PONE-D-23-35942Analysis of the alpha activity envelope in electroencephalography in relation to the ratio of excitatory to inhibitory neural activityPLOS ONE

Dear Dr. Hoshiyama,

Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process.

Two experts in the field have carefully reviewed the manuscript entitled, "Analysis of the alpha activity envelope in electroencephalography in relation to the ratio of excitatory to inhibitory neural activity". Their comments are appended below.

The first reviewer acknowledged that the manuscript is fairly well-written with leaving several serious concerns which should be considered before publication.

On the other hand, the second referee pointed out that there is the fundamental concern regarding the hypothesis the author posted.

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Academic Editor

PLOS ONE

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"Minoru Hoshiyama reports financial support was provided by JSPS Grant-in-Aid for Scientific Research (C) (20K07881) and Japan Agency for Medical Research and Development. The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. "

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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

Reviewer #2: Partly

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

Reviewer #1: Yes

Reviewer #2: I Don't Know

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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

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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: 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: General Comment:

I thank the authors for the opportunity to review this work. The amount of work put into this research is evident. For this reason, I hope to offer suggestions which will increase the effectiveness of the paper.

The paper offered an interesting new technique to evaluate EEG-based alpha activity within the human brain – one in which has not been thoroughly explored before. Although the paper was communicated coherently overall, minor specifications were missing which impact the reproducibility of the work. For that reason, I have highlighted these recommended changes along with some minor comments for the author to consider, for the work to be more impactful overall.

Abstract:

The abstract covers most of the necessary components in order to summarize the research but could have been a bit more quantitative in nature. Providing the supporting quantitative results would help solidify the significance of the findings and would render the paper as more impactful overall.

Page 2 – The abstract states that alpha waves are “the major components of cortical activity in the electroencephalography (EEG)”. Although this is not completely incorrect, I believe it to be critical to state that this is in reference to waking human brain activity. For instance, it is well established that during resting states, lower frequency bands (i.e., delta and theta) dominate neural activity in the brain, therefore this distinction is necessary.

Introduction:

The introduction provided a good balance of background knowledge and rational for the research. A few minor comments on the introduction include:

Page 7 – Line beginning with “the waxing and waning” - while introducing such concepts it, would be helpful if the authors provided more details on “the summations of multiple dynamics”.

Page 10 – The introduction ended very strongly. The authors were very clear in what their aims were, what the paper entailed, and the implications of the work.

Methods:

The methodology was presented in a logical structure, although was missing a few minor details. Further details are required on the following:

Page 10 – Please state why the authors opted to use eyes closed data.

For instance, the choice of using eyes closed EEG data is a great one as it avoids the need to discriminate neuronal signals associated with mechanisms of visual processing and oculomotor artifact (such as eye-blinks and eye-movements). For this reason, it would be of great value if the authors stated this, along with any other reasons why eyes closed data were used.

Page 12 section 2.2 – Please state why only 60 seconds of EEG data were evaluated.

Page 12 sections 2.2 – Specify which key features were involved in this selection process. In other words, please state which markers of noise were evaluated.

Page 12 – data analysis sections should be denoted as section 2.3.

Page 12 sections 2.3 – Were the peak alpha frequencies evaluated on an individual basis, e.g., in the form of the Individual Alpha Peak Frequency (IAPF)? If so, please specify. If not, please indicate why IAPFs were not used.

Page 13 section 2.3 - Please state the process involved in the signals being rectified.

Additionally, it would be helpful stating the purpose/why EEG rectification was used. This would ultimately allow the research to be more well received and applied to a wider audience (i.e., by those who may not be as familiar with EEG-based research and terminology).

Page 13 section 2.3 - Which MATLAB command was used? If this is in reference to Fourier Transform, please specify.

Page 14 section 2.3 – Please clarify why “An I value was originally a negative value, but in

this study an I value was expressed as a positive value”.

Page 14 section 2.4 – A minor note, but I would suggest changing the phrase “at each electrode” to “at each electrode site” as the former refers to a single electrode whereas the latter refers to all electrodes at a single scalp location (e.g., electrode site F3, etc.).

