A Protocol to Investigate Deep Brain Stimulation for Refractory Tinnitus: From Rat Model to the Set-Up of a Human Pilot Study

Round 1

Reviewer 1 Report

"A protocol for deep brain stimulation for refractory tinnitus..." describes a protocol for an on-going clinical trial, the first to implant tinnitus sufferers with Deep Brain Stimulation electrodes, hoping that DBS will provide relief from tinnitus in a significant part of the population that suffers greatly from constant chronic tinnitus. This was a very interesting paper to read, and I am looking forward to seeing the results of the study, personally. 

I have precious little to say about this manuscript, both because it is a protocol and so there are no results to discuss, and also because this manuscript is well written and easy to understand, for which I was thankful. I only have a few comments that go from simple to trivial. I trust the authors will take the following comments into account:

 

The only points I would want clarification on are:

1) why 2 (L/R) electrodes? The study team does not know the optimal working parameters, and there is no mention of whether the electrodes will be stimulated with the same parameters (particularly amplitudes), activated synchronously or not, and whether there is an expected asymmetry if only one side is stimulated (in tinnitus perception, lateralization and other characteristics). This is important to mention on line 24 of section 2.5.1: will the amplitudes be adjusted separately? Does activation of one electrode influence the effectiveness of the other?

2) At T0, patients take part in the optimization of their stimulation parameters. This implies that the tinnitus relief is expected to be instantaneous. But to me, it also means that patients are now unblinded. Please comment on that in the text. 

 

Simple comments:

- Section 2.5.1, line 24:  "current starting from 0.5 V up" -> currents are not in Volts. Voltage is mentioned correctly on line 10 of section 2.5.2.

- Same line: describe the pulse: is it uni- or bipolar, and indicate its polarity (anode/cathode?).

- Discussion line 29: "20% of tinnitus patients is willing": First it should be "are", but more importantly, what is the threshold of tinnitus severity in these patients? I doubt you mean "20% of the general tinnitus population". 

 

Trivial:

- Line 30, abstract: "is as a promising treatment" -> remove "as"

- Introduction, line 4: "Every tenth patient experiences": what population is this? 1 of 10 patients presenting with tinnitus, or the general population going to their primary care physician? Please specify.

- "in involved tinnitus networks" -> "in networks involved in tinnitus". 

- Section 2.3: "if they meet the in- and exclusion criteria" -> I think you mean "and none of the exclusion criteria"

- section 2.4.1: "(T0,T1,T2,T3)" should refer to Fig.1 or Table.2

- Table 2, last line with EEG and LFP was not formatted correctly. 

Author Response

Dear reviewer1,

 

Thank you for your kind and helpful feedback. Below you may find our replies.

 

1) why 2 (L/R) electrodes? The study team does not know the optimal working parameters, and there is no mention of whether the electrodes will be stimulated with the same parameters (particularly amplitudes), activated synchronously or not, and whether there is an expected asymmetry if only one side is stimulated (in tinnitus perception, lateralization and other characteristics). This is important to mention on line 24 of section 2.5.1: will the amplitudes be adjusted separately? Does activation of one electrode influence the effectiveness of the other?

 

Thank you for your questions and pointing out this issue. To clarify the bilateral implantation the following was added: “Tinnitus is a complex disorder for which to date the underlying mechanisms are not entirely clear. The auditory system is organized bilaterally, with a large number of interconnections and information crossing partially (80%) after the cochlear nucleus. To investigate safety and feasibility bilateral implantation was opted for.” (Line 231)

Initially voltages will be increased separately to assess side effects. Thereafter, voltages will initially be increased symmetrical, depending on the clinical effect and side effects these might be altered separately. From other disorders, such as Parkinson’s disease, it is known that stimulation of the electrode in the other hemisphere influences the clinical effect of the stimulation of the other electrode. We added: “Initially, the stimulation will be bilateral with the same parameters on both sides. Voltages will be increased symmetrically depending on the clinical effect and side effects.” (Line 262)

2) At T0, patients take part in the optimization of their stimulation parameters. This implies that the tinnitus relief is expected to be instantaneous. But to me, it also means that patients are now unblinded. Please comment on that in the text.

