially:

Small sample size

Lack of blinding

Short intervention duration

Overinterpretation should be reduced.

References

Some recent (last 5 years) high-impact studies on tDCS and SCI should be added.

Recommendations for Improvement

Clarify study design (single vs. double blind)

Provide detailed sample size calculation

Improve data availability compliance

Include effect sizes and confidence intervals

Add a clear distinction between primary and secondary outcomes

Tone down causal and mechanistic claims

Expand discussion on clinical implications and limitations

Major Revision Required

The manuscript has strong potential but requires substantial revisions in methodology reporting, statistical transparency, and interpretation before it can meet PLOS ONE publication standards.

Reviewer #3: This manuscript presents data analysis from a three-arm randomized clinical trial in 50 individuals with chronic paraplegia, comparing a reference rehabilitation group, a NEUROM group, and a combined NEUROM+tDCS group.

The topic is of importance, and the study was registered as a RCT within clinicaltrials.gov (with a valid NCT number), and was approved by the respective IRB/Ethics Committee. While the study objectives sound interesting, is important, and on target, some shortcomings were observed in regards to abiding by the CONSORT guidelines for conducting and reporting results of high-quality randomized controlled trials.

1. Methods:

Methods reporting need some work. An orderly manner is suggested, following CONSORT guidelines, without repeating information, such as Trial Design, Participant Eligibility Criteria and settings, Interventions, Outcomes, sample size/power considerations, Interim analysis and stopping rules, Randomization (details on random number generation, allocation concealment, implementation), Blinding issues, etc, should be mentioned. The authors are advised to create "separate subsections" for each of the possible topics (whichever necessary), and that way produce a very clear writeup. They are advised to write it carefully, following nice examples in the manuscript below:

https://www.sciencedirect.com/science/article/pii/S0889540619300010

Specific comments:

(a) For instance, the randomization and allocation concealment should be made very clear (they are NOT the same thing); the trial staff recruiting patients should NOT have the randomization list. Randomization should be prepared by the trial statistician, and he/she would not participate in the recruiting.

(b) More details on the randomization is needed; I could find no such details, other than saying that random numbers were generated via a web-based random generator. Was it a block randomization? What block size? Why was block randomization not conducted, since, BR helps to achieve equal sample sizes in the 2 arms.

(c) There seems to be design inconsistency! The abstract describes the study as single-blind, whereas the Methods section describes it as double-blind, and the randomization section later clarifies that it was effectively single-blind with blinded outcome assessment, since participants and therapists could not be blinded. This is confusing.

(d) Sample size: There doesn't seem to be any formal sample size/power statement provided! This is a serious limitation, given that the authors are analyzing data generated from a clinical trial. On the overall, the sample size seems to be small, wrt. a 3-arm superiority trial, with a variety of endpoints.

(e) Statistical Analysis writeup

(e1) The statistical analysis framework is not fully developed. Although ANCOVA (for continuous outcomes), and nonparametric tests (for ordinal outcomes) were used, there were no confidence intervals reported for treatment effects, no estimated adjusted mean differences, etc.

(e2) There seems to be errors in the reported ANCOVA degrees of freedom; for example, (2, 52) = 35.6, but with a total n = 50 subjects, it's not clear how 52 appears in (2, 52).

(e3) The single primary endpoint was not clearly mentioned, although, multiple outcomes were mentioned.

(e4) The study design as analyzed does not formally test synergy in the statistical interaction sense; hence, the claims of synergy should be reduced.

(e5) How missing data was handled is not clear.

(e6) The analysis was intention-to-treat, yet, the CONSORT flow diagram consists of words like "Excluded from Analysis (give reasons)". Not clear.

2. Results & Conclusions:

(a) The authors should check that any statement of significance should be followed by a p-value in the entire Results section. Otherwise, the Results section look OK; it's pretty straightforward.

(b) Conclusions should state that the current findings are ONLY based on the samples derived from the specific population, and should allude to future studies with much larger sample sizes and collected at other geographical areas to confirm the effectiveness of the NEUROM+tDCS group, over the other groups.

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Reviewer #1: No

Reviewer #2: No

Reviewer #3: No

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Additive Effect of tDCS and Neuromotor Recruitment on Functional Recovery in Chronic Paraplegia: A Randomized Controlled Trial

PONE-D-26-07973R1

Dear Sarraj,

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.

Kind regards,

Mohammad Sidiq, PhD, Physiotherapy, FAIMER Fellow

Academic Editor

PLOS One

Additional Editor Comments (optional):

Dear authors, I'm pleased to share that the current revision satisfies the quality and rigor as per PLOS ONE standards, and I'm happy to accept this version based on the positive feedback from the reviewers too.

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 #2: 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 #2: Yes

Reviewer #3: (No Response)

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

Reviewer #2: Yes

Reviewer #3: (No Response)

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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 #2: Yes

Reviewer #3: (No Response)

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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 #2: Yes

Reviewer #3: (No Response)

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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 #2: The manuscript can be considered for publication in its current form. Thankyou for giving me the opportunity.

Reviewer #3: (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 #2: No

Reviewer #3: No

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