Review Reports - Gravity in the Eye: How ‘Gravitational Ischemia’ in the Retina May Be Released and Resolved Through Rapid Eye Movement (REM), a Component of Gravity Opposition Physiology

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

The manuscript “Gravity in the eye—how 'gravitational ischemia' in the retina may be released and resolved through rapid eye movement (REM), a component of gravity-opposition physiology” by Jaster is a review article which summarizes focuses on its primary etiology, and how REM fits into the larger framework of neurophysiology and general physiology. The authors have drawn on research findings obtained from the clinical sciences, as well as from pathology, radiology, and public spaceflight medical data. The authors included a variety of research papers, which suggest that, during sleep, gravity may significantly reduce blood flow in some parts of the retina by creating a stratified compressive mass effect from neighboring eye structures. Finally, the authors attempted to place REM within the overall context of ‘gravity-opposition physiology’—those characteristics of terrestrial (on Earth) physiology which withstand gravitational forces. In general, this review article is critical in this field and contains essential contents. I have some concerns before this manuscript is accepted for publication.

The Abstract is too long. Please summarize the contents!

Conclusion is not clear in this narrative review.

Author Response

December 2, 2025

Re: Gravity in the eye—how 'gravitational ischemia' in the retina may be released and resolved through rapid eye movement (REM), a component of gravity-opposition physiology (Manuscript ID: physiologia-3983768)

Authors’ Responses to REVIEWERS’ Remarks

We thank the Editor and the two Reviewers for their constructive comments. Replies to individual comments are stated below each comment. The reviewer’s comments are shown in bold font and our responses are shown in italics.

TO REVIEWER # 1

The Abstract is too long. Please summarize the contents!

Response. In an effort to shorten the original Abstract, we have moved some of its contents to new locations within the manuscript. :

All of the material removed from the original Abstract is highlighted, so that it can be easily found throughout the revised manuscript. The word count of the original Abstract was 559. The word count of the revised Abstract is 375.

“This narrative review of rapid eye movement (REM) focuses on its primary etiology, and how it fits into the larger framework of neurophysiology and general physiology. For this study, we have drawn on research findings obtained from the clinical sciences, as well as from pathology, radiology, and public spaceflight medical data. We have included a variety of research papers, which when taken together suggest that, during sleep, gravity may significantly reduce blood flow in some parts of the retina, by creating a stratified compressive mass effect from neighboring eye structures, which are overlying during sleep. REM may provide a release from this 'gravitational ischemia' in the retina. Finally, we have attempted to place REM within the overall con-text of ‘gravity-opposition physiology’—those characteristics of terrestrial (on Earth) physiology which withstand gravitational forces. Arterial blood flow in the retina may be sensitive to the full overlying 'weight' of its adjacent and contiguous vitreous humor caused by the humoral mass effect in the Earth's gravitational field. During waking hours of the day, this 'weight' is continuously shifted in position due to changing head position and eye movements associated with ordinary environmental observations. This reduces its impact on any one point on the retinal field. However, during sleep, the head may maintain a relatively constant position (often su-pine), and observational eye movements are minimal—leaving essentially one retinal area ex-posed at the 'bottom' of each eye, relative to gravity. During sleep, REM may provide a mechanism for frequently repositioning the retina with respect to the weight it incurs from its adjacent (overlying) vitreous. Our findings were consistent with the intermittent terrestrial nocturnal development of 'gravitational ischemia' in the retina, wherein the decreased blood flow is accompanied metabolically by decreased oxygen tension—a critically important metric, with a detri-mental influence on nerve-related tissue generally. However, the natural mechanisms for re-leasing and resolving gravitational ischemia, which likely involve glymphatics and cerebrospinal fluid shifts, as well as REM, may gradually fail in old age. Concurrently associated with old age in some individuals is the deposition of alpha-synuclein and/or tau in the retina, together with similar deposition in the brain, and associated with the development of Parkinson's disease and/or Alzheimer's disease—possibly as a maladaptive attempt to release and resolve gravitational ischemia. This suggests that a key metabolic parameter of Parkinson's disease and Alzheimer's disease may be lack of oxygen in some neural tissues. There is some evidence that oxygen therapy (hyperbaric oxygen) may be an effective supplemental treatment.

