Ophthalmic changes are associated with visual cortex functional network reorganization after 90-day head-down tilt bed rest

Introduction

Prolonged microgravity exposure could lead to a constellation of physiologic and pathologic neuro-ocular findings in astronauts, known as spaceflight-associated neuro-ocular syndrome (SANS) (1,2). Decreased visual acuity is the main clinical manifestation of SANS. The pathological mechanism contributing to inadequate vision may involve multiple factors, with one potential factor being the cephalad fluid shifts (3,4). Naturally, changes in ocular blood flow (OBF) may occur in response to shifts in blood distribution towards the head.

The −6° head-down tilt bed rest (HDTBR) has become the preferred ground-based model for simulating microgravity to study SANS and the evaluation of potential prevention measures and interventions due to its convenience and comprehensiveness (5). More recently, a few ophthalmic changes have been demonstrated in HDTBR studies, including retinal nerve fiber layer thickening (under 14- and 70-day −6° HDTBR) (6), optic disc edema (under 30-day 6° HDTBR) (7), and chorioretinal folds (under 60-day 6° HDTBR) (8). However, only one study conducted during a 2-minute HDTBR revealed a reduction in pulsatile OBF in the choroid, indicating potential retinal hypoperfusion (9). Indeed, alteration in OBF has the potential to impact visual function adversely on Earth. For instance, a reduction in choroidal blood flow can result in scleral ischemia, altering the scleral structure and ultimately contributing to the development of myopia (10). At present, the alteration of visual function and OBF, and their relationship under long-duration simulated microgravity conditions, remains uncertain.

Importantly, the potential interrelation between the eye–brain axis suggests that eye-related disorders may induce aberrant changes in brain function (11). Several population-based studies have demonstrated the association of visual function changes and brain health (12,13). Further, previous studies have shown that the development of signs of SANS was associated with various resting-state functional connectivity (FC) changes upon exposure to short- and middle-duration HDTBR (14-16). Consequently, the utilization of ophthalmic change assessments has proven valuable in tracking the clinical and functional repercussions within the visual cortex functional network. This paper posits a hypothesis that OBF is a pivotal risk factor for decreased visual acuity in microgravity and may induce a functional network reorganization of the visual cortex by modifying visual function.

Overall, the present study, which employed a 90-day −6° HDTBR model, aimed to assess the relationship between ophthalmic changes and visual cortex network reorganization. We present this article in accordance with the STROBE reporting checklist (available at https://qims.amegroups.com/article/view/10.21037/qims-24-1989/rc).

Methods

Study design

This research was conducted as a part of the “Earth-Star II” 90-day HDTBR and was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. The study was approved by the Ethics Committee of China Astronaut Research and Training Center (No. ACC201904). A cohort of 36 native Chinese-speaking participants [mean (standard deviation) age, 31.39 (5.03) years] was recruited, and each was thoroughly briefed through detailed verbal and written explanations of the 90-day HDTBR protocols. Before engaging in the experiment, they formalized their participation by signing an informed consent form. This document encompasses a comprehensive outline of the study design, inherent risks, and provisions for financial compensation.

All participants underwent extensive physical and psychological examinations. The exclusion criteria were as follows: (I) contraindications for magnetic resonance imaging (MRI); (II) any kind of ophthalmic disease and history of oculopathy; and (III) any cardiovascular or cerebrovascular diseases.

The HDTBR regimen was delineated into three distinct phases: a 15-day adaptation and baseline measurement interval, followed by the 90-day HDTBR, and concluding with a recovery period. In the adaptation period, participants were mandated to adhere to a −6° head-down tilt for eating, bathing, urination, and defecation but maintained a normal posture at other times and slept in a horizontal position. In the 90-day HDTBR period, participants remained in a strict −6° head-down tilt position at all times without using a pillow, under continuous 24-hour surveillance camera. In the recovery period, participants resumed normal posture in our research center. The diets and daily routine were strictly controlled throughout the whole experiment period.

