Thermoregulation in Sleep Disorders—Comprehensive Review

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

This comprehensive review examined how thermoregulation intersect with sleep physiology and contribute to the pathophysiology of different sleep disorders such as ADHD, insomnia, narcolepsy, OSA, depression, and RLS. I have the following questions:

1. Authors described the melatonin and temperature manipulation in children with ADHD, does it keep the same for the adults? Other thermoregulation in patients with different disease were conducted in child or adult patients?
2. “Narcolepsy is a cerebral disorder that affects orexin (hypocretin) production. Its spectrum may vary from loss of production to the dysfunction of hypocretin, which is produced in the lateral hypothalamus by neurons.”  Please revise this sentence.
3. Introduction is too short, introduction should detail the sleep-wakefulness mechanism and why do authors choose to review on these sleep related disease, such as ADHD, insomnia, narcolepsy, OSA, depression, and RLS? Why do authors focus on the thermoregulation in these disease? Please revise the introduction.
4. Authors wrote this manuscript would like to address “disorders with impaired sleep quality, evaluates the role of temperature regulation in their pathophysiology and symptoms, and compares characteristic thermoregulatory patterns across these conditions.” what is the final conclusion? “Thermoregulatory dysregulation likely contributes to sleep disturbances??” Is this true? If it is true, in which extent? the causal links should be cautiously given? Please revise the conclusion.
5. Concerning the table 1. Is it necessary to add author or journal’s information.
6. After Table, is that possible to give a message showing how each component of thermoregulation was changed compared to other disease and why do they change in the same way or not?
7. Please update the latest references associated.

Author Response

Comment 1: Authors described the melatonin and temperature manipulation in children with ADHD, does it keep the same for the adults? Other thermoregulation in patients with different disease were conducted in child or adult patients? 

Response 1: We added information on the prevalence of ADHD in adults and the sleep disturbances commonly associated with the disorder. We also included studies investigating the effects of melatonin on dim light melatonin onset (DLMO) and sleep timing, as well as research describing temperature manipulations that can help alleviate sleep disturbances in both children and adults. Line: 153, 170-173

 

Comment 2: “Narcolepsy is a cerebral disorder that affects orexin (hypocretin) production. Its spectrum may vary from loss of production to the dysfunction of hypocretin, which is produced in the lateral hypothalamus by neurons.”  Please revise this sentence. 

Response 2: We have revised the sentence to improve clarity and to better reflect current understanding of narcolepsy pathophysiology, distinguishing between different types of the disorder with respect to hypocretin system dysfunction.Line: 270-271, 275-279

 

Comment 3: Introduction is too short, introduction should detail the sleep-wakefulness mechanism and why do authors choose to review on these sleep related disease, such as ADHD, insomnia, narcolepsy, OSA, depression, and RLS? Why do authors focus on the thermoregulation in these disease? Please revise the introduction. 

Response 3: We have revised the manuscript to address this comment in several ways. First, we expanded the Introduction to provide a more detailed overview of the physiological mechanisms underlying sleep onset, including the roles of melatonin, the distal-proximal temperature gradient (DPG), core body temperature (CBT), and the process of falling asleep. Second, we added a paragraph in the sleep disorders section (3.0)  explaining why these specific disorders were selected for review. We also included background on the broader categories of disorders in which thermoregulatory disturbances may occur, to better justify our focus on thermoregulation in the chosen conditions. Line: 31-41, 47-50, 59-61, 65-68, 74-77,  80-86, 90-93, 114-117. 

 

Comment 4: Authors wrote this manuscript would like to address “disorders with impaired sleep quality, evaluates the role of temperature regulation in their pathophysiology and symptoms, and compares characteristic thermoregulatory patterns across these conditions.” what is the final conclusion? “Thermoregulatory dysregulation likely contributes to sleep disturbances??” Is this true? If it is true, in which extent? the causal links should be cautiously given? Please revise the conclusion. 

Response 4:  We revised the conclusion section (4) to address causality more cautiously and explicitly. We now state that most available evidence is observational or cross-sectional and therefore does not support firm causal conclusions. We also clarify that the role of thermoregulatory dysfunction likely differs by disorder: in some conditions it may contribute directly to sleep disruption, whereas in others it may be secondary to underlying circadian, autonomic, or disease-specific mechanisms. Line: 630-638, 644-667. 