In normal terrestrial physiology, the superior retinal hemisphere receives significantly more blood flow than the inferior hemisphere—this includes the influence of the cilioretinal artery (which is congenitally present in 30% of the population), and which significantly localizes to the superior temporal retinal quadrant. This may be an evolutionary adaptation to protect the blood circulation in the superior temporal retinal quadrant, which is exposed to gravitational ischemia during sleep, when the eyes are typically rotated up and out—rolling the superior temporal retinal quadrant into the 'bottom' position, when sleeping in supine position with the nose up. Many of the cardinal features of Spaceflight Associated Neuro-Ocular Syndrome (SANS) may potentially be explained as features of gravity-opposition physiology, which become unopposed by gravity during spaceflight. Gravity-opposition physiology may, in fact, create significant challenges for humans involved in long-duration space travel (long-term microgravity). Possible solutions may include the use of artificial gravitational fields in space, such as centrifuges.”

[Abstract, pages 1-2, lines 15-56]

Conclusion is not clear in this narrative review.

Response. We created a new section called 'Conclusions', which received some material from our original Abstract. Our intention is for this new section to clarify the conclusions of our narrative review.

“11. Conclusions

In normal terrestrial physiology, the superior retinal hemisphere receives significantly more blood flow than the inferior hemisphere—this includes the influence of the cilioretinal artery (which is congenitally present in 30% of the population), and which significantly localizes to the superior temporal retinal quadrant. This may be an evolutionary adaptation to protect the blood circulation in the superior temporal retinal quadrant, which is exposed to gravitational ischemia during sleep, when the eyes are typically rotated up and out—rolling the superior temporal retinal quadrant into the 'bottom' position, when sleeping in supine position with the nose up.
Some of the possible contributions of gravitational ischemia in the brain to normal terrestrial physiology may be inferred by observing what happens when gravity is re-moved. Spaceflight may reveal the most immediate, prominent, and least integrated of the brain’s natural counter-forces to gravity—which find themselves suddenly unopposed. Gravity on earth acts continuously on the brain and on both eyes—with each of the three responding as a separate globe.
In micro-gravity (in space), gravitational ischemia in the brain does not occur. But regional ischemia may still form around the cortical vertex due to the upwardly directed forces of gravity-opposition physiology, compressing brain tissue and blood vessels there against the interior of the skull. This may itself induce sleep by directly trig-gering terminal cortical receptors in the RAS. But this sleep may be non-physiological and ineffective at releasing or resolving the regional brain ischemia associated with gravity-opposition physiology. This could create an unfavorable situation for astronauts.
Essentially all humans and land mammals experience dysconjugate eye twitching for a couple of hours every night during sleep—and no one knows why. This phenomenon is called REM.
The primary physiological (teleological) purpose of REM may be to mitigate gravitational ischemia in the retina.”

[Conclusions, pages 16-17, lines 642-669]

Additionally, we created a new section called 'Methods and Focus', which also received some material from our original Abstract.

“2. Methods and Focus

For this study of REM, we have drawn on research findings obtained from the clinical sciences, as well as from pathology, radiology, and public spaceflight medical data. We have included a variety of research papers, which when taken together suggest that, during sleep, gravity may significantly reduce blood flow in some parts of the retina, by creating a stratified compressive mass effect from neighboring eye structures, which are overlying during sleep.

These reports were consistent with the possibility that REM may provide a release from this 'gravitational ischemia' in the retina. Finally, we have attempted to place REM within the overall context of ‘gravity-opposition physiology’—those characteristics of terrestrial (on Earth) physiology which withstand gravitational forces.”

[Methods and Focus, page 8, lines 92-103]

We hope to have exhaustively responded to all comments. Many thanks for the pertinence and accuracy of the comments.

Sincerely,

Howard Jaster, MD

Joshua Ong, MD

Giulia Ottaviani, MD, PhD

Author Response File: Author Response.pdf

Reviewer 2 Report

Comments and Suggestions for Authors

Thanks for the invitation to review this work. The paper extends findings from brain ischemia to the retina without accounting for anatomical differences (e.g., retinal vasculature lacks autoregulation comparable to the brain). Core hypotheses are unsubstantiated by direct experimental data, relying instead on anecdotes, analogies.