Physiological assessments, MRI scans, and visual function evaluations were conducted at three critical timepoints: baseline (Pre), day 1–3 during recovery after HDTBR (BR90), and day 26–33 during recovery after HDTBR (R28). Since visual function data prior to HDTBR were not collected, the baseline level was established using 180-day recovery data. A graphical depiction of the study’s chronological progression is available in Figure 1.

Figure 1 Illustration of the study design. Pre, baseline; BR90, day 1–3 during recovery after HDTBR; R28, day 26–33 during recovery after HDTBR. HDTBR, head-down tilt bed rest; MRI, magnetic resonance imaging.

Data collection

Basic physiological data

Each participant’s blood pressure and heart rate (HR) were continuously tracked using an electronic sphygmomanometer on the arm (BP7100; Omron Healthcare Inc., Dalian, China). Additionally, their heights and weights were measured while lying in a bed with a −6° head-down-tilt position.

MRI data and preprocessing

All MRI data were acquired using a 3-T Discovery MR750W MRI system (GE Healthcare, Chicago, IL, USA) equipped with a commercial body coil for transmission and a sixteen-channel head coil. Resting state functional MRI (rs-fMRI) images were acquired using a gradient-recalled echo echo-planar imaging (GRE-EPI) sequence that is sensitive to blood-oxygenation-level-dependent (BOLD) contrast. The scanning parameters were set as follows: repetition time (TR) =2,000 ms, echo time (TE) =35 ms, flip angle (FA) =90°, slice thickness =4.0 mm, matrix size =64×64, field of view (FOV) =240×240 mm², and gap =1 (voxel size 4×4×5 mm³). Additionally, a high resolution 3-dimensional T1-weighted sequence was obtained for anatomical reference: TR =8.8 ms, TE =3.5 ms, FA =15°, slice thickness =1.0 mm, matrix size =256×256, FOV =240×240 mm², and gap =0 (voxel size 1×1×1 mm³). The three-dimensional pseudo-continuous arterial spin labeling sequence (3D-pcASL) was obtained using a multislice fast spin-echo acquisition with background suppression: TR =4,854 ms, TE =10.7 ms, post-labeling delay =2,000 ms, slice thickness =4.0 mm, FOV =240×240 mm², matrix size =512×8, number of slices =36, and gap =0 (voxel size 1.875×1.875×4.0 mm³).

Before the scanning session, participants were instructed to keep their eyes closed, avoid eye movements, refrain from thinking about anything specific, and remain awake throughout the examination. Foam pads and earplugs were provided to participants to minimize noise and head movements.

Structural and functional images preprocessing were conducted by DPABISurf toolbox, which was implemented in MATLAB (R2021b; MathWorks, Natick, MA, USA). The T1-weighted structural images were corrected for intensity nonuniformity with N4BiasFieldCorrection, followed by skull-stripping using the antsBrainExtraction workflow from advanced normalization tools employing OASIS30ANTs as the target template. Brain tissue segmentation encompassed cerebrospinal fluid (CSF), white matter (WM), and gray matter. Subsequently, brain surfaces were reconstructed utilizing recon-all from FreeSurfer (version 6.0.1; Laboratory for Computational Neuroimaging, Athinoula A. Martinos Center for Biomedical Imaging, Massachusetts General Hospital, Boston, MA, USA) and spatial normalization in Montreal Neurological Institute space.

The preprocessing of functional images involved the removal of the initial 10-time points volumes to facilitate signal equilibration, followed by slice-time correction and head motion correction (the thresholds of head movements were set as 3 mm or 3 degrees in any direction). Additionally, mean framewise displacement (FD Jenkinson) was calculated to assess the volume-to-volume head position, and the mean FD was included as a covariate in the group-level analysis to further mitigate the influence of head motion in the rs-fMRI signal (17). All included participants had a mean FD Jenkinson <0.2 mm, with no significant group differences among Pre (0.076±0.028), BR90 (0.08±0.033), and R28 (0.09±0.039) timepoints (P=0.35). As a result, no participant was excluded from additional analysis by excessive motion criterion and FD values.