Discussion:

I commend the authors on the work, as the findings seem novel and were fascinating to learn about. In order to more accurately represent the value of the findings, I recommend the following minor alterations of the discussion section:

Page 18 – I recommend putting all limitations and future work in a section toward the end of the discussion, as this would allow the findings to be presented in a stronger and more convincing manner.

Page 19 section 4.1 – When discussing the findings, I suggest tying them in with previous work which may be similar in concept (even if not of similar methodology, but of similar underlying neuronal mechanism). Doing so would strengthen this section, and thereby further substantiating the findings of this study.

Page 19 section 4.1 – Regarding the sentence: “That is, the excitatory force or second derivative that increased the amplitude was, on average, greater than the force that decreased the amplitude.” - What does this indicate on a neural level?

Page 20 section 4.1 – “Since both E and I were positively correlated with amplitude, a region of higher mean envelope amplitude, resulting from higher amplitude alpha activity, had more inhibitory than excitatory power operating.” – What are the implications of this finding, more specifically, in relation to healthy participants?

Page 21 section 4.1 – “the present study, we might observe that excitatory and inhibitory components or factors in one frequency band, i.e., the alpha frequency band, resulted from the effects of other frequency bands” – Well noted and a strong end to this section.

Page 22 section 4.2 – “We thought that this alpha envelope analysis method allowed us to evaluate the E-I ratio from a temporal sequence of the alpha rhythm obtained at a region or electrode.” – I suggest adding a point or two to this sentence as to why the authors believed this, as a means of strengthening the statement.

Page 22 section 4.2 – “less in the number of electrodes” – are the authors referring to less in all of the electrodes or specific electrodes. If the latter, please specify which electrodes this is in reference to.

Page 22 section 4.2 – “this result could simply related with the severity of dementia” – it would strengthen this statement if a previous research was used to substantiate this assumption. Are there any underlying mechanisms which could further support this statement?

Page 24 section 4.2 – “Further studies with participants with AD and FTD with similar MMSE scores are needed to clarify the relationship between the E-I ratio and deterioration of brain

function.” – Great concluding sentence.

Conclusion:

The conclusion was clear and concise, and very effective overall. With that said, I recommend moving the limitations section to before the conclusion section as I believe this would increase the effectiveness of the work by ending on a positive note.

Page 24 – the phrase "quite simple" downplays the method, making it seem less strong overall. I would suggest rephrasing this to something along the lines of "Although, this novel analysis method does not involve high degrees of complexity..", as the value of the work is presented in a more convincing and persuasive manner.

Figures:

Figure 1 – “Methods of analysis of electroencephalography (EEG) signals.” I would recommend changing this to “ A representation of the method of analysis” as this figure supports the methodology, but is not the “method” per se.

I appreciate this opportunity to review this work and hope that the constructive feedback will be of benefit to the Authors.

Reviewer #2: In this study, the authors investigate the link between the phenomenon of waxing and waning amplitude in the alpha frequency band (8-12 Hz) and the E/I (excitation/inhibition) ratio. This research goal is pursued by first extracting the envelope of the 8-12 Hz band-pass filtered signal. Consequently, the second derivative of the envelope was extracted, assuming that negative values corresponded to a higher influence of inhibitory populations, while positive values to be driven by excitatory ones. As a practical example: in this study, a higher E/I ratio is equivalent to a steeper increase of the amplitude in the alpha frequency range. The differences with respect to these parameters, and its relevance to clinical populations of patients with AD and FTD is then used as a benchmark for these EEG quantitative metrics.

Although the subject of this study is currently of great interest, I would recommend that the authors address a few major points before publication. After a brief summary of my suggestions and comments, I will detail every comment, referring to the exact manuscript line (where possible).

Authors assume that the waxing and waning of alpha frequency amplitude is driven by a dynamic disequilibrium in the balance between excitatory and inhibitory populations, irrespective of which cortical/subcortical region we are subjecting to investigation; they make this assumption by advancing that ERP studies support this view. However, it is my personal opinion that this claim needs stronger evidence. From my point of view, providing more literature that backs up this claim is at least necessary to improve the quality of the manuscript. In an ideal case, authors might want to establish their claims by providing evidence in a computational model: as they don't make any region-specific claim, I think that a neural mass model should be sufficient in this case. Without these precautions, I believe that the authors' claims are not really supported by the data presented, which also makes it very difficult to intepret their clinical results even for an expert reader.