Figure 2: The claim that "CSF reabsorption at the superior sagittal sinus is obstructed by upward brain shifting" is supported only by a Wikipedia reference (ref16)—a non-peer-reviewed source unacceptable for scientific rigor. No empirical data (e.g., post-flight CSF dynamics measurements) validates this obstruction. C: The schematic of "stratified ischemic layers" does not explain how bottom-layer ischemia leads to Parkinson’s/Alzheimer’s disease (as claimed in the caption). No molecular/cellular mechanism links gravitational stratification to protein aggregation (alpha-synuclein/tau). E: The cartoon of REM resolving retinal pressure lacks direct evidence (e.g., retinal perfusion MRI during REM vs. non-REM sleep) to confirm the "plumb line" impact shifting hypothesis.
The distinction between "gravitational ischemia" (Earth gravity) and "gravity-opposition ischemia" (space) is not clearly defined in captions, leading to reader ambiguity.
Figure 1 the claim of "increased Parkinson’s incidence among astronauts" is labeled as anecdotalwith no numerical data (sample size, control group, p-values). References 3–7 do not provide a statistically significant correlation.
Figure 5 the garden hose metaphor for gravitational ischemia ignores complex vascular physiology (e.g., autoregulation, blood-brain barrier) and lacks empirical correlation to biological processes.
The paper’s central claim (REM resolves retinal gravitational ischemia) has no direct experimental support (e.g., retinal blood flow measurements during sleep stages). Indirect evidence (spaceflight data, pathology) fails to establish a causal link. The paper claims "gravitational ischemia is distinct from typical cerebrovascular disease" but does not clarify how this distinction applies to retinal ischemia (e.g., arteriolar tortuosity in Parkinson’s patients).
The link between retinal ischemia and alpha-synuclein/tau deposition is purely speculative—no data shows low oxygen tension directly induces protein aggregation in the retina/brain.
As a narrative review, it fails to systematically evaluate conflicting evidence(e.g., alternative functions of REM, non-gravitational causes of astronaut neurodegeneration).
Multiple key claims rely on Wikipedia (refs16,33)or non-academic websites (ref17)—these sources lack the rigor required to support scientific conclusions.
The claim "80% of sleep is preserved in space" is uncited or linked to irrelevant literature (ref20 focuses on yawning, not space sleep). References for CSF dynamics in space (e.g., ref21) do not directly validate the paper’s hypothesis of "gravity-opposition ischemia". Critical claims (e.g., "retinal arterial tortuosity is ischemic in origin") are not cited to primary data (e.g., retinal perfusion studies) but to review articles.
Consider citation of npj Digit. Med.8, 655 (2025)

Author Response

December 2, 2025

Authors’ Responses to REVIEWERS’ Remarks

TO REVIEWER # 2

Thank you for your useful comments. We have attempted to respond to issues in the order in which you presented them, numbered 1-10. We have created a new section at the end of our manuscript called 'Acknowledging weaknesses in our narrative review'.

“12. Acknowledging weaknesses in our narrative review

Our paper extends the concept of 'gravitational ischemia' from the brain to the retina without accounting for anatomical differences, which are significant. Specifically regarding vasculature, the retina is a thin layer of neural tissue with its own vasculature. It's underlying choroidal layer is very vascular and provides circulatory assistance to the retina. It's overlying vitreous is essentially non-vascular.

The concept of 'gravitational ischemia' is focused on a theoretical point in space, within either the brain or retina, which is infinitely small and dimension-less. It simply incurs the weight of overlying body tissue, which in the case of the brain is other brain tissue, and in the case of the retina is mostly vitreous humor. The overlying mass is considered simply as weight—essentially as if it were Silly Putty. This may seem in conflict with Figure 2C, which implies a large relatively homogeneous vascular structure (the brain). It may also seem in conflict with the garden hose story, which called attention to the weight of overlying vasculature. But in fact each layer in Figure 2C is simply a collection of points with a different amount of overlying mass. In the case of the retina, the different layers would look more like a 3-dimensional bowl (retina) filled with Silly Putty (vitreous) transected by a superimposed stack of horizontal planes—analogous to the 2-dimensinal lines of Figure 2C. The bowl (retina) would have some thickness, although narrow. Many pieces of the retinal bowl would have a small amount of overlying retina, and a large amount of overlying vitreous.