T1-weighted images were co-registered with the functional images of each participant. Covariates, including the Friston 24-parameters model of head motion, WM, and CSF signals, were linearly regressed out. Finally, band-pass filtering (0.01–0.08 Hz) was used to eliminate physiological noise and smoothing using a Gaussian kernel of 6 mm full-width at half maximum of 6 mm.

Visual function data

Participants underwent clinical ocular examinations that encompassed the measurement of near visual acuity (NVA), distance visual acuity, and best-corrected visual acuity (BCVA) using a retro-illuminated logarithm of the minimum resolving angle (logMAR) chart with tumbling-E optotypes. Additionally, contrast sensitivity (CS) assessments were conducted utilizing Pelli Robson CS charts, and stereopsis evaluations were performed using TNO stereographic charts. The ocular examinations in Pre and R28 were carried out with participants in a seated position, whereas the BR90 assessment was conducted with participants in the –6° head-down-tilt position. All ocular examinations adhered to a consistent testing sequence and were administered at approximately the same time.

Surface-based fMRI measures

Four different fMRI metrics, namely surface-based amplitude of low-frequency fluctuations (ALFF) (18), fractional amplitude of low-frequency fluctuations (fALFF) (19), regional homogeneity (ReHo) (20), and seed-based FC, were selected to represent various functional aspects.

Regions exhibiting significant differences in surface-based ReHo values were defined as regions of interest (ROIs) for subsequent seed-based FC analysis. The FC values between these ROIs and the entire cortex were calculated to further investigate visual cortex functional network reorganization under simulated microgravity. A Fisher’s r-to-z transformation was applied to normalize correlation values.

OBF measures

The OBF map was automatically derived from the 3D-pcASL images. The ROIs were independently annotated by a radiologist and an ophthalmologist with more than 5 years of experience using ITK-SNAP software, version 4.0.2 (https://www.itksnap.org/pmwiki/pmwiki.php). The ROIs were 2-dimensional and covered the retina or choroid plexus, and the average value of each ROI was automatically calculated (Figure 2). The consistency of OBF values between the two annotators was assessed using Kappa statistics, yielding a Kappa value of 0.86.

Figure 2 ROIs of one participant on the OBF map. Red colored indicates the ROI of the right eye, and green colored indicates the ROI of the right eye. (A) ROIs in Pre; (B) ROIs in BR90; (C) ROIs in R28. Pre, baseline; BR90, day 1–3 during recovery after HDTBR; R28, day 26–33 during recovery after HDTBR. HDTBR, head-down tilt bed rest; OBF, ocular blood flow; ROIs, regions of interest.

Statistical analysis

All statistical analyses were performed utilizing SPSS (version 24.0; IBM Corp., Armonk, NY, USA) and GraphPad Prism (version 8.0.0 for Mac; GraphPad Software, San Diego, CA, USA). From a statistical perspective, this study adopted a 2-eye design as both eyes of each participant were subjected to microgravity. Normal distribution of the data was confirmed using the Shapiro-Wilk tests for all variables. We used the Mauchy’s test to test for sphericity and the Greenhouse-Geisser correction method to correct for non-sphericity.

The values of OBF and visual function parameters were calculated by averaging the binoculus. One-way repeated measures analysis of variance (ANOVA) with Bonferroni-corrected multiple comparisons post hoc tests was used to investigate differences basic physiological parameters, OBF, visual function, and FC among different timepoints (i.e., Pre, BR90, and R28). Bonferroni correction was applied with an alpha level set to 0.017. Paired t-test was used to analyze surface-based ALLF, fALLF, and ReHo differences between two timepoints, along with the covariates of FD. For FC analyses, the voxel threshold was set at P<0.001 and cluster-level threshold was set at P<0.025 corrected for multiple comparisons according to the false discovery rate (FDR) method.