 

We agree with reviewer on this and do not expect the tinnitus relief to be instantaneous. The goal of the optimization phase is mostly to investigate side effects and tolerability of the stimulation in daily life before stimulating for a longer period of time during the test phases. Since side effects are also expected to be transient (e.g. diminishing gradually over a few minutes after the start of stimulation) we do not consider the patients unblinded since this effect is mimicked at the start of the OFF test phases. The following phrase was added: “During this period, side effects and tolerability of the stimulation in daily life are evaluated, however no instant alleviation of tinnitus loudness and burden is expected.” (Line 265)

 

 

 

Simple comments:

- Section 2.5.1, line 24: "current starting from 0.5 V up" -> currents are not in Volts. Voltage is mentioned correctly on line 10 of section2.5.2.

Thank you for your correction, we have adjusted the manuscript accordingly.

 

- Same line: describe the pulse: is it uni- or bipolar, and indicate its polarity (anode/cathode?).

 

Thank you for the question, we added the information in the manuscript. “Stimulation is monopolar, the deepest contact of the electrode is the anode and the internal pulse generator is the reference.” (Line 245)

 

- Discussion line 29: "20% of tinnitus patients is willing": First it should be "are", but more importantly, what is the threshold of tinnitus severity in these patients? I doubt you mean "20% of the general tinnitus population".

 

Thank you for the critical note, this questionnaire study was indeed performed in a general tinnitus population, which is now included in the text. Additionally the following sentence was added: “The willingness increased with the amount of therapies already tried.” (Line 367)

 

Trivial:

- Line 30, abstract: "is as a promising treatment" -> remove "as"

- Introduction, line 4: "Every tenth patient experiences": what population is this? 1 of 10 patients presenting with tinnitus, or the general population going to their primary care physician? Please specify.

- "in involved tinnitus networks" -> "in networks involved in tinnitus".

- Section 2.3: "if they meet the in- and exclusion criteria" -> I think you mean "and none of the exclusion criteria"

- section 2.4.1: "(T0,T1,T2,T3)" should refer to Fig.1 or Table.2

- Table 2, last line with EEG and LFP was not formatted correctly

 

Thank you for your keen eye, we have adjusted the manuscript according to your remarks.

Author Response File: Author Response.docx

Reviewer 2 Report

It is a very interesting project with a correct scientific design on a possible new application in tinnitus therapy without any consideration about the possible outcome.

Author Response

Reviewer 2:

 

It is a very interesting project with a correct scientific design on a possible new application in tinnitus therapy without any consideration about the possible outcome.

 

We would like to thank the reviewer for their time and positive feedback.

Author Response File: Author Response.docx

Reviewer 3 Report

Dear authors,

I think the study is very promising, but with any result in the hands, it is not possible to assess the feasibility of your project. I would wait 2023 until resubmit the full article.

Author Response

Reviewer 3:

 

Dear authors,

I think the study is very promising, but with any result in the hands, it is not possible to assess the feasibility of your project. I would wait 2023 until resubmit the full article.

 

We would like to thank the reviewer for their time and positive feedback. We intend to report outcomes once these data are available but for good practice, we aim to publish the study protocol before inclusion has finished. 

 

Author Response File: Author Response.docx

Reviewer 4 Report

Dear Ladies and Gentlemen, Dear Journal-Team,

the study aims to investigate the outcome of deep brain stimulation for tinnitus backed up by own animal studies. Progress and efforts in elctrophysiological understanding and therapy is long awaited.

1. For reasons of ethical balancing, an innovative and invasive study needs the mentioning or better listing of already existing preclinical and clinical data and/or alterations in the study protocol for study justification. Besides a discussion of current knowledge and reviews has to be done (e.g. Dehleck AN et al., "Invasive neuromodulation as a treatment for tinnitus: a systematic review"). The authors can fully express their opinion and classify the therapy as an individual-based decision with no other alternatives in patients with strong suffering. Due to this shortcomings I cannot favour the described study protocol in the manuscript. 

2. Please explain all abbreviations when mentioned first, although when already explained in tables or the abbreviation list: GPIAS, page 2, line 44, (Gap-prepulse inhibition of the acoustic startle reflex), WHO, page 4, line 16 (please chack WHO, World Health Organization?), VAS, page 2, line 44 (visual analogue scale), CTCM, page 10, line 9 (Clinical Trial Center Maastricht), EDC, page 9, line 4 (Electronic Data Capture), STN, page 19, line 9 (subthalamic nucleus), AC-PC, page 10, line 5 (anterior commissure-posterior commissure), ANT, page 10, line 12 (anterior nucleus of thalamus), GPi, page 10, line 17 (Globus pallidus internus).

3. Please change on page 7, line 21 to 'a reliable response'. Check for explanation of 'cognitive functioning **' in Table 2.