Direct experimental data regarding this topic is very limited. Data from spaceflight has been very helpful, but is also limited—especially to the general public. Nonetheless, it may be beneficial to at least frame the conversation regarding a primary etiology for REM, and let others contribute to it in the future.

In Figure 2B we suggested that 'CSF reabsorption at the superior sagittal sinus is obstructed by upward brain shifting' (via the increased intra-parenchymal pressure created there). The Wikipedia graphic is intended only to help explain the issues involved, and not to support them. We do not have any direct experimental evidence from astronauts, measuring CSF at various locations within the ventricular system. Our thought process was based on the reported observations of brain MRI scans of astronauts and ocular examinations, which revealed upward shifting of the brain, ventricular enlargement, and papilledema. Although our conclusion may not be the only one possible, it seemed to be reasonably likely in light of all of the attending circumstances (a group of astronauts engaging in long-duration spaceflight).

In Figure 2C, the schematic of 'stratified ischemic layers' does not explain in detail how bottom-layer ischemia leads to Parkinson’s/Alzheimer’s disease, as suggested in the caption. There is literature suggesting a plausible mechanism through blood-brain barrier alterations as well as abnormal glymphatic function, discussed elsewhere [9]. However, a specific molecular/cellular mechanism linking gravitational stratification to protein aggregation (alpha-synuclein/tau) has not been established.

In Figure 2E, the cartoon of REM resolving gravitational ischemia in the retina lacks direct supportive evidence, such as retinal perfusion MRI during REM vs. non-REM sleep. And this future research would potentially be very helpful.

Legend Figure 2B. Revision. We have referred to this positioning of CSF outlets together with this configuration of CSF flow as being one component of 'gravity-opposition physiology'. We have identified other components as well.
In Figure 1, we noted an increased incidence of Parkinson’s disease among astronauts. We characterized this as 'anecdotal', without including numerical data regarding sample size, and terrestrial incidence for comparison. As of 2025 the total number of astronauts and cosmonauts who have participated in long-duration spaceflight is approximately 300. There is no public access to the vast majority of medical records regarding these participants. Of the very few who have publicly announced health issues subsequent to spaceflight, we have noticed what we considered to be a high prevalence of Parkinson's disease. But we have not comprehensively organized all of this data. References 3–7 are only public announcements of disease presence in each astronaut.
Figure 5 and the garden hose story-depiction of gravitational ischemia ignores complex vascular physiology, such as autoregulation, and the blood-brain barrier. It is simply a metaphor—but, as such, we tried to use it to focus our readers attention on relationships that might easily be overlooked. Our history of medicine was similarly limited and focused.
In this paper we are exploring uncharted territory. We are seeking an answer to the question, 'what is the primary causation and etiology of REM'? 'Why do our eyeballs twitch intermittently at night while we sleep'? In a vast ocean of medical literature, very few investigators have considered this question at all. No one seems to know where to start. We would like to frame a conversation around this topic. It's not going to be perfect, and it's not going to be pretty.

There is precious little real data from anywhere that reflects directly on this topic. But spaceflight is producing medical data, about the brain, sleep, and REM, from a place where life is very different from what we know on Earth, because of a very limited number of variables—mostly the Earth's gravitation field and magnetic field. Conditions like 'lack of atmosphere' are mostly secondary.

The early stages of exploration are going to consist largely of trying to stitch together half-truths and 'maybe-relationships'. There is no low-hanging fruit in sight. Still the question is important enough to motivate us forward. Problems revolving around ischemia can potentially be mitigated by something fairly simple and available—oxygen.

And this set of problems about gravity, ischemia, and REM and interfacing with a another set of problems about Parkinson's disease involving both the brain and the eyes, arterial tortuousities, and evidence of preceding cerebrovascular disease involving the blood-brain barrier, glymphatics, and complex immune phenomena. It is at least plausible that problems involving the release and resolution of gravitational ischemia could be at play in this mix.