Spearman correlation analysis was conducted to examine the relationships between OBF, visual function, and FC, respectively. Mean values with 95% confidence intervals (CIs) are presented throughout. A significance level of P<0.05 was considered statistically significant.

Results

Physiological characteristics analysis

Table 1 lists the physiological characteristics of 36 participants at different timepoints, including Pre, BR90, and R28. The results indicate that 90-day HDTBR lowered the body mass index (BMI) [Δ: −0.6 kg/m² (95% CI: −1.0 to −0.3); P=0.002] and HR [Δ: −11.8 kg/m² (95% CI: −15.3 to −8.3); P<0.001]. The systolic blood pressure (SBP) and the diastolic blood pressure (DBP) remained stable in the entire HDTBR period (all P>0.05).

Ophthalmic changes

Long-duration HDTBR acutely lowered NVA [Δ: −0.17 (95% CI: −0.23 to −0.12); P=0.0002] and BCVA [Δ: −0.19 (95% CI: −0.25 to −0.13); P<0.0001], respectively. The NVA recovered to the Pre in the recovery period, whereas BCVA remained smaller than the value of Pre. There were no statistically significant differences in DVA, CS, and stereopsis from Pre to BR90 (all P>0.05).

The OBF value showed significant differences after 90-day HDTBR (Figure 3). Particularly, a significant decrease in OBF in BR90 [Δ: −5.34 mL/min/100 g (95% CI: −9.92 to −1.63); P=0.0376]. The OBF remained declined at R28 compared to Pre [Δ: −7.11 mL/min/100 g (95% CI: −10.42 to −2.50); P<0.0001].

Figure 3 Comparison of the ophthalmic changes during 90-day HDTBR. (A) Change in NVA among Pre, BR90 and R28. (B) Change in BCVA among Pre, BR90 and R28. (C) Change in OBF among Pre, BR90 and R28. ****, P<0.0001; ***, P<0.001; **, P<0.01; *, P<0.05. Pre, baseline; BR90, day 1–3 during recovery after HDTBR; R28, day 26–33 during recovery after HDTBR. ANOVA, analysis of variance; BCVA, best corrected visual acuity; HDTBR, head-down tilt bed rest; NVA, near visual acuity; OBF, ocular blood flow.

Visual cortex network reorganization

Significant alteration in surface-based ReHo was observed in the left primary visual cortex (V1) within the visual cortex across different timepoints (Figure 4), whereas no significant differences were found in ALFF and fALFF.

Figure 4 Brain regions with significant ReHo differences during 90-day HDTBR with visual cortex. (A) A significant increase in ReHo within the left primary visual cortex (V1) was observed at BR90 compared with the Pre. (B) A significant increase in ReHo within left V1 were observed at R28 compared with Pre. (C) A significant decrease in ReHo within the left V1 was observed at R28 compared with the BR90. The voxels with warm colors represent ReHo increase, and cool colors indicate decrease (vertex P<0.001, cluster P<0.025, FDR corrected). Pre, baseline; BR90, day 1–3 during recovery after HDTBR; R28, day 26–33 during recovery after HDTBR. FDR, false discovery rate; HDTBR, head-down tilt bed rest; L, left; R, right; ReHo, regional homogeneity.

Specifically, compared to the Pre, there was a notable increase in ReHo within the left V1 (x, y, z = −12, −100, −3, t=4, voxel level P<0.001, cluster level P<0.025, FDR corrected; Table 2) after 90-day HDTBR. Consequently, the left V1 was defined as an ROI for seed-based FC analysis.

As shown in Figure 5 and Table 3, the left V1 exhibited a strengthened FC with the right visual area 3 (V3; x, y, z =34, −89, −6, t=5.29, voxel level P<0.001, cluster level P<0.025, FDR corrected) and PFm (x, y, z =53, −51, 40, t=4.91, voxel level P<0.001, cluster level P<0.025, FDR corrected) after 90 days of HDTBR. However, even after a 28-day recovery period, these FC alterations did not fully return to baseline level (P<0.01, FDR corrected).

