Activity driven sleep dynamics: A conceptual modeling study

Dmitry Postnov; Ksenia Merkulova; Oxana Semyachkina-Glushkovskaya; Jürgen Kurths

doi:10.1371/journal.pone.0341279

Peer Review History

Original SubmissionAugust 25, 2025
3 Nov 2025 Decision Letter - Gennady Cymbalyuk, Editor PONE-D-25-46278Activity Driven Sleep Dynamics: a Conceptual Modeling StudyPLOS ONE Dear Dr. Postnov, 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. Please submit your revised manuscript by Dec 18 2025 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. 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The PLOS ONE style templates can be found at https://journals.plos.org/plosone/s/file?id=wjVg/PLOSOne_formatting_sample_main_body.pdf and https://journals.plos.org/plosone/s/file?id=ba62/PLOSOne_formatting_sample_title_authors_affiliations.pdf 2. Thank you for stating the following financial disclosure: “DP and KM were supported by Russian Science Foundation, grant 25-15-00174. OSG and JK were supported by Russian Science Foundation, grant 23-75-30001.” Please state what role the funders took in the study. If the funders had no role, please state: "The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript." If this statement is not correct you must amend it as needed. Please include this amended Role of Funder statement in your cover letter; we will change the online submission form on your behalf. 3. 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Additional Editor Comments: The authors should expand the discussion to outline possible applications, validation strategies, and quantitative development pathways. Limitations should be more explicitly addressed, particularly regarding the model’s lack of sleep stage differentiation and its implications for brain clearance mechanisms. In addition, minor language corrections and clearer labeling of figures (particularly the x-axes in Figures 2, 4, 6, and 7) are required to improve readability and precision. [Note: HTML markup is below. Please do not edit.] 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: Yes ******** 2. Has the statistical analysis been performed appropriately and rigorously? Reviewer #1: N/A Reviewer #2: N/A ****** 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 ****** 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 ****** 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: The authors study a two population bistable model that switches between sleep and wake states, and includes SCN input and homeostatic drive, derived in prior work. In this work the authors incoroporate a psycho-sensory drive to simulate the effects of internal states and external influences on the system. They also incorporate distributed individual sleep units that can enter sleep-like states and that interact with the central sleep-wakefulness regulator; they use this framework of interaction between distributed sleep units and the central regulator to model naps. While there is a lack of detailed biological data on the functioning of individual sleep units distributed throughout the brain, and their interaction with the central sleep-wake switch, the authors provide an interesting and reasonable hypothesis through modeling of the nature of this dynamical system. A language edit may be useful prior to publication. I have found the following language errors/typos: Line 6: “extracellular fluid” Line 55: “Kruger says...” What does he say? Rewrite sentence Line 61: On what time scale? Line 78: Remove “be” Line 303: how efficient the proposed structures (are) Line 483 “substantial” should be “substantially” Additionally, for Figure 2,4,6,7 the x axis should be clearly labeled (what are t and h?) Reviewer #2: The authors present a novel mathematical model that integrates the central sleep-wake switch with the concepts of a "psycho-sensory drive" (PSD) and distributed neuro-glia-vascular "sleep units". They showed that the model reproduced the phenomena of local sleep and short nap episodes, which lie beyond the scope of traditional global sleep models. This approach is timely and addresses a significant gap in the computational neuroscience of sleep, offering a promising theoretical foundation for future, more detailed investigations. The manuscript is well-structured and will be of interest to researchers in sleep science, computational neuroscience, and mathematical biology. To further strengthen the work, the following points should be addressed: Major 1. The model is currently presented as a conceptual proof-of-principle. To enhance its impact, the authors should show its potential applications and the pathways for its future validation and quantitative development. 2. The discussion of limitations is good but could be expanded to include, for example, the model's current lack of sleep stage differentiation (NREM/REM) and more concrete hypotheses for its application to brain clearance mechanisms. Minor 1. The manuscript requires minor language edits. For example, Line 79, “in the spirit of” what? Line 210, missing “is” after “D”; Line 257, “Level” =>” level”; Line 532, “Ca2+” =>” Ca^2+” . ****** 6. 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 ******** [NOTE: If reviewer comments were submitted as an attachment file, they will be attached to this email and accessible via the submission site. Please log into your account, locate the manuscript record, and check for the action link "View Attachments". If this link does not appear, there are no attachment files.] To ensure your figures meet our technical requirements, please review our figure guidelines: https://journals.plos.org/plosone/s/figures You may also use PLOS’s free figure tool, NAAS, to help you prepare publication quality figures: https://journals.plos.org/plosone/s/figures#loc-tools-for-figure-preparation. NAAS will assess whether your figures meet our technical requirements by comparing each figure against our figure specifications. https://doi.org/10.1371/journal.pone.0341279.r001