The cause of the alpha-synuclein/tau deposition associated with Parkinson's disease and Alzheimer's is largely unknown, but is under intense investigation. A large body of research involving human pathological specimens and animal models has produced results from which many inferences can be made, although nothing has been conclusively demonstrated. Among the inferences is the possibility that ischemia and reduced neural oxygen tension may play a role in the etiology or either or both neurodegenerative diseases.
This narrative review has not systematically evaluated alternative functions of REM. Most of what is described in the literature is secondary functions associated with memory, and abnormal REM physiology, such as REM behavioral disorder. We also did not discuss possible non-gravitational causes of astronaut neurodegeneration, such as radiation exposure.
We used Wikipedia graphics for illustrative purposes only, and not to substantiate information.
We cited direct spaceflight measurements of sleep times compared to direct terrestrial measurements in the same astronauts (13). The numbers varied from one night to the next, and from one astronaut to another. Overall, the duration of time (in hours) spent sleeping in space per 24-hour cycle is less than the typical nightly sleep duration on Earth. We characterized it as 80%.

We gave already commented on CSF dynamic measurements, retinal arterial tortuosities, and retinal perfusion studies.

We conclude by mentioning several very recent publications regarding various aspects of this topic [61–70]. Although none directly addresses the conclusions of our paper, they each contribute significantly to the mosaic of information that currently serves as our foundation.”

[Acknowledging weaknesses in our narrative review, pages 17-19, lines 673-780]

Figure 2: The claim that "CSF reabsorption at the superior sagittal sinus is obstructed by upward brain shifting" is supported only by a Wikipedia reference (ref16)—a non-peer-reviewed source unacceptable for scientific rigor. No empirical data (e.g., post-flight CSF dynamics measurements) validates this obstruction. C: The schematic of "stratified ischemic layers" does not explain how bottom-layer ischemia leads to Parkinson’s/Alzheimer’s disease (as claimed in the caption). No molecular/cellular mechanism links gravitational stratification to protein aggregation (alpha-synuclein/tau). E: The cartoon of REM resolving retinal pressure lacks direct evidence (e.g., retinal perfusion MRI during REM vs. non-REM sleep) to confirm the "plumb line" impact shifting hypothesis.

Response. Following the reviewer’s suggestions, the following paragraphs have been added to the text:

“In Figure 2B we suggested that 'CSF reabsorption at the superior sagittal sinus is obstructed by upward brain shifting' (via the increased intra-parenchymal pressure created there). The Wikipedia graphic is intended only to help explain the issues involved, and not to support them. We do not have any direct experimental evidence from astronauts, measuring CSF at various locations within the ventricular system. Our thought process was based on the reported observations of brain MRI scans of astronauts and ocular examinations, which revealed upward shifting of the brain, ventricular enlargement, and papilledema. Although our conclusion may not be the only one possible, it seemed to be reasonably likely in light of all of the attending circumstances (a group of astronauts engaging in long-duration spaceflight).

[Acknowledging weaknesses in our narrative review, page 17, lines 697-715]

The distinction between "gravitational ischemia" (Earth gravity) and "gravity-opposition ischemia" (space) is not clearly defined in captions, leading to reader ambiguity.

Response. To clarify, a sentence has been added to the legend for Figure 2B:

“We have referred to this positioning of CSF outlets together with this configuration of CSF flow as being one component of 'gravity-opposition physiology'. We have identified other components as well.”

[Sleeping in space, Legend for Figure 2, page 5, lines 162-164]

[Acknowledging weaknesses in our narrative review, page 17, lines 716-718]

Figure 1 the claim of "increased Parkinson’s incidence among astronauts" is labeled as anecdotal with no numerical data (sample size, control group, p-values). References 3–7 do not provide a statistically significant correlation.

Response. In response to the reviewer comment, the following paragraph has been added to the manuscript:

“In Figure 1, we noted an increased incidence of Parkinson’s disease among astronauts. We characterized this as 'anecdotal', without including numerical data regarding sample size, and terrestrial incidence for comparison. As of 2025 the total number of astronauts and cosmonauts who have participated in long-duration spaceflight is approximately 300. There is no public access to the vast majority of medical records regarding these participants. Of the very few who have publicly announced health issues subsequent to spaceflight, we have noticed what we considered to be a high prevalence of Parkinson's disease. But we have not comprehensively organized all of this data. References 3–7 are only public announcements of disease presence in each astronaut.”