Figure 5 Brain regions with significant alterations in FC after 90-day HDTBR. The nodes in the figures are color-coded, with the seed region shown in yellow and the FC differential region in red (voxel-level P<0.001, cluster-level P<0.025, FDR corrected). The FC between nodes is represented by lines, with grey indicating an increase in connectivity. (A) A significant increase in FC between left V1 and the right V3 (voxel-level P<0.001, cluster-level P<0.025, FDR corrected) after 90-day HDTBR and not return Pre in the recovery period. (B) A significant increase in FC between left V1 and the right PFm after 90-day HDBR and not return Pre in the recovery period. Pre, baseline; BR90, day 1–3 during recovery after HDTBR; R28, day 26–33 during recovery after HDTBR. ANOVA, analysis of variance; FC, functional connectivity; FDR, false discovery rate; HDTBR, head-down tilt bed rest; PFm, left parietal area F, part M.

Correlation between OBF, visual function, and visual cortical function

Compared to Pre, we observed a correlation between the alteration in OBF (ΔOBF) and the alteration in BCVA (ΔBCVA) after 90-day HDTBR (r=0.3981, P=0.0162). Similarly, the ΔBCVA demonstrated a significant correlation with the FC of left V1 region and right PFm region (ΔFC of L.V1 and R.PFm) after 90-day HDTBR (r=−0.3394, P=0.0429) (Figure 6).

Figure 6 Correlation analysis between OBF, BCVA, and FC during 90-day HDTBR. The colored regions indicate a 95% confidence interval. (A) Correlation between ΔOBF and ΔBCVA. (B) Correlation between reduction ΔBCVA and ΔFC of L.V1–R.PFm. BCVA, best corrected visual acuity; FC, functional connectivity; HDTBR, head-down tilt bed rest; OBF, ocular blood flow.

Discussion

In this study, we investigated alterations of visual function, OBF, and visual cortex functional network, as well as their interrelationships, employing a 90-day −6° HDTBR as a microgravity analogue. A within-subject design, where participants served as their own controls, allowed us to track temporal dynamics in both eye and brain under simulated microgravity. Our findings support the hypothesis that OBF may be a key risk factor for decreased visual acuity in microgravity, potentially driving functional reorganization of the visual cortex by modifying visual function. These insights contribute to a new insight into ophthalmic health risks associated with human spaceflight.

Alterations of ophthalmic changes induced by simulated microgravity

Microgravity-induced fluid redistribution from the lower body to the head has been linked to varying degrees of visual impairment (21). In this study, we observed significant decreases in NVA and BCVA after 90-day HDTBR, whereas distance vision remained noticeable change—findings consistent with previous research (22). The diminution of vision is usually attributed to shortening of the ocular axis; however, our team found no alteration in optic nerve diameter following the 90-day HDTBR (23). This result underscores the need to explore other potential mechanisms underlying impaired ocular functions.

Unexpectedly, we found that the OBF showed a short-term irreversible decrease after 90-day HDTBR. Noninvasive ASL MRI provides volumetric BF in quantitative absolute units, which measures BF values of the optic nerve head region of the retina/choroid complex. To go a step further, ASL signal detected at the retina is dominated by the choroidal blood flow contribution (24). Indeed, the choroid receives the highest volume of blood flow, which is primarily drained by vortex veins and is likely sensitive to impeded outflow produced by microgravity. Increased capillary permeability and a sudden increase in pressure within the vortex vein have been demonstrated after long-duration bed rest (25), impeding venous drainage and thus decreasing OBF. We further speculated that the continuous decline of OBF in recovery period is due to the impaired autoregulation ability of the choroidal vasculature.

