Can the Brain’s Thermostatic Mechanism Generate Sleep-Wake and NREM-REM Sleep Cycles? A Nested Doll Model of Sleep-Regulating Processes

Round 1

Reviewer 1 Report

In this manuscript by Dr. Putilov, titled “Can the brain thermostatic mechanism generate the sleep-wake and (NREM-REM) sleep cycles? A nested doll model of sleep-regulating process”, the author proposes a model for understanding sleep cycles in relation to a thermostat mechanism. However, the manuscript is very difficult to follow and there is a lack of data and evidence to support the arguments made. The following are additional comments:

-        Data is presented from human participants, some of whom were sleep deprived, but there is no mention of IRB approval or an exemption process

-        Process S (sleep homeostatic pressure) is mentioned throughout the manuscript, but there is no specific mention of Process C (circadian rhythm in wakefulness) which is a key contributor to sleep-wake regulation. Some mention of circadian cycling is included but it is not clear how Process C is accounted for in the model presented.

-        The model is tested on data from a sample of n=17 and n=14 people that has been used in their prior work. Why not use larger sample sizes and different samples to avoid generalizing a model of sleep regulation using such a specific subset of data?

-        Figures 1 and 2 are difficult to decipher.

-        The work would benefit from wider reading of the literature. One paper to read may be this one: Athanasouli C, Kalmbach K, Booth V, Diniz Behn CG. NREM-REM alternation complicates transitions from napping to non-napping behavior in a three-state model of sleep-wake regulation. Math Biosci. 2023 Jan;355:108929. doi: 10.1016/j.mbs.2022.108929. Epub 2022 Oct 30. PMID: 36448821.

Extensive editing required

Author Response

Author's Reply to the Review Report (Reviewer #1)

Review Report Form

In this manuscript by Dr. Putilov, titled “Can the brain thermostatic mechanism generate the sleep-wake and (NREM-REM) sleep cycles? A nested doll model of sleep-regulating process”, the author proposes a model for understanding sleep cycles in relation to a thermostat mechanism. However, the manuscript is very difficult to follow and there is a lack of data and evidence to support the arguments made.

Reply. The manuscript, especially the results section, was rewritten to formulate clearer the major argument of this article that the results provide additional, model-based argument for a thermostatic regulator underlying sleep cyclicities.

The following are additional comments:

-        Data is presented from human participants, some of whom were sleep deprived, but there is no mention of IRB approval or an exemption process

Reply. Since the simulated datasets were already published more than 10 years ago, the description of these data was placed in Supplementary Material including the statements that the experiments were performed in accordance with the ethical standards laid down in the Declaration of Helsinki, that the experimental protocols were approved by the Biomedical Research Ethics Committee and that informed written consent was obtained from each study participant.

-        Process S (sleep homeostatic pressure) is mentioned throughout the manuscript, but there is no specific mention of Process C (circadian rhythm in wakefulness) which is a key contributor to sleep-wake regulation. Some mention of circadian cycling is included but it is not clear how Process C is accounted for in the model presented.

Reply. Fully agree that the process C is a key contributor to sleep-wake regulation. In a new Table it is characterized in a separate 3^rd column, it is included in the formulation of the process S (1) as (2) of Methods and as (12) in (11) in Supplementary Material. Moreover, it was accounted in preliminary simulations with results described in section 2.4 and reported in Table S1 of Supplementary Material. Its contribution to the simulations was also mentioned in section 4.1 of Methods on the page 12 and in Discussion on the page 10. Finally, a new section 1.5 was added in Supplementary Material to provide details on the mechanism by which this process C contributes to sleep-wake regulation.

-        The model is tested on data from a sample of n=17 and n=14 people that has been used in their prior work. Why not use larger sample sizes and different samples to avoid generalizing a model of sleep regulation using such a specific subset of data?

Reply. Unfortunately, I do not know such available datasets (i.e., with data on the time courses of the indexes of regulatory processes for the intervals within and between sleep cycles). In the previously published papers, including papers mentioned in the reference list [15,16], the spectral EEG indexes are only plotted in small-size figures. The sample sizes were the same (n=14). There are only tables with data on duration of sleep cycles, their NREM and REM phases, etc. It is not enough for simulation study. Moreover, the necessity of replications of the simulations using independent and larger datasets was mentioned in the last (limitation) paragraph of Discussion. Finally, the result section was fully rewritten to shift its focus from simulations to predictions of in silico study and to explanation of the content and major characteristics of the components of the proposed model.

-        Figures 1 and 2 are difficult to decipher.

Reply. To make the figures simpler, the second halve of each figure was relocated in a new (last) section 2.6 of Supplementary Material. Moreover, the text of Results concerning these figures was rewritten to explain them clearer, and the legends of these figures were enlarged to provide more details on how was support for predictions of in silico study provided by these simulations. Finally, the predictions supported by simulations shown in these figures were explained and illustrated by a new figure in a new section 2.1 of Results.  

-        The work would benefit from wider reading of the literature. One paper to read may be this one: Athanasouli C, Kalmbach K, Booth V, Diniz Behn CG. NREM-REM alternation complicates transitions from napping to non-napping behavior in a three-state model of sleep-wake regulation. Math Biosci. 2023 Jan;355:108929. doi: 10.1016/j.mbs.2022.108929. Epub 2022 Oct 30. PMID: 36448821.

Reply. By the way, this publication did not remain unnoticed, and it was cited in our previous publications among other publications of models of sleep cycle (reference [27]). Indeed, this publication also desires to be mentioned in the present article, and it was mentioned twice in section 3.2 of Discussion at the page 10.

Comments on the Quality of English Language

Extensive editing required

Reply. A native English speaker reviewed and corrected the text. The entire text was mostly rewritten to improve its clarity.

Reviewer 2 Report

The author posits an interesting addition to the 2-process model with their nesting doll thermostatic regulation equations.

-A diagram explaining the concept graphically would really improve readability, especially since the equations are presented after the Results.

-The discussion should describe the study's limitations, such as how this study was done using simulations rather than real world data and explain how this step is necessary to advance the state of the science.

There is some awkward phrasing, overly technical language, paragraph issues and incomplete sentences. None of this limits the article's readability, but it would be a shame not to fix such simple issues when the content is so interesting.

Author Response

Author's Reply to the Review Report (Reviewer #2)

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Comments and Suggestions for Authors

The author posits an interesting addition to the 2-process model with their nesting doll thermostatic regulation equations.

-A diagram explaining the concept graphically would really improve readability, especially since the equations are presented after the Results.

Reply. This was done in the form of new Table 1. The model and its predictions were additionally explained in Figure 1.

-The discussion should describe the study's limitations, such as how this study was done using simulations rather than real world data and explain how this step is necessary to advance the state of the science.

Reply. The last paragraph concerning the limitations of the study was added in the end of Discussion. The term “simulation” was used in this article in its usual meaning that is fitting real data by means of derivation of the parameters of the model (Tables 2 and S1) from the model’s equations (3-5).

Comments on the Quality of English Language

There is some awkward phrasing, overly technical language, paragraph issues and incomplete sentences. None of this limits the article's readability, but it would be a shame not to fix such simple issues when the content is so interesting.

Reply. The entire text was mostly rewritten to improve its clarity. A native English speaker reviewed and corrected the text. In particular, the result section was fully rewritten to focus on predictions of in silico study and to provide more details in the explanation of the content and major characteristics of the components of the proposed model by using not only texts but also new Figure 1 and Table 1.