[Acknowledging weaknesses in our narrative review, pages 17-18, lines 719-728]

Figure 5 the garden hose metaphor for gravitational ischemia ignores complex vascular physiology (e.g., autoregulation, blood-brain barrier) and lacks empirical correlation to biological processes.

Response. Following the reviewer’s suggestions, the following paragraphs have been added to the text:

“Figure 5 and the garden hose story-depiction of gravitational ischemia ignores complex vascular physiology, such as autoregulation, and the blood-brain barrier. It is simply a metaphor—but, as such, we tried to use it to focus our readers attention on relationships that might easily be overlooked. Our history of medicine was similarly limited and focused.”

[Acknowledging weaknesses in our narrative review, page 18, lines 729-733]

The paper’s central claim (REM resolves retinal gravitational ischemia) has no direct experimental support (e.g., retinal blood flow measurements during sleep stages). Indirect evidence (spaceflight data, pathology) fails to establish a causal link. The paper claims "gravitational ischemia is distinct from typical cerebrovascular disease" but does not clarify how this distinction applies to retinal ischemia (e.g., arteriolar tortuosity in Parkinson’s patients).

Response. Following the reviewer’s suggestions, the following paragraphs have been added to the text:

“In this paper we are exploring uncharted territory. We are seeking an answer to the question, 'what is the primary causation and etiology of REM'? 'Why do our eyeballs twitch intermittently at night while we sleep'? In a vast ocean of medical literature, very few investigators have considered this question at all. No one seems to know where to start. We would like to frame a conversation around this topic. It's not going to be perfect, and it's not going to be pretty.

[Acknowledging weaknesses in our narrative review, page 18, lines 734-755]

The link between retinal ischemia and alpha-synuclein/tau deposition is purely speculative—no data shows low oxygen tension directly induces protein aggregation in the retina/brain.

Response. Following the reviewer’s suggestions, the following paragraphs have been added to the text:

“The cause of the alpha-synuclein/tau deposition associated with Parkinson's disease and Alzheimer's is largely unknown, but is under intense investigation. A large body of research involving human pathological specimens and animal models has produced results from which many inferences can be made, although nothing has been conclusively demonstrated. Among the inferences is the possibility that ischemia and reduced neural oxygen tension may play a role in the etiology or either or both neurodegenerative diseases.”

[Acknowledging weaknesses in our narrative review, page 18, lines 756-762]

As a narrative review, it fails to systematically evaluate conflicting evidence(e.g., alternative functions of REM, non-gravitational causes of astronaut neurodegeneration).

Response. Following the reviewer’s suggestions, the following paragraphs have been added to the text:

“This narrative review has not systematically evaluated alternative functions of REM. Most of what is described in the literature is secondary functions associated with memory, and abnormal REM physiology, such as REM behavioral disorder. We also did not discuss possible non-gravitational causes of astronaut neurodegeneration, such as radiation exposure.”

[Acknowledging weaknesses in our narrative review, page 18, lines 763-767]

Multiple key claims rely on Wikipedia (refs16,33)or non-academic websites (ref17)—these sources lack the rigor required to support scientific conclusions.

Response. Following the reviewer’s suggestions, the following sentence has been added to the text:

“We used Wikipedia graphics for illustrative purposes only, and not to substantiate information.”

[Acknowledging weaknesses in our narrative review, page 18, lines 768-769]

The claim "80% of sleep is preserved in space" is uncited or linked to irrelevant literature (ref20 focuses on yawning, not space sleep). References for CSF dynamics in space (e.g., ref21) do not directly validate the paper’s hypothesis of "gravity-opposition ischemia". Critical claims (e.g., "retinal arterial tortuosity is ischemic in origin") are not cited to primary data (e.g., retinal perfusion studies) but to review articles.

Response. Following the reviewer’s suggestions, the following paragraphs have been added to the text:

“We cited direct spaceflight measurements of sleep times compared to direct terrestrial measurements in the same astronauts (13). The numbers varied from one night to the next, and from one astronaut to another. Overall, the duration of time (in hours) spent sleeping in space per 24-hour cycle is less than the typical nightly sleep duration on Earth. We characterized it as 80%.

We have already commented on CSF dynamic measurements, retinal arterial tortuosities, and retinal perfusion studies.”