Revision 1
15 Dec 2025 Author Response We are grateful to the reviewers for their positive assessment of our study and helpful suggestions for improvement. Below are our responses to each of the reviewers' comments. All changes made to the manuscript are highlighted in blue. Reviewer #1: Line 6: “extracellular fluid” Our response: It was rephrased: “Thus, it has been shown that during deep sleep, the volume of extracellular space increases significantly.” Line 55: “Kruger says...” What does he say? Rewrite sentence Our response: It was rephrased as follows: “In the paper \cite{krueger2023tripping} the author expresses the opinion that "sleep is a property and is initiated by small groups of closely interconnected neurons." Line 61: On what time scale? Our response: It was rephrased: “From a temporal perspective, the main challenge for a two-process model is that it does not assume ''extra'' short episodes of sleep. “ Line 78: Remove “be” Our response: It has been done Line 303: how efficient the proposed structures (are) Our response: It was rephrased: “Since we propose the model structure from general considerations, although taking into account physiology, a numerical experiment is necessary to evaluate the effectiveness of the proposed structures.” Line 483 “substantial” should be “substantially” Our response: It was corrected. Additionally, for Figure 2,4,6,7 the x axis should be clearly labeled (what are t and h?) Our response: The x-axis in Figures 2,4,6,7 has been clarified (also in one of the graphs in Figure 5). The designation "t, h" has been changed to "Time, hours". Reviewer #2: Major 1. The model is currently presented as a conceptual proof-of-principle. To enhance its impact, the authors should show its potential applications and the pathways for its future validation and quantitative development. Our response: Further validation of the model is desirable at various levels. Specifically, at the level of an individual NGVU, it is necessary to clarify the nature of state changes (e.g., the dynamics of gliotransmitter release) during overconsumption of metabolic reserves, such as astrocytic glycogen. At the system level, further validation of the model would highly require objective data on brain activity patterns in simulated situations that activate and overload as few neural structures as possible. This direction is the most promising, as it also offers potential for practical applications. Just as the two-process model was adapted for purely practical tasks on a daily time scale, our model may also be useful for studying the more rapid processes of drowsiness episodes during prolonged periods of concentration (long night drives, dispatchers working at a control panel, etc.). Another important potential application is the use of the model as one of the tools in a comprehensive study of the possibility of non-simultaneous (local, sequential) activation of brain cleaning. It has already been shown that the phenomenon of local sleep is associated with local accelerated recovery after cognitive load. It is conceivable that during prolonged sleep deprivation, such local events could serve to protect the brain and, to a certain extent, replace global sleep. Of course, experimental work is crucial here, but a suitable modeling paradigm is also important. Regarding the quantitative development of the model, there are at least two approaches focused on different goals. Specifically, at the level of cellular structures, there are known studies on quantitative modeling of processes in NGVU. This makes it possible to quantify molecular transport in the parenchyma. However, the authors believe that accurate quantitative timing of the local portion of the model is a more attractive and achievable goal, similar to what was done for the two-process model. The main challenge here is to accurately estimate the characteristic timing of processes such as various signaling pathways, for example, from parenchymal astrocytes to centers that sense sleep propensity. We have included everything described above in the Discussion text. 2. The discussion of limitations is good but could be expanded to include, for example, the model's current lack of sleep stage differentiation (NREM/REM) and more concrete hypotheses for its application to brain clearance mechanisms. Our response: We are grateful to the reviewer for this very pertinent comment. We indeed failed to address this issue in the previous version of the manuscript. In the revised manuscript, we have supplemented the