Effectiveness of Unihemispheric Concurrent Dual-Site Stimulation over M1 and Dorsolateral Prefrontal Cortex Stimulation on Pain Processing: A Triple Blind Cross-Over Control Trial

Round 1

Reviewer 1 Report

The authors have addressed all my concerns. I have no further comments.

Author Response

thank you very much for your effort in reviewing this work, as you have no further comments I attach the updated manuscript with the changes requested by another reviewer.

Author Response File: Author Response.docx

Reviewer 2 Report

This is a very well written manuscript about an interesting topic. However, I have some suggestions, which may improve the quality of this paper.

1. Please justify the stimulation intensity and duration of 2 mA.

2. The Sham protocol seems unusual. Please provide a reference.

3. Men and women respond differently to pain. Furthermore, tDCS has a different effect on men and women (Rudroff et al. 2020 Front. Psychiatry; Workman et al. 2020 Eur J Neurosci). I strongly recommend to analyze men and women separately. 

4. I totally agree with the authors about a possible ceiling effect of tDCS on CPM and TS in healthy subjects. Therefore, this study should be done in patients with neurological diseases, such as people with Multiple Sclerosis and neuropathic pain. Not in healthy subjects! This should be discussed. 

Author Response

Thanks you very  for your efffort in reviewing this manuscript. I attached the manuscript with the changes requested.

best whidses

Josué

Author Response File: Author Response.docx

Round 2

Reviewer 2 Report

All my comments are well addressed.

This manuscript is a resubmission of an earlier submission. The following is a list of the peer review reports and author responses from that submission.

Round 1

Reviewer 1 Report

In the present manuscript, the authors aimed to test the effect of anodal tDCS over left M1 and DLPFC in releasing pain in healthy controls as compared with tDCS over M1 only and sham tDCS. It has a triple-blind cross-over design. Pain function pre- and post-tDCS was assessed using various tests and scales. Overall, neither tDCS over M1 nor tDCS over M1 and DLPFC showed significant effects on pain modulation as compared with sham tDCS.

This is a study with proper study design and a moderate sample size. The topic of the study is highly relevant, addressing an important topic of the field, and of clinical importance. Although negative findings may still add knowledge to the field (i.e., no superior effect of tDCS over M1 and DLPFC), the failure of replicating the pain modulation effect using tDCS over left M1 leads to the question that whether the tDCS and/or pain function measurements were done properly. Although the authors provided several possibilities in the Discussion for the null results, in my mind, the current findings did not provide significant information to the field. Unfortunately, I cannot recommend the publication of this manuscript in its current form.

One additional comment: what’s the duration of each test and how long do you expect the tDCS effect to last? Does the overall duration of the tests within the lasting effect of tDCS? If some tests were conducted beyond the duration of tDCS effects, this may explain some of the negative findings.

Reviewer 2 Report

There are several major issues of this study. First, this study used a cross-over trial design without enough washout period. Several articles showed tDCS effect lasts several weeks, so 72 hours of a wash-out period between interventions is not enough. Second, this study did not follow standard tDCS procedures or outcome measures. It is well known that at least 5 consecutive tDCS sessions are needed to illicit efficacy, but this study used a single tDCS session for 20 minutes. Moreover, 1mA tDCS, which was used in this study, is not recommended by many studies. Third, they recruited healthy subjects so that their outcome measures have floor effects (depression, anxiety, catastrophizing, sleep). Fourth, their description in the results sections does not match with their design. This study is not a randomized controlled trial but a cross-over trial study, but they described it as a randomized trial. For example, line 295-297 showed “ randomized their first session into one of the three experimental groups: unilateral application 295 tDCS at M1 (M1-tDCS, n=30), combined tDCS at M1 and DLPFC (UHCDS-tDCS, n=30) or sham-tDCS 296 groups (sham-tDCS, n=30)”, which is not matched with their design. Additionally, figure 1 is not matched with their design. Fifth, they did not describe the underlying mechanisms of a possible explanation of the different results among intervention groups in the discussion section. Lastly, there are several grammatical or punctuational errors.