In the manuscript, there is also some missing information that I think are very important for a thorough understanding of their work, but I'm confident that authors can fill in the gaps very quickly.

Major issue: at the current state, it's really hard to confirm that the authors' assumptions and results are backed up by the data presented. Because of this, I would suggest a few steps before publication:

- provide, at least in the introduction, literature supporting the validity of using the second derivative of the alpha frequency envelope as a proxy measure to the E/I ratio;

- ideally, showing this link in a computational model (I would suggest using a neural mass model) is a major key point is solidifying this work's results.

- addressing the minor issues, which will be detailed in the next paragraph, citing the exact manuscript page where possible.

Introduction

- page 8: "In the case of evoked

potentials, the increase or decrease in amplitude of the components was

considered to be the sum of excitation and inhibition processes that occurred

prior to the generation of the wave. Such excitation and inhibition could be

considered not only for afferent neural signals evoked by external stimuli,

but also for intrinsic neural activity, e.g., neural activity producing alpha

waves, at the cortical and subcortical levels." Reference is needed here, even if the study was already cited in the previous paragraphs.

- page 10: "We believe that this study was conducted using a new method

with potential future applications." claims of novelty are not really necessary in the introduction. However, this is my personal view and I haven't found anything against it in the journal's editorial guidelines, which makes it not really necessary to address.

Methods

- page 11. How many ICs were rejected, on average? and is there a reason for not using a CAR rereferencing before ICA?

- page 12. I'm not really sure of why a 60s window was selected for all EEG recordings. It's my understanding that the reason is probably related to too many artifacts present in these datasets, but can you elaborate more on this?

- page 13: if I'm not mistaken, authors use "differentiated" to indicate derivatives. I might be wrong, and I apologize if that's the case, but it would be better to mantain a certain degree of consistency when using technical jargon.

- page 14. Some important details are missing in the description of the statistical methods used here. In order: which statistical test did you use to compare the metrics presented here? which type of correlation did you apply (Pearson, Spearman's, etc...)? how was significance for the correlation computed?

Results

- page 15. Maybe MMSE (mini mental state exam) needs to be introduced before the results.

Discussion

- page 19, "The mean E-I

ratio was 1.38 for normal participants using the present analysis". Is this value comparable to what has been found in other studies, even if they used different methods?

- page 19, "These results suggested that the waxing and waning of the alpha envelope was regulated by a pattern of balance between excitatory and inhibitory forces." In light of my earlier comments, I would suggest to advance these claims only if the link between E/I ration and alpha amplitude are clarified.

- page 20 I'm not sure of what "balistic" means, in this context. Please clarify.

- page 21, " In the present study, we might observe that

excitatory and inhibitory components or factors in one frequency band, i.e.,

the alpha frequency band, resulted from the effects of other frequency bands." I'm not really sure of this sentence's meaning. It would be very kind of the authors if this could be rephrased to improve readabilty.

Figures

Please write titles for each part of the figure, as for instance in Figure 2's graphs. As of now, it's really hard to follow what's depicted in the figures.

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Reviewer #1: No

Reviewer #2: No

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PONE-D-23-35942R1Analysis of the alpha activity envelope in electroencephalography in relation to the ratio of excitatory to inhibitory neural activityPLOS ONE

Dear Dr. Hoshiyama,

Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process.

The original referees have carefully reviewed the revision. They are almost satisfied with the manuscript with leaving some minor concerns which should be considered before publication.

I will make the final decision after receiving the necessary revised manuscript and the reply mail to each critique.

Please submit your revised manuscript by Jun 24 2024 11:59PM. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at plosone@plos.org. When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file.

Please include the following items when submitting your revised manuscript:

• A rebuttal letter that responds to each point raised by the academic editor and reviewer(s). You should upload this letter as a separate file labeled 'Response to Reviewers'.
• A marked-up copy of your manuscript that highlights changes made to the original version. You should upload this as a separate file labeled 'Revised Manuscript with Track Changes'.
• An unmarked version of your revised paper without tracked changes. You should upload this as a separate file labeled 'Manuscript'.