Introduction as follows: Note that there is a general consensus that activation of harmful metabolite clearance during sleep is due to an increase in the proportion of extracellular space, which facilitates the transport of any molecules within the parenchyma. Since this increase occurs at low neural activity, all our considerations assume a state of deep sleep, NREM sleep, when SWA is recorded in the electroencephalogram. We have also expanded the Discussion as follows: As mentioned in the Introduction, one limitation of the model is that it does not distinguish between REM and NREM sleep states. Note that this is not possible in the original model of the two processes, which we supplement with "low-level" components. Specifically, since REM sleep is characterized by high levels of neural activity, it contributes little (if anything) to accelerating the clearance of harmful metabolites and does not fit with our current working hypothesis. In our view, a different organizational level of model construction is required to adequately incorporate REM-NREM transitions. This could presumably be achieved by identifying typical spatial patterns of activity during REM sleep and associating them with various "medium-sized" sleep modules. Currently, the authors are unaware of experimental data that would allow for the valid construction of such a model. Minor 1. The manuscript requires minor language edits. For example, Line 79, “in the spirit of” what? Our response: It was rephrased: “Next, we introduce a psycho-sensory drive signal into the model following the ideas expressed in the work ~\cite{george2018psycho}. “ Line 210, missing “is” after “D”; Line 257, “Level” =>” level”; Line 532, “Ca2+” =>” Ca^2+”. Our response: It has been done. Attachments Attachment Submitted filename: rebuttal_letter_R1.pdf https://doi.org/10.1371/journal.pone.0341279.r002
5 Jan 2026 Decision Letter - Gennady Cymbalyuk, Editor Activity Driven Sleep Dynamics: a Conceptual Modeling Study PONE-D-25-46278R1 Dear Dr. Postnov, 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. An invoice will be generated when your article is formally accepted. Please note, if your institution has a publishing partnership with PLOS and your article meets the relevant criteria, all or part of your publication costs will be covered. Please make sure your user information is up-to-date by logging into Editorial Manager at Editorial Manager® and clicking the ‘Update My Information' link at the top of the page. For questions related to billing, please contact billing support. 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, Gennady S. Cymbalyuk, 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 Reviewer #2: All comments have been addressed ******** 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: Partly ****** 3. Has the statistical analysis been performed appropriately and rigorously? Reviewer #1: N/A Reviewer #2: N/A ****** 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: No ****** 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: (No Response) Reviewer #2: The authors have addressed all my comments. I have no further questions. I believe the manuscript is now substantially strengthened. ****** 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 ******** https://doi.org/10.1371/journal.pone.0341279.r003
Formally Accepted
Acceptance Letter - Gennady Cymbalyuk, Editor PONE-D-25-46278R1 PLOS One Dear Dr. Postnov, I'm pleased to inform you that your manuscript has been deemed suitable for publication in PLOS One. Congratulations! Your manuscript is now being handed over to our production team. At this stage, our production department will prepare your paper for publication. This includes ensuring the following: * All references, tables, and figures are properly cited * All relevant supporting information is included in the manuscript submission, * There are no issues that prevent the paper from being properly typeset You will receive further instructions from the production team, including instructions on how to review your proof when it is ready. Please keep in mind that we are working through a large volume of accepted articles, so please give us a few days to review your paper and let you know the next and final steps. Lastly, if your institution or institutions have a press office, please let them know about your upcoming paper now to help maximize its impact. If they'll be preparing press materials, please inform our press team within the next 48 hours. 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. You will receive an invoice from PLOS for your publication fee after your manuscript has reached the completed accept phase. If you receive an email requesting payment before acceptance or for any other service, this may be a phishing scheme. Learn how to identify phishing emails and protect your accounts at https://explore.plos.org/phishing. If we can help with anything else, please email us at customercare@plos.org. Thank you for submitting your work to PLOS ONE and supporting open access. Kind regards, PLOS ONE Editorial Office Staff on behalf of Dr. Gennady S. Cymbalyuk Academic Editor PLOS One https://doi.org/10.1371/journal.pone.0341279.r004

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