Safety of Deep Repetitive Transcranial Magnetic Stimulation (drTMS) against Medical Refractory Symptoms in Parkinson Syndromes: First German Real-World Data with a Specific H5 Coil

Round 1

Reviewer 1 Report (New Reviewer)

In this study, the authors investigated the safety and feasibility of deep repetitive transcranial magnetic stimulation (drTMS) application in patients with different Parkinson Syndromes and medical refractory symptoms.

This manuscript is interesting; nevertheless, it needs very substantial improvements and corrections before publishing may be possible.


General points:

Please add a list of abbreviations before the References section to your manuscript.

Please do your List of References at the end of the manuscript according to “Neurology International”.

Please check your manuscript for spells very carefully once again.

 

Special points:

 Keywords: please add also to keywords: patients.

Please add the future perspectives sections to your manuscript.

Introduction

 Please describe very exactly the existing up to date treatments of PD.

Lines 34-36: please add the multiple references after each of these sentences.

Lines 42-43: please add more references at the end of this sentence.

Lines 44-53: please describe exactly all these publications.

Lines 54-59: please add the multiple references after each of these sentences.

Lines 59-61: please add to this sentence the information about the speech problems in PD patients after drTMS. 

 

Materials and Methods

 Lines 80-81: please add the exactly number of the female and male patients.

 Line 84: please describe the edition information about the diagnosis of the PD in all patients.

 Lines 91-92: please add the exact date of the permission for all your experiments.

 Table 1: please add the references to each score used in this Table.

 

2.3. Stimulation

 Please add according to which scientific group or publication you did this method.

 

 2.4. Data processing and analysis

 Please describe this section more exactly

 

 Figures

 Please add to each Figure (1-3) Legend the exact description of this Figure.

 

 Discussion

 This discussion is too short, please discuss all results more exactly and step by step.

 Please add the Future perspectives section to your manuscript.

Author Response

Please see the attachment.

Author Response File: Author Response.docx

Reviewer 2 Report (New Reviewer)

Authors report an interesting retrospective study about the use of deep TMS in Parkinson syndromes. It is useful for all clinician in the field, since NIBS are a promising therapeutical tool that should be known more and several protocols should be better defined. I have some major and minor concerns about the work presented. 

Major concerns: 

About stimulation:  

 - how did authors choose which patients would undergo 5 and who would undergo 6, 7, 8, .. 11 stimulations? The number of stimulations each patient received should be expressed among results or in table 1. 

- how did authors evaluate the maximum index finger movement looking for resting M1? Were surface EMG used to calculate any MEP?

- Which stimulation intensity was chosen to identify M1?

- did you use the 10-20 system to initially identify M1 location?

- "stimulation intensity was calculated according to the manufacturer’s guidelines (Brainsway ltd) and manufacturer’s stimulation protocol was followed", where can we find such stimulation protocol (add a reference)? Stimulation at 90% of what? Of the maximum intensity possible with the machine the authors used? Have authors used any stimulation parameter based on resting motor threshold? 

About depression scales: there is no p value about the scores before and after the treatment, despite a reduction of the symptoms appears to be present. 

In the analysis there should be a correlation among the number of the stimulations performed and symptomatic response; in the discussion authors should try to identify a minimum number or to express it from literature.  

Minor concern: 

- there are several English errors and format issues. 

- it could be nice to have a picture of the H5 coil. 

Author Response

Please see the attachment.

Author Response File: Author Response.docx

Reviewer 3 Report (New Reviewer)

Hello Dear authors,

It was my pleasure to read and review your paper and it is great work and provide some new light into PD research.

Overall paper is very well written and was easy to read. I have some minor comments of the english wordings. I found that some words have "-" in between. I tries to list down the line number and words, however i would suggest that please one more look at the overall paper and clear the errors.

Line 39: devel-opment

Line 48: stim-ulation

Line 49: add-on

Line 55: indica-tions

Line 103: med-ication

Line 143: as-sessment

Line 145: symptom-dominant

Line 153: stimu-lation

Line 157: in-tervals

Line 165: correla-tional

Line 167: func-tions

Line 177: stimu-lation

Line 185: sleep-lessness

Line 277: Sec-ondly

Author Response

Please see the attachment.

Author Response File: Author Response.docx

Round 2

Reviewer 1 Report (New Reviewer)

Dear authors, thank you for your corrections.

However, the manuscript still needs some substantial improvements before publishing may be possible.

Special points:

 Introduction

 Lines 34-58: please add some references after each of these sentences.

Lines 47-58: please describe exactly all these publications.

 

Materials and Methods

2.3. Stimulation 

Please add according to which scientific group or publication you did this method.

 Discussion

This discussion is too short, please discuss your results more exactly and step by step.

 

Author Response

Please see the attachment.

Author Response File: Author Response.docx

Reviewer 2 Report (New Reviewer)

authors answered to all my major and minor considerations, so I believe that a very good job was done. 

Author Response

Thank you.

Round 3

Reviewer 1 Report (New Reviewer)

Now, the manuscript fullfils the recommendations that were made.

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

This study had great potential, showing the real-world efficacy of H5 dTMS stimulation of non-ideopathic PD symptoms & potentail effects on cognition. However, the lack of UPDRS data (available from only 4 patients) strongly hinders the relevance of the study and its conclusions. A lot of analysis is given on side effects (which apparently was the data available). In the other scores except from the NRS, no mention is given of the number of patients that was included in the analysis, or if any of the effects were found to be significant. For example, in the BDAI-FS it says "revealed a decrease or a maintenance in the reported symptoms in 10 from 11 PS patients". There is no mention of significance, or how large the symptom reduction was. Not even if there was a symptom reduction at all. There is also no mention of the results using the other BDI scale. The way the Manuscirpt is written, it seems as there is no effect anywhere but the NRS, but then the discussion says there were effects in depression. In MoCA, again there is no mention of the number of patients that had the data, was it obtained from all the patients? is the MoCA sufficiently sensitive to measure improvements? were the MoCA score values showing cognitive deficits in patients at the start of treatment? (data is not shown, show the data!)  Finally, the only results shown besides side effects, is that the greater the age, the greater the improvements in the NRS. However, as the authors correctly state in the discussion, previous studies have shown that improvements are proportional to symptom severity. Hence, to really say that age is relevant, you would need to determine if in your sample, symptom severity (in the UPDRS) matched or did not match age. As the authors do not have UPDRS scales for enough patients (only 4), it is very little that can be concluded from the results. Perhaps the Manuscript could be changed to "side effects of dTMS in PD patients" and focus the analysis on the side effects.     

Reviewer 2 Report

The study presented explores the effect of drTMS in ameliorating the spectrum of Parkinson symptoms. It is a relatively novel approach in addressing the clinical/functional aspect of therapy.

All three hypothesis focusses on drTMS effects. Is there stimulation protocol of 1Hz universal? Are there stimulation/inhibition frequencies?  

What about differences between cognitive and motor symptoms?

Line 217: : “The most common main symptom was walking complications, reported by 11 patients” – What kind of complication??

What was the time interval between treatment and symptom assessment? This needs to be addressed at in the discussion and in the results section.

Is the NRS result in Figures 2 & 3 inclusive of Becks and MoCA scale? These have not been explained clearly.