If you would like to make changes to your financial disclosure, please include your updated statement in your cover letter. Guidelines for resubmitting your figure files are available below the reviewer comments at the end of this letter.

If applicable, we recommend that you deposit your laboratory protocols in protocols.io to enhance the reproducibility of your results. Protocols.io assigns your protocol its own identifier (DOI) so that it can be cited independently in the future. For instructions see: https://journals.plos.org/plosone/s/submission-guidelines#loc-laboratory-protocols. Additionally, PLOS ONE offers an option for publishing peer-reviewed Lab Protocol articles, which describe protocols hosted on protocols.io. Read more information on sharing protocols at https://plos.org/protocols?utm_medium=editorial-email&utm_source=authorletters&utm_campaign=protocols.

We look forward to receiving your revised manuscript.

Kind regards,

Manabu Sakakibara, Ph.D.

Academic Editor

PLOS ONE

Journal Requirements:

Please review your reference list to ensure that it is complete and correct. If you have cited papers that have been retracted, please include the rationale for doing so in the manuscript text, or remove these references and replace them with relevant current references. Any changes to the reference list should be mentioned in the rebuttal letter that accompanies your revised manuscript. If you need to cite a retracted article, indicate the article’s retracted status in the References list and also include a citation and full reference for the retraction notice.

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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

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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

Reviewer #2: Yes

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

Reviewer #1: Yes

Reviewer #2: 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: 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

Reviewer #2: 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 first would like to commend the authors for the improvement in the manuscript. With that said, I believe there to be a view minor points to address before being ready for acceptance. These are the following:

Abstract:

Line 34-39: I strongly recommend breaking the sentence up into two to increase readability. E.g., Second sentence starting line 37 "This was done in 36....."

Highlights:

Line 71: I recommend changing the starting of the second point so it varies slightly from the first (i.e., not starting with "a new" once again.

Introduction:

Line 91-98: Very well improved!

Line 105-108: Once again, a bit difficult to read. I recommend re-structuring/ splitting into two sentences.

Line 114: Move this to the sentence after, e.g., by stating "Such aims were based upon previous work, which defines.... (then state where it is based upon).

Line 136: I would move this to the discussion/limitation section as keeping it in the introduction weakens the argument of the current exploration.

Line 167: This sentence comes off weak. Perhaps saying "This study is believed...." rather than "thought". A minor recommendation but wording does strengthen the argument of the work to the reader!

Methods:

The authors have put in evident work to drastically improve the methods section, making it a lot more cohesive and sound. With that stated, I highly recommend adding some visual support (e.g., figures or diagrams) which support the research/analysis. As the concepts explore are fairly complex in nature, I strongly believe a visual component will strengthen receptivity of the work immensely.

I hope that these minor suggestions help improve the manuscript further beyond the already evident improvement!

Reviewer #2: All comments were adequately addressed by the authors.

I would like to thank the authors for the patience taken to revise their work. I also suggest, as a future direction, to investigate the mechanisms underlying the acceleration/deceleration of the envelope in the alpha band, as it might provide an interesting window into neural activity.

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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: No

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While revising your submission, please upload your figure files to the Preflight Analysis and Conversion Engine (PACE) digital diagnostic tool, https://pacev2.apexcovantage.com/. PACE helps ensure that figures meet PLOS requirements. To use PACE, you must first register as a user. Registration is free. Then, login and navigate to the UPLOAD tab, where you will find detailed instructions on how to use the tool. If you encounter any issues or have any questions when using PACE, please email PLOS at figures@plos.org. Please note that Supporting Information files do not need this step.

Analysis of the alpha activity envelope in electroencephalography in relation to the ratio of excitatory to inhibitory neural activity

PONE-D-23-35942R2

Dear Dr. Hoshiyama,

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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If your institution or institutions have a press office, please notify them about your upcoming paper to help maximize its impact. If they’ll be preparing press materials, please inform our press team as soon as possible -- no later than 48 hours after receiving the formal acceptance. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information, please contact onepress@plos.org.

Kind regards,

Manabu Sakakibara, Ph.D.

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

Reviewers' comments: