PONE-D-20-06961

Electrophysiological correlates of focused attention on low- and high-distressed tinnitus.

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: Yes

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

Reviewer #1: 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

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4. Is the manuscript presented in an intelligible fashion and written in standard English?

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Reviewer #1: 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: General:

This study addresses resting-state EEG in humans subjects with tinnitus, which has been an area of substantial interest and influence in the field of tinnitus neuroscience for at least 2 decades. Unfortunately this field has almost entirely neglected to control for some factors that might well impact greatly on ongoing brain activity, namely hearing loss and, particularly, attention. This study is one of only two to explicitly control and measure the correlates of attention in this context, and is the only one to include the all-important condition of diverting attention away from tinnitus.

Some general notes are below, followed by a moderate number of suggestions that might improve the quality of results and impact of the findings. However, nothing is ‘wrong’ as such with the manuscript in its present form, so I have generally kept these as optional.

Good sample size

Clear novelty over the Neff study (62), and is the first study to contrast attention toward vs away from tinnitus. This is a very important area of resting-state brain activity research in tinnitus, which until the present study and (62) has been totally neglected in the past 2 decades of this line of research.

Quality of writing is satisfactory

Introduction is generally factual, and avoids unwarranted speculation

Subjects well-matched for age, sex, tinnitus variables and hearing

Appropriate and well-performed methods. Appropriate use of statistical tests, and control for multiple comparisons.

The discussion is categorised by finding, but within those categories is rather sprawling and vague, discussing many possibilities for each finding, and arguing in favour of none specifically. However, I do not think there is necessarily anything wrong with this, and it is definitely preferable to confidently stating unjustified conclusions. The discussion in its present form does speculate a lot in many places, including into some rather tenuous explanations, but in every case it is clearly presented as speculation, and therefore I think that is, once again, fine.

Major:

There is little mention made of how the brain changes associated with tinnitus distress compare to those associated with other chronic aversive sensory conditions, such as chronic pain, on which there is a substantial literature. When I last looked at this, albeit some years ago, there were striking parallels. I do not feel strongly that a discussion of this should necessarily be added to the manuscript, as it would require significant work, but if included I think it would make the manuscript considerably more interesting and useful, as it would help determine the extent to which the observed results are generic features of distress or chronic symptoms (more likely) or specific to tinnitus (less likely).

Was any analysis done on gamma band activity? There has been a lot of interest in resting-state EEG gamma in tinnitus, and it would be useful to know whether the present findings can contribute to this ongoing area of interest.

It is a shame that all analysis has been performed in sensor space as opposed to source space. As there is such a loose correspondence between specific electrodes and brain areas, this means that it is hard to compare the present findings with most of the previous literature, which was presented in source space, mainly using sLORETA. Again this is optional (PLoS One only requires the experiments to be properly conducted and reported), but the findings would be so very much more useful, interesting and impactful if an sLORETA analysis were performed. The sLORETA software is very easy and quick to use, free, and accepts data in a .txt file format following simple conventions such that it can easily accept preprocessed data from other software packages. Reanalysis with sLORETA should take less than a week, and would add so much. But, this is the authors’ decision.

I rarely say this in peer reviews, but I wonder if the authors’ analysis has been overly conservative, in that I do not think depression and anxiety scores necessarily need to be factored out when conducting the statistical analyses. Yes, they are correlated to tinnitus distress, but unless the subjects had pre-existing mental health conditions prior to tinnitus then these scores are probably consequences of tinnitus distress (or at least an inherent part of the mechanism of tinnitus distress), and hence factoring them out will probably remove a lot of variance from the data that genuinely reflects the variable of interest (tinnitus distress). Other variables (age, sex, hearing, duration, ear) did not vary significantly between groups, and therefore I would be satisfied to just leave it at that and not address them in the analysis. With this in mind, I am not sure the PCA-based analysis is necessary, but I will leave this to the authors’ discretion.