Sincerely,

Author Response

Reviewer 4:

 

Dear reviewer 4,

 

Thank you for your kind and helpful feedback. Below you may find our replies.

 

Dear Ladies and Gentlemen, Dear Journal-Team,

the study aims to investigate the outcome of deep brain stimulation for tinnitus backed up by own animal studies. Progress and efforts in elctrophysiological understanding and therapy is long awaited.

1. For reasons of ethical balancing, an innovative and invasive study needs the mentioning or better listing of already existing preclinical and clinical data and/or alterations in the study protocol for study justification. Besides a discussion of current knowledge and reviews has to be done (e.g. Dehleck AN et al., "Invasive neuromodulation as a treatment for tinnitus: a systematic review").The authors can fully express their opinion and classify the therapy as an individual-based decision with no other alternatives in patients with strong suffering. Due to this shortcomings I cannot favour the described study protocol in the manuscript.

 

We agree with the reviewer that this could be emphasized more in the manuscript. The following information was added: “Other implants that could potentially influence tinnitus, and have been investigated, are a cochlear implant (CI) [24] and an auditory brainstem implant (ABI) [25], however these can only be used in patients with severe hearing loss. In addition, other neuromodulation techniques, such as vagal nerve stimulation and cortical, have been investigated with various degree of success.” (Line 101)

We included the review by Declerck and colleagues.

Deklerck AN, Marechal C, Pérez Fernández AM, Keppler H, Van Roost D, Dhooge IJM. Invasive Neuromodulation as a Treatment for Tinnitus: A Systematic Review. Neuromodulation. 2020 Jun;23(4):451-462.

 

2. Please explain all abbreviations when mentioned first, although when already explained in tables or the abbreviation list: GPIAS, page 2, line 44, (Gap-prepulse inhibition of the acoustic startlereflex), WHO, page 4, line 16 (please check WHO, World Health Organization?), VAS, page 2, line 44 (visual analogue scale),CTCM, page 10, line 9 (Clinical Trial Center Maastricht), EDC,page 9, line 4 (Electronic Data Capture), STN, page 19, line 9(subthalamic nucleus), AC-PC, page 10, line 5 (anteriorcommissure-posterior commissure), ANT, page 10, line 12 (anteriornucleus of thalamus), GPi, page 10, line 17 (Globus pallidusinternus).

 

Thank you for your remark. We added the explanations where needed. The abbreviation WMO is a reference to Medical Research Involving Human Subjects Act in the Netherlands which in Dutch is ‘Wet Medisch-wetenschappelijk Onderzoek met mensen’. We clarified this in the text.

 

3. Please change on page 7, line 21 to 'a reliable response'. Check for explanation of 'cognitive functioning **' in Table 2.

 

Thank you for your keen eye, we adjusted accordingly.

Author Response File: Author Response.docx

Round 2

Reviewer 2 Report

The Authors have modified the paper according to reviewer observations.

Now the paper can be published. 

Author Response

Dear reviewer 2, 

Thank you for your contribution to our manuscript. 

 

Reviewer 3 Report

Dear authors, I can’t understand to publish a protocol without any result which support it. 

Author Response

Dear reviewer 3, 

Thank you for your contribution to our manuscript. 

 

Reviewer 4 Report

Dear Ladies and Gentlemen, Dear Journal Team,

the manuscript 'A protocol of deep brain stimulation for refractory tinnitus: from rat model to a human pilot study' is improved. The mentioning or better listing of already existing preclinical and clinical data and/or alterations in the study protocol for study justification is still mssing.

Sincerely,

Author Response

Dear reviewer 4,

We have added more information on both DBS in animal models as well as information on neuromodulation techniques in the introduction. Further elaboration on this subject is outside the scope of this protocol.

Thank you for your contributions to our manuscript. 

Round 3

Reviewer 4 Report

Dear Ladies and Gentlemen, Dear Journal-Team,

as described in my early reviews, although progress and efforts in elctrophysiological understanding and therapy is long awaited, I cannot favour a publication of this clinical study protocol without gathering all possible preclinical and clinical already published data and discussing the differences and the connected ethical issues.

Sincerely,

Author Response

Dear reviewer 4, 

Thank you for you reply. We have adjusted the introduction and added an overview of previous preclinical and clinical studies that focused on dbs primarily for tinnitus. Additionaly we have added a section to the discussion going into ethics concerning dbs in refractory patients. 

We hope to have adjusted sufficiently. 

Kind regards