Additionally, a continuous blood supply to the retina was essential for the maintenance of visual function and decreased OBF impaired visual acuity (26). We found that the acute decrease of OBF was associated with concomitant alterations in BCVA, which may partially explain why steady OBF is important for maintaining visual performance in microgravity. Further research is necessary to elucidate the interaction between the OBF and visual acuity and may contribute to further exploring countermeasures to protect the eyes of astronauts during spaceflight.

Visual cortex functional network reorganization under simulated microgravity conditions

ReHo serves as an indicator of the temporal coherence of spontaneous neural activities of a local brain region. We found a significant increase in ReHo within the V1 region after HDTBR. V1 is involved in processing low-level visual features and is indispensable for conscious visual stimuli processing (27). The changes observed in ReHo within V1 may be attributed to reduced visual input to the retina in a closed environment, prompting adaptive or compensatory modulation of V1 to accommodate the intricate demands of visual information processing.

Changes in FC typically indicate alterations in neural communication patterns. In this study, we observed a significant increase in FC between the left V1 and both the right PFm and V3 following 90-day HDTBR. V3, a crucial region for higher-level visual processing within the dorsal optic flow, receives direct inputs from V1. PFm, an integral visual region located in the parietal cortex, has been implicated in visuospatial processing and interacts with the visuospatial component of the posterior cingulate cortex (28). During the recovery period, FC between these regions decreased but did not return to the baseline level.

Similar FC alterations were reported in a study involving 30-day of HDTBR under a mild hypercapnic environment (14). It was found that individuals who developed SANS exhibited reduced FC between PCC and V1 during HDTBR followed by a post-bed rest reversal. In contrast, individuals who did not develop SANS exhibited increased FC between the posterior cingulate cortex and V1, as well as between V1 and V3. One hypothesis emerging from our study is that the observed functional reorganization of visual cortex may contribute to resistant SANS. However, differences in bed rest duration and atmospheric conditions across studies may influence the results, necessitating caution in interpretation. In addition, cerebral blood flow has received much attention in brain function-related studies due to its close relationships with brain connectivity. Previous research has reported a significant decrease in cerebral blood flow following HDTBR (29). Consequently, neurovascular coupling studies carried out during HDTBR may provide valuable insights into the underlying mechanisms of microgravity-induced functional reorganization.

Visual impairment is associated with enhanced visual cortex FC under simulated microgravity conditions

Previous study has suggested a strong association between visual impairment and brain neurodegeneration (12). In our study, decreased BCVA was correlated to FC strength. One possible explanation is that visual impairment following prolonged exposure to altered gravity reduces brain stimulation, leading to FC alteration that could be considered a maladaptive process or compensatory plasticity in response to the microgravity environment. Future investigations should combine diffusion tensor imaging to assess the structural organization and trajectory patterns of WM fiber pathways, which may provide deeper insight into the causal relationship between increased FC and visual impairment. Overall, our findings suggest that the ocular examination in astronauts has the potential to serve as an early diagnostic indicator for certain neurological conditions during spaceflight.

Limitations

Several limitations warrant consideration in interpreting the findings of this study. First, the relatively small sample size of participants in the HDTBR trial, combined with the exclusion of female participants, constrains the generalizability of the results. Previous studies have reported increased retinal thickness among women in both HDTBR and spaceflight cohorts, suggesting that sex may not be a significant factor associated with SANS (7). However, due to the inherently small sample size of female HDTBR participants and astronauts, sex-based differences in SANS remain inconclusive. Moving forward, data sharing across research groups will be essential for enabling more comprehensive analyses in this field. Second, due to the strict adherence to protocol restrictions and limited MRI devices, all MRI measurements were performed within 3 days at the end of HDTBR. We strongly encourage future studies to consider conducting assessment earlier, as this may reveal more pronounced ophthalmic changes and visual cortex functional network reorganization, thereby enhancing the robustness of our findings. We are also actively collecting data from astronauts during spaceflight to further verify these changes in a real microgravity environment. Furthermore, group-level analyses may not effectively capture individual differences, such as variations in susceptibility to microgravity effects. Incorporating factors such as genetics, biological sex, and individual variability in ground-based research could help advance personalized medicine for astronauts. Finally, the mild hypercapnic environment, which is similar to the carbon dioxide (CO₂) level occurring on the International Space Station, is hypothesized to be another factor contributing to ocular structural and functional changes. In future work, we plan to establish a control group exposed to mild hypercapnia to further explore the relationship between elevated CO₂ level and ophthalmic changes.

