PONE-D-21-27156Exercise-induced increase in blood-based brain-derived neurotrophic factor (BDNF) in people with multiple sclerosis: a systematic review and meta-analysis of exercise intervention trialsPLOS ONE

Dear Dr. Nima Rezaei,

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Reviewer #1: Yes

Reviewer #2: Yes

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

Reviewer #1: Yes

Reviewer #2: Yes

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3. Have the authors made all data underlying the findings in their manuscript fully available?

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Reviewer #1: Yes

Reviewer #2: Yes

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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: This is a systematic review and meta-analysis of exercise intervention trials focused on the exercise-induced serum levels of brain-derived neurotrophic factor (BDNF) in persons with multiple sclerosis (pwMS).

The review is very comprehensive, the analysis is well conducted, and deals with a particularly relevant topic in the field of MS. In particular, it confirms that concentrations of serum BDNF increase after exercise, supporting the hypothesis that physical activity is useful for promoting neuroprotection through brain plastic changes, which in turn is particularly relevant in limiting MS progression.

We must take into account the limitations that affect most of the studies analyzed, which make the conclusions refer to relatively selected patient cohorts (low levels of neurological disability, mainly relapsing-remitting courses , exclusion of patients with comorbidities).

In addition, the reported findings are not particularly original, since they are also reported by other meta-analyzes. In particular, the current study is quite similar to a previous one (The Effect of Aerobic Exercise on Brain-Derived Neurotrophic Factor in People with Neurological Disorders: A Systematic Review and Meta-Analysis. Mackay CP, Kuys SS, Brauer SG. Neural Plast. 2017), which also highlighted the effect of exercise on BDNF levels in patients with neurological diseases (MS included), and that should be discussed.

Reviewer #2: Title:

Exercise-induced increase in blood-based brain-derived neurotrophic factor (BDNF) in people with multiple sclerosis: a systematic review and meta-analysis of exercise intervention trials.

General comments:

The authors are commended for a well-written manuscript. In my opinion, the investigation is well-structured, and all methodological standards for this kind of study were observed. I believe there are only minor issues with the manuscript in its current form that need to be addressed before publication. I hope that the following critique will be received in the way it is delivered and be used to improve the quality of the manuscript.

Minor concerns:

The following minor concerns are presented in order of appearance.

Abstract.

The authors stated that meta-analyses have not been previously performed comparing pre- and post-intervention BDNF concentrations in patients with multiple sclerosis, however, in the discussion section (lines 388-389) they cited the meta-analysis by Ruiz-Gonzàles et al. (2021). Please check these statements and if appropriate reformulate the sentences. In addition, did the authors check the articles collected in the Ruiz-Gonzàles’ review for their work?

Introduction.

The Introduction is well-structured, however, there is no information about mechanisms lying to the increase of BDNF due to exercise. Why exercise increases the BDNF level? If possible, could you provide a brief explanation about this?

Results. Lines 198-200.

In this sentence, the authors reported the studies’ countries. This information is also present in table 1. In my opinion, this information is not relevant to the aim of the study, so it is not necessary to report it also in the text. Please consider removing this sentence.

Results. Lines 270; 331; and Fig. 9.

Regarding the subgroup analysis, the authors refer to two kinds of exercise: aerobic vs anaerobic, but sometimes they referred to anaerobic exercise as resistance training. However, in table 1, only one article was classified as resistance training, while another one that used pilates as training was not considered in any classification but reported as an anaerobic exercise during the analysis. Can “Anaerobic exercise” and “Resistance training” terms be considered interchangeably? The subgroup analysis was performed considering also combined training, but it was not reported in the title. Please consider specify better the classification criteria and reporting the same terminology in all parts of the manuscript. Consider also re-grouping the articles in table 1 following the final classification.

Discussion. Lines 323-328; 333-336.

These two paragraphs report the same information. Please consider removing the second.

Discussion. Lines 339-343.

In my opinion, this paragraph should be re-written to enhance comprehension of the link between the benefits of exercise on cognitive function and the role of the BDNF.

Discussion. Lines 356-357.

This sentence seems to be unrelated to the previous information, while the quality of life of people with MS depends largely on the MS progression. Please consider expanding information about exercise, MS progression and quality of life in multiple sclerosis or remove the sentence.

Discussion. Lines 363.

“improvement in” is in bold.

Discussion. Lines 368-374.

Please consider moving this information into the introduction section.

Figures 1-10.

The number of figures in the manuscript is high. Please consider including only relevant ones and move the rest (e.g., 3, 4, 5, and 7) to the supplementary.

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Reviewer #1: No

Reviewer #2: Yes: Luca Correale

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Exercise-induced increase in blood-based brain-derived neurotrophic factor (BDNF) in people with multiple sclerosis: a systematic review and meta-analysis of exercise intervention trials

PONE-D-21-27156R1

Dear Dr. Nima Rezaei,

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,

Cosme F. Buzzachera, Ph.D.

Academic Editor

PLOS ONE

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

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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: (No Response)

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

Reviewer #2: (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: (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: (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: (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: Yes: Luca Correale