 

Comment 5: Concerning the table 1. Is it necessary to add author or journal’s information.

Response 5: We have added the citations accordingly in the Table 1.

 

Comment 6: After Table, is that possible to give a message showing how each component of thermoregulation was changed compared to other disease and why do they change in the same way or not?

Response 6: We added a comparative synthesis after Table 1 to highlight both shared and disorder-specific thermoregulatory patterns across the reviewed conditions. Line : 553-558

Comment 7: Please update the latest references associated.  

Response 7: We updated the reference list and incorporated more recent literature throughout the revised manuscript

Reviewer 2 Report

Comments and Suggestions for Authors

The most significant addition for a "comprehensive review" would be a table summarizing the thermoregulatory "signatures" of each disorder. This should compare CBT nadir timing, DPG efficiency, and Melatonin onset (DLMO) across the covered conditions (e.g., ADHD, Insomnia, Narcolepsy, OSA, etc.).

While you discuss various temperature manipulations, the draft would benefit from a dedicated section on the future of wearable technology. Discuss how non-invasive, continuous monitoring of distal and core temperatures could lead to personalized "chrono-therapeutics" for sleep disorders.

In Section 3.3.1, you mention that hypocretin deficiency leads to reduced vasoconstriction. It would be beneficial to elaborate on the specific neuroanatomical pathways where hypocretin neurons interact with the sympathetic nervous system to regulate skin blood flow.

In the Narcolepsy section (3.3.3), you rightly note the "divergence" regarding CBT findings (some studies find no difference, others find elevation). To improve this, briefly discuss why these discrepancies might exist, for example, differences in measurement methods (rectal vs. intestinal) or the severity of hypocretin deficiency in the patient cohorts.

Section 3.4.4 notes that CPAP "partially restored" distal skin temperature rhythms. It would be valuable to discuss whether this restoration is due to improved oxygenation or a reduction in the sympathetic surges associated with respiratory events.

You describe a temporal relationship where melatonin rises two hours before RLS symptoms intensify. Explicitly stating whether this suggests a causal link or merely a circadian synchronization would clarify the physiological interpretation for the reader.

Ensure that terms like "SOL" (Sleep Onset Latency) and "SWS" (Slow Wave Sleep) are consistently used after their first definition.

Consider adding a diagram illustrating the "Process of Falling Asleep" (Section 2) that visually maps the divergence of falling CBT and rising DPG as melatonin increases.

Ensure all temperature units (e.g., 37∘C) and gradient ranges (e.g., 0.8−1.2∘C) are formatted consistently throughout the final LaTeX/Word output.

Each disorder currently has its own "Temperature Manipulation" subsection. You might consider a final synthesis section that compares the effectiveness of these treatments (e.g., why foot baths work for insomnia vs. why whole-body hyperthermia is used for depression) to provide a more cohesive clinical takeaway.

Author Response

Comment 1: The most significant addition for a "comprehensive review" would be a table summarizing the thermoregulatory "signatures" of each disorder. This should compare CBT nadir timing, DPG efficiency, and Melatonin onset (DLMO) across the covered conditions (e.g., ADHD, Insomnia, Narcolepsy, OSA, etc.).

Response 1: We agree that a summary table of thermoregulatory signatures is valuable for a comprehensive review. However, we believe that this information is already captured in Table 1, which was specifically designed to provide a cross-disorder overview of the main thermoregulatory features discussed in the manuscript. In particular, it already compares melatonin profile/DLMO, CBT characteristics, DPG or skin temperature patterns, and related clinical implications across the covered conditions, including ADHD, insomnia, narcolepsy, OSA, depression, and RLS. For this reason, we feel that adding a new table would largely duplicate information already presented and would not substantially improve clarity. Therefore, we have retained the current table without adding an additional one.

 

Comment 2: While you discuss various temperature manipulations, the draft would benefit from a dedicated section on the future of wearable technology. Discuss how non-invasive, continuous monitoring of distal and core temperatures could lead to personalized "chrono-therapeutics" for sleep disorders.