Conclusions

Our findings suggest that the decreased OBF during simulated microgravity is associated with impaired vision, thereby inducing a functional network reorganization of the visual cortex. Further prospective studies are needed to explore their relationship to SANS. Although the visual phenomena and adaptive neural responses delineated here do not conventionally fall within the definition of SANS, they could serve as potential biomarkers for visual mechanisms during spaceflight, and guide the development of preventive strategies or therapeutic interventions to ameliorate its adverse effects.

Acknowledgments

None.

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://qims.amegroups.com/article/view/10.21037/qims-24-1989/rc

Funding: This work was supported by the Space Medical Experiment Project of China Manned Space Program (No. HYZHXMH01005), China Manned Space Advanced Research Project (Earth-Star II-0038), Beijing Hospitals Authority Innovation Studio of Young Staff Funding Support (No. 202302) and Beijing Scholar 2015 (to Z.W.).

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://qims.amegroups.com/article/view/10.21037/qims-24-1989/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. The study was approved by the Ethics Committee of China Astronaut Research and Training Center (No. ACC201904) and informed consent was provided by all participants.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

References

1. Lee AG, Mader TH, Gibson CR, Tarver W, Rabiei P, Riascos RF, Galdamez LA, Brunstetter T. Spaceflight associated neuro-ocular syndrome (SANS) and the neuro-ophthalmologic effects of microgravity: a review and an update. NPJ Microgravity 2020;6:7. [Crossref] [PubMed]
2. Taibbi G, Vizzeri G. Terrestrial analogs for Spaceflight Associated Neuro-Ocular Syndrome. In: Lee AG, Ong J. editors. Spaceflight Associated Neuro-Ocular Syndrome. Cambridge, MA: Academic Press, 2022:149-54.
3. Sulhan S, Davidov V, Baskin DS. Spaceflight Associated Neuro-Ocular Syndrome in astronauts the ICP hypothesis. In: Lee AG, Ong J. editors. Spaceflight Associated Neuro-Ocular Syndrome. Cambridge, MA: Academic Press, 2022:175-97.
4. Hearon CM, Dias KA, Babu G, Marshall JET, Leidner J, Peters K, Silva E, MacNamara JP, Campain J, Levine BD. Effect of Nightly Lower Body Negative Pressure on Choroid Engorgement in a Model of Spaceflight-Associated Neuro-ocular Syndrome. JAMA Ophthalmol 2022;140:59-65. [Crossref] [PubMed]
5. Ong J, Lee AG, Moss HE. Head-Down Tilt Bed Rest Studies as a Terrestrial Analog for Spaceflight Associated Neuro-Ocular Syndrome. Front Neurol 2021;12:648958. [Crossref] [PubMed]
6. Taibbi G, Cromwell RL, Zanello SB, Yarbough PO, Ploutz-Snyder RJ, Godley BF, Vizzeri G. Ocular Outcomes Comparison Between 14- and 70-Day Head-Down-Tilt Bed Rest. Invest Ophthalmol Vis Sci 2016;57:495-501. [Crossref] [PubMed]
7. Laurie SS, Lee SMC, Macias BR, Patel N, Stern C, Young M, Stenger MB. Optic Disc Edema and Choroidal Engorgement in Astronauts During Spaceflight and Individuals Exposed to Bed Rest. JAMA Ophthalmol 2020;138:165-72. [Crossref] [PubMed]