I also wonder (though am not sure) if the use of ANOVA here has applied too harsh a statistical penalty. We must bear in mind that the different ROIs, and different frequency bands, are far from independent. This is because many effects are common across multiple frequency bands, and most brain sources project much more widely to the scalp than just one of the authors’ ROIs as used here. I believe that the ANOVA will assume independence of frequencies and ROIs, and therefore its results will be much too conservative. In situations such as these, I tend to base all my stats on non-parametric permutation testing (i.e. run the analysis, say, 1000 times over but randomising the subject group labels each time, and taking the maximum group difference observed in each permutation to construct a null distribution, and finally use the 0.05 position in the sorted null distribution as the significance threshold for the real data). This technique works across all types of data, makes no assumptions about distributions, corrects appropriately for multiple comparisons, and is well-suited to large multivariate datasets. Once again, I do not feel strongly that the authors do this in this case, but if they choose not to then it should be made clear how conservative the results are likely to have been as a result of the methods chosen, and how this impacts on the interpretation of any negative results in particular frequency bands and/or brain locations. Note that sLORETA has this method, or an equivalent, built into its functionality, should the authors decide to follow my recommendation to perform a source space analysis.

Related to my comment in the ‘general’ section, regarding the discussion. Given the lack of a clear unifying interpretation of the findings, the authors might consider adopting a ‘less is more’ approach, and trying to keep the discussion brief and tidy, as the huge number of potential, and potentially conflicting, speculative interpretations in the present version is hard to derive any kind of take-home message from, and therefore does not really give any additional value to the reader. However, it is the authors’ right to speculate as much as they wish, and I will not insist on this section being changed.

Minor:

Two successive sentences in the abstract describe results with and without different degrees of correction, and appear to contradict each other. I would advise sticking to just one analysis, hence one set of findings, in the abstract. As I argue in ‘major’, I would for once advocate focusing on the less conservative analysis.

In the introduction, discussion of the resting-state EEG literature does not mention that all these prior studies failed to control for hearing loss (and sometimes even for age), and omits Adjamian et al. (2012 – JARO) which is rare in actually controlling for hearing loss (and did not replicate most of the previously reported difference).

The introduction presents the thalamocortical dysrhythmia theory as if it is accepted fact. I would suggest stating it as a possible theory, and also perhaps acknowledging that the studies supporting it did not control for hearing loss (or attention!), and likewise that they only recorded from cortex, to the link to thalamus is speculative.

The statement “probably due to impaired habituation” should be rephrased, as by definition what the authors are describing is impaired habituation.

The statement “whereas less persistent tinnitus is associated”: the authors presumably mean ‘less bothersome’, or noticeable a smaller proportion of the time.

Line 102 should read “… is related to…”

129: “highly” not “high”

135: why “paradoxical”? It seems intuitive that this should be the case

142: “suggest” not “confirm”

145: “correlates of their EEG” does not make sense. Do the authors mean “EEG correlates of tinnitus-directed attention” or similar?

Lines 148-151: The rationale is not made clear for why the present study should provide insights not already provided by the Neff study (62). In my mind, the novelties of the present study are the stratification by distress level, and the use of an ‘attend-away’ condition (the body-focused condition). In principle, there might not be much or any difference between attending to tinnitus vs. resting state if subjects are already attending to their tinnitus in resting state, whereas a condition requiring attention away from tinnitus might be more likely to reveal differences.

Was any verification made, after the experiment, of how much subjects adhered to the instructed focus of attention for each block (and whether they had their eyes open or closed)?

Where statistical results are reported, are the authors able to provide p values? Readers will find these the easiest measures to gain a quantitative impression of. I note there are p values in the figures, but it would be nice to have them in the text also.

Line 504: I wouldn’t make too much of ref (39), because in hindsight the results almost certainly just indicated an excess of jaw muscle artefact in the tinnitus group

My PDF file did not seem to include any captions for the main text figures. I assume that these are present somewhere.

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Reviewer #1: Yes: William Sedley

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Electrophysiological correlates of focused attention on low- and high-distressed tinnitus.

PONE-D-20-06961R1

Dear Dr. Milner,

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,

Manuel S. Malmierca, 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

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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: Yes

**********

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

Reviewer #1: Yes

**********

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: 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: Yes

**********

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: I really appreciate the authors' careful consideration of all my points, and the substantial work and effort they have undergone in order to fully embrace and address these.

The new version of the manuscript is much improved by the additional source space analysis, and more relaxed statistical analyses, and the results that these have produced. I also note the numerous instances of rewording in the manuscript which has helped it read in a more even-handed way (though this was never much of an issue to begin with).

The synthesis of results, and discussion, seem to deliver more of a clear take-home message too.

Overall, I continue to like this manuscript, and think it has been greatly further improved by the additional work and effort. I am enthusiastic to recommend publication in its present form.

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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.

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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: Yes: William Sedley