Response 2: We added a new section, “Continuous monitoring and thermoregulatory devices in sleep disorders,” in which we discuss non-invasive continuous monitoring of body temperature, including wearable approaches to CBT assessment, and outline how these tools may support circadian phase tracking, phenotyping of thermoregulatory dysfunction, and the development of individualized chrono-therapeutic strategiesnight. Line: 599 - 634. 

 

Comment 3: In Section 3.3.1, you mention that hypocretin deficiency leads to reduced vasoconstriction. It would be beneficial to elaborate on the specific neuroanatomical pathways where hypocretin neurons interact with the sympathetic nervous system to regulate skin blood flow. 

Response 3: We have expanded this section to provide additional detail on the neuroanatomical pathways linking hypocretin neurons with the sympathetic nervous system. Specifically, we have described projections from the lateral hypothalamus to autonomic centers, including the paraventricular nucleus and rostral ventrolateral medulla and their role in regulating vasomotor tone and skin blood flow.Line: 270 - 280

 

Comment 4: In the Narcolepsy section (3.3.3), you rightly note the "divergence" regarding CBT findings (some studies find no difference, others find elevation). To improve this, briefly discuss why these discrepancies might exist, for example, differences in measurement methods (rectal vs. intestinal) or the severity of hypocretin deficiency in the patient cohorts. 

Response 4: We briefly discussed why these discrepancies might exist. Line: 295-306

 

Comment 5: Section 3.4.4 notes that CPAP "partially restored" distal skin temperature rhythms. It would be valuable to discuss whether this restoration is due to improved oxygenation or a reduction in the sympathetic surges associated with respiratory events. 

Response 5: We have expanded this section to further discuss the potential mechanisms underlying the partial restoration of distal skin temperature rhythms with CPAP therapy. Specifically, we now highlight the role of reduced sympathetic activation associated with respiratory events and arousals, as well as the possible contribution of improved oxygenation, in normalizing peripheral vasomotor regulation.Line: 372 -376

 

Comment 6: You describe a temporal relationship where melatonin rises two hours before RLS symptoms intensify. Explicitly stating whether this suggests a causal link or merely a circadian synchronization would clarify the physiological interpretation for the reader. Ensure that terms like "SOL" (Sleep Onset Latency) and "SWS" (Slow Wave Sleep) are consistently used after their first definition.

Response 6: We clarified that this suggests circadian synchronization rather than a causal relationship. We have revised the manuscript to ensure that abbreviations such as SOL (Sleep Onset Latency) and SWS (Slow Wave Sleep) are defined at first use and used consistently throughout the text.Line: 120

 

Comment 7: Consider adding a diagram illustrating the "Process of Falling Asleep" (Section 2) that visually maps the divergence of falling CBT and rising DPG as melatonin increases.  

Response 7: We added a new diagram (Figure 1) in Section 2 illustrating the process of falling asleep. It shows the temporal relationship between melatonin, DPG, and CBT around lights off, emphasizing that the evening rise in melatonin is accompanied by increased heat dissipation (higher DPG) and a decline in CBT, which together promote sleep onset and consolidation.Line: 96-97

 

Comment 8: Ensure all temperature units (e.g., 37∘C) and gradient ranges (e.g., 0.8−1.2∘C) are formatted consistently throughout the final LaTeX/Word output.

Response 8: We have reviewed the manuscript for consistency of temperature units, symbols, and gradient formatting, and we will ensure that these are standardized throughout the final LaTeX/Word version.

 

Comment 9: Each disorder currently has its own "Temperature Manipulation" subsection. You might consider a final synthesis section that compares the effectiveness of these treatments (e.g., why foot baths work for insomnia vs. why whole-body hyperthermia is used for depression) to provide a more cohesive clinical takeaway.  

Response 9: We added Section 3.8, “Comparative Synthesis of Temperature-Based Interventions Across Disorders,” to provide a cross-disorder clinical synthesis of temperature manipulations. In this section, we compare why localized distal warming is most relevant for insomnia and ADHD, why systemic heating approaches are more applicable to depression, why proximal warming may be preferable in narcolepsy, and why thermal interventions in OSA and RLS likely operate through different mechanisms. Line: 559 - 597.