[Acknowledging weaknesses in our narrative review, pages 18-19, lines 770-776]

Consider citation of npj Digit. Med.8, 655 (2025)1. Could the authors comment on why sleep is still needed if changing body position by itself could release gravitational ischemia?

Response. Following the reviewer’s suggestions, the following paragraph has been added to the text:

“We conclude by mentioning several very recent publications regarding various aspects of this topic. Although none directly addresses the conclusions of our paper, they each contribute significantly to the mosaic of information that currently serves as our foundation.”

[Acknowledging weaknesses in our narrative review, page 19, lines 777-780]

Accordingly, the following new References have been added to the manuscript:

“61. Jiang, N.; Ji, H.; Guan, Z.; Pan, Y.; Deng, C.; Guo, Y.; Liu, D.; Chen, T.; Wang, S.; Wu, Y.; et al. A Deep Learning System for Detecting Silent Brain Infarction and Predicting Stroke Risk. Nat. Biomed. Eng. 2025, 9, 1907–1919, doi:10.1038/s41551-025-01413-9.

Ge, M.; Wang, Y.; Xu, S. From Retina to Brain: How Deep Learning Closes the Gap in Silent Stroke Screening. NPJ Digit. Med. 2025, 8, 655, doi:10.1038/s41746-025-02021-2.
Drachmann, J.; Petersen, L.; Jeppesen, S.K.; Bek, T. Systemic Hypoxia Increases Retinal Blood Flow but Reduces the Oxygen Saturation Less in Peripheral Than in Macular Vessels in Normal Persons. Invest. Ophthalmol. Vis. Sci. 2025, 66, 43, doi:10.1167/iovs.66.6.43.
Magonio, F. REM Phase: An Ingenious Mechanism to Enhance Clearance of Metabolic Waste from the Retina. Exp. Eye Res. 2022, 214, 108860, doi:10.1016/j.exer.2021.108860.
Limoli, C.; Khalid, H.; Wagner, S.K.; Huemer, J. Retinal Ischemic Perivascular Lesions (RIPLs) as Potential Biomarkers for Systemic Vascular Diseases: A Narrative Review of the Literature. Ophthalmol. Ther. 2025, 14, 1183–1197, doi:10.1007/s40123-025-01148-5.
Ma, X.; Liu, Y.; Xie, M.; Li, C.; Li, X.; Shang, D.; Chen, M.; Chen, H.; Su, W. Parkinson’s Disease with Possible REM Sleep Behavior Disorder Correlated with More Severe Glymphatic System Dysfunction. NPJ Park. Dis. 2025, 11, 82, doi:10.1038/s41531-025-00962-9.
Conti, M.; Ferrari, V.; Pierantozzi, M.; Simonetta, C.; Carparelli, F.; D’Angelo, V.; Bagetta, S.; Di Giuliano, F.; Mercuri, N.B.; Schirinzi, T.; et al. Increased Blood-Brain Barrier Permeability Is Associated with Dysfunctional α Band Connectivity in Early-Stage Parkinson’s Disease. J. Neural Transm. 2025, doi:10.1007/s00702-025-03002-1.
McDevitt, E.A.; Kim, G.; Turk-Browne, N.B.; Norman, K.A. The Role of Rapid Eye Movement Sleep in Neural Differentiation of Memories in the Hippocampus. J. Cogn. Neurosci. 2025, 1–18, doi:10.1162/jocn.a.82.
Zhang, Y.-T.; Zhang, H.; Su, W.; Liu, W.; Chen, Y.-T.; Ren, H.-Y.; He, M.; Zhang, Y.-X.; Fan, Y.-P.; Liu, W.; et al. Age-(in)Dependent Altered Molecular Mechanisms in Parkinson’s Disease through Extracellular Vesicle Proteome and Lipidome. Cell reports. Med. 2025, 6, 102432, doi:10.1016/j.xcrm.2025.102432.
Erhardt, E.B.; Mayer, A.R.; Lin, H.C.; Pirio Richardson, S.E.; Shaff, N.A.; Vakhtin, A.A.; Caprihan, A.; van der Horn, H.J.; Hoffman, N.; Phillips, J.P.; et al. The Influence of Intermittent Hypercapnia on Cerebrospinal Fluid Flow and Clearance in Parkinson’s Disease and Healthy Older Adults. NPJ Park. Dis. 2025, 11, 334, doi:10.1038/s41531-025-01179-6. “

[References, page 22-23, lines 941-964]

We hope to have exhaustively responded to all comments. Many thanks for the pertinence and accuracy of the comments.

