PONE-D-24-10523The aperiodic exponent of neural activity varies with vigilance state in mice and menPLOS 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

Reviewer #2: No

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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: No

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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

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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: - **Novel Contribution**:

- The paper investigates the influence of vigilance state on the 1/f signal in EEG data, addressing a gap in existing literature. It provides valuable insights into the importance of considering vigilance state during EEG analysis, which can impact the interpretation of results and the identification of biomarkers for neurological disorders.

- **Comprehensive Approach**:

- The study utilizes both animal (mouse) and human EEG data, providing a comprehensive analysis across species. This approach enhances the generalizability of the findings and allows for comparisons between preclinical and clinical settings.

- **Methodology**:

- The methodology employed in the study is robust, involving the use of the FOOOF pipeline for EEG data analysis and careful scoring of vigilance states. Additionally, ethical considerations are addressed, with animal work conducted in accordance with EU directives and human data obtained through approved protocols.

- **Significant Findings**:

- The results demonstrate significant effects of vigilance state on the 1/f signal, both in mouse models of schizophrenia and in human cohorts with schizophrenia and Alzheimer's disease. These findings underscore the importance of proper vigilance state labeling and correction in EEG analysis to accurately assess disease-related changes.

- **Implications for Clinical Practice**:

- By highlighting the impact of vigilance state on EEG signals, the paper has practical implications for clinical practice. It emphasizes the need for clinicians and researchers to carefully account for vigilance state variations, particularly in the context of neurological disorders, to ensure accurate diagnosis and treatment monitoring.

- This study delves into the impact of vigilance state on the 1/f signal within EEG data, filling a notable void in current research. By exploring this aspect, the paper offers crucial revelations regarding the necessity of factoring in vigilance state when conducting EEG analyses. Such consideration proves pivotal in ensuring the accuracy and reliability of findings, consequently refining the identification of potential biomarkers for various neurological disorders. Recognizing and incorporating this specific aspect into EEG measurements not only enhances the precision of analyses but also contributes to elevating the overall quality of EEG data interpretation and subsequent research outcomes.

- Minor Adjustments to Consider:

- It is recommended to integrate the plots within the main body of the document rather than placing them at the end.

- Additionally, the supplementary material could be included within the main document, preferably in an appendix section, for improved accessibility and coherence.

Reviewer #2: The authors investigated the influence of various factors (including vigilance state, sex, diagnostic group (in humans), genetics (in mice)) on the aperiodic component of resting state electroencephalography (EEG) recordings. The results showed that some of these factors were associated with differences in the aperiodic exponent, both in mice and in humans.

The manuscript is short, and I found it a confusing read. It suffers from a lack of focus, a lack of detail in the methods and left me with many questions regarding the rationale, methodology, results, and interpretation. Additionally, I believe the conclusions of the study are not strongly supported by the evidence as presented. Although the research question is interesting, I have major concerns about various aspects of the study which I have listed below:

1. Perhaps the main claim of the paper is that vigilance state influences the aperiodic exponent in both humans and mice. However, how vigilance state was defined based on the EEG data is confusing. The three awake states are labelled a1, a2, and a3 throughout, and as far as I could tell from the methods these were defined based on which frequency bands were dominant in the signal. Far more detail is needed about how the vigilance state groupings were assigned to EEG data for both humans and mice. I have not come across this way of dividing EEG data before and do not believe that this way of splitting the data would be universally accepted to index differences in vigilance state. There are many reasons why delta, theta, alpha or other frequency bands might dominate the signal at a given time, not just vigilance state.

2. In general, far more methodological details are required for the reader to fully understand how the data were analysed. For instance, please describe fully the pre-processing steps for the EEG data in both mice and humans. For the various ANOVAs performed, was multiple comparison correction applied for follow-up tests? A critical methodological detail that is missing (at least I couldn’t find it) is over which frequency range the authors fit the Fooof algorithm and which Fooof settings were selected?

3. The introduction is very short and provides no rationale for many of the analyses performed. For instance, why is data being analysed from schizophrenia and preclinical Alzheimer’s disease patients when the research question is about influence of vigilance state of the aperiodic component? Similarly, why was genotype a factor in the mouse experiment? Why is sex a variable of interest in the human experiment? The inclusion of all these (apparently irrelevant) makes the results section difficult to follow and complicates interpretation of the results. Additionally, if multi-variable ANOVA interactions are truly of interest, then it would be important to show that both experiments are sufficiently statistically powered to detect them. Is this the case?

4. Pearson’s correlations were calculated for the correlations presented in Figure S2 but some of the variables are not continuous (i.e., sex, state, site). Also, why would participant ID correlate with any of the other variables (including significantly with age)? This seems very strange.

5. Why is autism included among the key words?

6. The lack of an overall discussion makes it very difficult for the reader to gauge what the take home message(s) of the study are and how they fit into existing literature. Some highly relevant recent studies are not cited and should be. For instance, Kopcanova et al., (2024) showed that the aperiodic exponent of resting state EEG does not differentiate Alzheimer’s patients from healthy controls (see also Azami et al., 2023). Additionally, in the intro a more comprehensive coverage of relevant literature is required. For example, the following is from the intro: “It has been suggested that this may be an expression of the balance between neuronal excitation and inhibition” Who suggested this? Citation(s) required.

7. What were the criteria for excluding participants based on noisy EEG?

8. In the Figure S1 caption, what does ‘Frequency accounts for the number of electrodes’ mean?

References

Azami, H., Zrenner, C., Brooks, H., Zomorrodi, R., Blumberger, D. M., Fischer, C. E., ... & PACt-MD Study Group. (2023). Beta to theta power ratio in EEG periodic components as a potential biomarker in mild cognitive impairment and Alzheimer’s dementia. Alzheimer's Research & Therapy, 15(1), 133.

Kopčanová, M., Tait, L., Donoghue, T., Stothart, G., Smith, L., Flores-Sandoval, A. A., ... & Benwell, C. S. (2024). Resting-state EEG signatures of Alzheimer's disease are driven by periodic but not aperiodic changes. Neurobiology of Disease, 190, 106380.

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Reviewer #1: Yes: Ioannis Iossifidis

Reviewer #2: No

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The aperiodic exponent of neural activity varies with vigilance state in mice and men

PONE-D-24-10523R1

Dear Dr. Ostergaard,

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.

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Kind regards,

Prof. Dr. Dragan Hrncic, MD, PhD

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

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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: Yes

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

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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: Thank you for addressing my initial comments and concerns. I have no further comments to make on the manuscript.

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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: Yes: Ioannis Iossifidis

Reviewer #2: No

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