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PONE-D-21-19751

A randomized, double-blind, sham-controlled study of left prefrontal cortex 15 Hz repetitive transcranial magnetic stimulation in cocaine consumption and craving.

PLOS ONE

Dear Dr. Lolli,

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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: Partly

Reviewer #2: Yes

Reviewer #3: Yes

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

Reviewer #1: No

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: 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: The objective of this single-center, parallel group, randomized (sham) controlled trial (RCT) is to assess the effectiveness rTMS therapy for treating cocaine use disorder (CUD). The study was registered as a RCT within the clinicaltrials.gov registry (with a legit NCT number), and was approved by the respective IRB/Ethics Committee. While the study objectives sound interesting, is important, and on target, a number of shortcomings were observed, in regards to abiding by the CONSORT guidelines for conducting and reporting results of high-quality randomized controlled trials (RCTs). Some other (statistical) comments were also added.

1. Methods:

Methods reporting require an orderly manner 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), and Blinding considerations should be mentioned explicitly. The authors are advised to create separate subsections for each of the possible topics (whichever necessary), and that way produce a very clear writeup. I see the Authors already made a sincere attempt; however, they are advised to write it carefully, following nice examples in the manuscript below:

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

Specific comments below:

(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) Sample size/power: There is no sample size/power paragraph presented; it is also not clear whether sample size determinations were done using the primary outcome variable (time to urine negativization). Also, sample size calculations should consider the desired effect size under consideration.

(c) Statistical Analysis:

(i) For the survival analytic endpoint, how is the (right) censoring determined? Is it administrative censoring, or something else?

(ii) Fig 2 is not really a Kaplan-Meier plot; one needs to plot the survival curves for urine negativization corresponding to the "sham" and "active" groups, and then conduct a log-rank test to produce the desired p-value.

(iii) The fit of the multivariate Cox model should be accompanied by necessary goodness-of-fit assessments, and checking the proportional hazards assumptions, through popular tests.

2. Results:

(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 adequate followed by a detailed discussion.

Reviewer #2: The paper by Lolli et al describes the effect of rTMS treatment on cocaine treatment-seeking cocaine addicts. The paper is well written and well designed representing yet another experimental effort that ultimately supports the use of rTMS in the treatment of cocaine addiction. Analysis of experimental data is now more accurate than a previous version of the paper I had seen elsewhere.

I would simply encourage the authors to comment on the possible neurobiological basis for TMS effects.

As such the discussion is merely clinical and reflections/ideas about the the neurobiology underlying clinical effects would help in reducing the 'exoteric aura' around TMS.

Reviewer #3: Lolli and colleagues report on a single site, randomized, double-blind, parallel-group, randomized controlled trial of high frequency rTMS vs. sham for cocaine use disorder. They describe strengths in their trial design and large sample size, however note their challenges with retention of participants as drop-out rates were high (equally in both groups). They did not find any significant differences in their primary outcome of urine toxicology, however a number of important secondary measures did show superiority of rTMS, including outcomes related to self reported use, depression, certain indices of craving, and impulsivity. Importantly, they note that rTMS was well tolerated without any significant adverse effects.

Given the growing interest in neuromodulation for addictive disorders, this study is a welcome addition to the literature. The authors are correct in stating that the vast majority of currently published studies are far too small and under-powered in nature to be confident about clinically significant therapeutic benefit. Given the unique and substantial risks in managing severe substance using populations, it also needs to be demonstrated in clinical trials that these treatments that require intensive follow up (e.g. daily treatment visits required of rTMS) can be feasible in those that abuse substances. This may be particularly challenging for very destabilizing substances such as cocaine. This manuscript provides data to address these current shortcomings in the literature well.

The main significant criticism is that this manuscript fails to address is the issue of rTMS targeting, which has become a field of intense debate and study. Current approaches typically include MRI based anatomical targeting, fMRI-based connectivity targeting, or other brain biomarkers (e.g. EEG). The rationale and excitement for neuromodulation in the addictions field is the ability to more specifically target aberrant neurocircuitry. Thus, the current paper’s target of “PMC/DLPFC” is very imprecise according to current standards. The PMC and DLPFC are relatively disparate regions of the cortex. Standard rTMS procedures, even those using only scalp-based measurements, aim to target only the DLPFC. One such method is the “Beam F3 method” which the uses the 10-20 EEG placement system is likely more precise. The authors do cite the Beam F4 method in their discussion, stating it is the most anatomically accurate non-MRI navigated method, but do not seem to use it themselves.

Other comments I have are relatively minor, but there are many of them, mostly related to increasing clarity of the writing of the manuscript. It will be important for the authors to address issues like blinding and statistical analyses to account for missing data, as these relate to the methodological issues that are important to the paper.

Introduction

- Line 61-62 is too definitive of a statement for such preliminary research cited.

- Life 65 don’t recommend wording of “restoring symptoms”, should be treating or alleviating symptoms

- Line 66-67 needs citations.

Methods

- Please consider reporting your protocol according to the CONSORT checklist of information to include when reporting a randomised trial.

- For clarity, I would suggest listing inclusion criteria and exclusion criteria separately

- For clarify, I would recommend using a different word than biweekly. It is a little bit unclear since this word can mean every 2 weeks or it can mean twice a week.

- Line 119: suggest using terminology, thus T0 should be “baseline” as previously described in the page before.

- Line 123: What does a “neurophysiology technician” refer to?

- Blinding was reported for participants and medical operators. Please comment on blinding by the raters for standardized scales. Was blinding successful and were any measures conducted to assess for fidelity of blinding? As mentioned above, it is not clear who the “neurophysiology technicians” are, but it is mentioned that they were not blinded – does this affect the integrity of the results in any way?

- I recommend using standard terminology for describing the motor threshold method. It is described in a confusing way, with it first referenced as an “individual threshold level” on line 126, then there is some vague description of MEPs around line 134-135 (is this using EMG? Was this resting motor threshold? Then it is mentioned again later in line 141-142 where this is more of a discussion based point about what the motor threshold represents. This can all be consolidated into a few lines or a paragraph all together.

- Please explain the rationale for targeting of the premotor cortex. It was not mentioned in the introduction or the beginning of the methods and was named for the first time on line 129 with just the acronym.

- The description of the target site and landmarking is difficult to follow. Line 132 to 134 seem to suggest there is landmarking done, but it is not clear what these landmarks are, when later it seems to suggest the landmarking is just based on uniform measurements (regardless of individual head shape and size). Where does this landmarking protocol come from? Has it been standardized or referenced before?

- It is not clear why the stimulation sits is “PMC/DLPFC”. These are relatively different sites on the cortex, and it is rather imprecise to lump these together. Furthermore, in the Abstract, the target site is only described as “DLPFC” alone.

- Line 154-156 is better reserved for an introduction or discussion section.

- The VAS protocol needs to be better described. It is not clear how the “VAS base” and “cocaine use-related activities” was actually conducted. Those descriptions provided (e.g. “meeting people who consume the drug”) do not explain whether these are imagined, or whether they are based on image or video cues as is standard in this field. I understand that the citations provided may better describe it, but a brief version of the steps should be available within the paper.

- For the Cocaine Craving Questionnaire, it is not clear how this “here and now” assessment is any different than the VAS. The VAS as currently described also sounds like it is a current craving assessment.

- For the self reported data on cocaine use, was there any specific method used? For example the Timeline Follow Back Method? Was quantity of use collected?

- Line 171 – the word “relevant” symptoms meant to say more severe total burden of symptoms? Does the scale differentiate between different types of symptoms in terms of importance and how would this be described in a total score?

- Please reword line 180-181, it is too difficult to understand in this form

- Statistical analysis: please describe how missing data was accounted for, particularly as your primary outcome is negativity at the end of available observation, may have biased the results towards an effect by missing participants that dropped out due to relapse.

Results:

- For the differences stated between the drop outs and those that continued the study, are those measures listed in line 207-208 referring to baseline cocaine use or throughout the study?

- Were the drop out percentages listed referring to drop out before T1 or T2? Did this affect the analysis?

Discussion:

- Beam F3 may have been more accurate but this is not the way the authors did it in this study

- The discussion of dropouts and difficulty obtaining urine samples is a very interesting paragraph. The authors propose alternate biomarkers of cocaine consumption. However, would an alternate biomarker have any influence on the drop out rate?How much is the drop out rate related to the issues with urine collection? In other words, is it a significant problem that participants that do not drop out yet still a urine sample cannot be obtained?

- The authors discuss using a daily interview and the swimmer’s plot as a good way of identifying daily use. Is there a reason why the Timeline Followback Method was not used? The authors cite Garza-Villarreal et al (2021) who did indeed use the TLFB.

- In describing the strengths of this study as being large and a blinded RCT, the authors do not credit other such studies including Garza-Villarreal et al. (2021), who similarly present a rigorous study design. It may be interesting to include a brief comparison with this study in the discussion section. Similarly, there are other large, well designed RCTs published in methamphetamine use disorder, which although is not exactly the same as CUD, has obvious overlap. It may be interesting to have some discussion of these studies as well in relation to this manuscript.

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Reviewer #1: No

Reviewer #2: Yes: Marco Diana

Reviewer #3: No

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A randomized, double-blind, sham-controlled study of left prefrontal cortex 15 Hz repetitive transcranial magnetic stimulation in cocaine consumption and craving.

PONE-D-21-19751R1

Dear Dr. Lolli,

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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Kind regards,

Bernard Le Foll, M.D., Ph.D.

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 #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 #1: (No Response)

Reviewer #2: (No Response)

Reviewer #3: Yes

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

Reviewer #1: (No Response)

Reviewer #2: (No Response)

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: (No Response)

Reviewer #2: (No Response)

Reviewer #3: 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: (No Response)

Reviewer #2: (No Response)

Reviewer #3: Yes

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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 #1: (No Response)

Reviewer #2: (No Response)

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 #1: No

Reviewer #2: Yes: Marco Diana

Reviewer #3: No