Sincerely,

Howard Jaster, MD

Joshua Ong, MD

Giulia Ottaviani, MD, PhD

Author Response File: Author Response.pdf

Round 2

Reviewer 2 Report

Comments and Suggestions for Authors

Thanks for the invitation to review this work. The authors have tried to solve the previous concern. This review presents a hypothesis that REM sleep may alleviate retinal gravitational ischemia by counteracting gravity-driven physiological stress. By integrating space medicine data with mechanisms relevant to neurodegenerative diseases, the manuscript offers a fresh perspective to the field.

However, the final section (12. Acknowledging weaknesses) lists detailed limitations of specific figures (e.g., Figure 2B, 2C, 2E). This style is not fully aligned with the concise and integrative nature expected of a review article.

A review’s purpose is to synthesize existing evidence and construct a coherent viewpoint, rather than to provide a consolidated limitations section as in original research. I recommend integrating the figure-specific limitations directly into the figure legends—for instance, adding notes such as “mechanism is hypothetical and requires further validation” to the legend of Figure 2B—or briefly acknowledging them in the corresponding sections of the main text (e.g., when discussing Figure 2C, adding a parenthetical remark such as “molecular pathway remains to be elucidated”).

Author Response

December 4, 2025

Authors’ Responses to REVIEWER’ S Remarks

We thank the Reviewer for the constructive comments. Replies to individual comments are stated below each comment. The reviewer’s comments are shown in bold font and our responses are shown in italics.

TO REVIEWER # 2

However, the final section (12. Acknowledging weaknesses) lists detailed limitations of specific figures (e.g., Figure 2B, 2C, 2E). This style is not fully aligned with the concise and integrative nature expected of a review article.

A review’s purpose is to synthesize existing evidence and construct a coherent viewpoint, rather than to provide a consolidated limitations section as in original research.

Response. In reply to the reviewer’s suggestions, the following paragraphs have been removed from to the text:

“1. In Figure 2B we suggested that 'CSF reabsorption at the superior sagittal sinus is obstructed by upward brain shifting' (via the increased intra-parenchymal pressure created there). The Wikipedia graphic is intended only to help explain the issues involved, and not to support them. We do not have any direct experimental evidence from astronauts, measuring CSF at various locations within the ventricular system. Our thought process was based on the reported observations of brain MRI scans of astronauts and ocular examinations, which revealed upward shifting of the brain, ventricular enlargement, and papilledema. Although our conclusion may not be the only one possible, it seemed to be reasonably likely in light of all of the attending circumstances (a group of astronauts engaging in long-duration spaceflight).

We have referred to this positioning of CSF outlets together with this configuration of CSF flow as being one component of 'gravity-opposition physiology'. We have identified other components as well.”

[Acknowledging weaknesses in our narrative review, page 16, lines 686-707]

I recommend integrating the figure-specific limitations directly into the figure legends—for instance, adding notes such as “mechanism is hypothetical and requires further validation” to the legend of Figure 2B—or briefly acknowledging them in the corresponding sections of the main text (e.g., when discussing Figure 2C, adding a parenthetical remark such as “molecular pathway remains to be elucidated”).

Response. In response to the reviewer comment, the following sentences has been added to the legends for Figures and the text:

“Details of this mechanism remain to be resolved and confirmed.”

[Legend for Figure 2B, page 5, lines 159-160]

“Details of this mechanism remain to be resolved and confirmed.”

[Legend for Figure 2C, page 5, lines 170-171]

“Details of this mechanism remain to be resolved and confirmed.”

[Legend for Figure 2E, page 5, lines 180-181]

“Details of this mechanism remain to be resolved and confirmed.”

[Gravity, page 5, lines 192-193]

We hope to have exhaustively responded to all comments. Many thanks for the pertinence and accuracy of the comments.

Sincerely,

Howard Jaster, MD

Joshua Ong, MD

Giulia Ottaviani, MD, PhD

Author Response File: Author Response.pdf