8. Laurie SS, Greenwald SH, Marshall-Goebel K, Pardon LP, Gupta A, Lee SMC, Stern C, Sangi-Haghpeykar H, Macias BR, Bershad EM. Optic disc edema and chorioretinal folds develop during strict 6° head‐down tilt bed rest with or without artificial gravity. Physiol Rep 2021;9:e14977. [Crossref] [PubMed]
9. Kergoat H, Lovasik JV. Seven-degree head-down tilt reduces choroidal pulsatile ocular blood flow. Aviat Space Environ Med 2005;76:930-4. [PubMed]
10. Liu Y, Wang L, Xu Y, Pang Z, Mu G. The influence of the choroid on the onset and development of myopia: from perspectives of choroidal thickness and blood flow. Acta Ophthalmol 2021;99:730-8. [Crossref] [PubMed]
11. Marchesi N, Fahmideh F, Boschi F, Pascale A, Barbieri A. Ocular Neurodegenerative Diseases: Interconnection between Retina and Cortical Areas. Cells 2021;10:2394. [Crossref] [PubMed]
12. Garzone D, Finger RP, Mauschitz MM, Koch A, Reuter M, Breteler MMB, Aziz NA. Visual impairment and retinal and brain neurodegeneration: A population-based study. Hum Brain Mapp 2023;44:2701-11. [Crossref] [PubMed]
13. Ferguson EL, Thoma M, Buto PT, Wang J, Glymour MM, Hoffmann TJ, Choquet H, Andrews SJ, Yaffe K, Casaletto K, Brenowitz WD. Visual Impairment, Eye Conditions, and Diagnoses of Neurodegeneration and Dementia. JAMA Netw Open 2024;7:e2424539. [Crossref] [PubMed]
14. McGregor HR, Lee JK, Mulder ER, De Dios YE, Beltran NE, Kofman IS, Bloomberg JJ, Mulavara AP, Smith SM, Zwart SR, Seidler RD. Ophthalmic changes in a spaceflight analog are associated with brain functional reorganization. Hum Brain Mapp 2021;42:4281-97. [Crossref] [PubMed]
15. Lee JK, De Dios Y, Kofman I, Mulavara AP, Bloomberg JJ, Seidler RD. Head Down Tilt Bed Rest Plus Elevated CO(2) as a Spaceflight Analog: Effects on Cognitive and Sensorimotor Performance. Front Hum Neurosci 2019;13:355. [Crossref] [PubMed]
16. Mahadevan AD, Hupfeld KE, Lee JK, De Dios YE, Kofman IS, Beltran NE, Mulder E, Bloomberg JJ, Mulavara AP, Seidler RD. Head-Down-Tilt Bed Rest With Elevated CO(2): Effects of a Pilot Spaceflight Analog on Neural Function and Performance During a Cognitive-Motor Dual Task. Front Physiol 2021;12:654906. [Crossref] [PubMed]
17. Yan CG, Wang XD, Lu B. DPABISurf: data processing & analysis for brain imaging on surface. Sci Bull (Beijing) 2021;66:2453-5. [Crossref] [PubMed]
18. Yang H, Long XY, Yang Y, Yan H, Zhu CZ, Zhou XP, Zang YF, Gong QY. Amplitude of low frequency fluctuation within visual areas revealed by resting-state functional MRI. Neuroimage 2007;36:144-52. [Crossref] [PubMed]
19. Zou QH, Zhu CZ, Yang Y, Zuo XN, Long XY, Cao QJ, Wang YF, Zang YF. An improved approach to detection of amplitude of low-frequency fluctuation (ALFF) for resting-state fMRI: fractional ALFF. J Neurosci Methods 2008;172:137-41. [Crossref] [PubMed]
20. Zang Y, Jiang T, Lu Y, He Y, Tian L. Regional homogeneity approach to fMRI data analysis. Neuroimage 2004;22:394-400. [Crossref] [PubMed]
21. Van Ombergen A, Jillings S, Jeurissen B, Tomilovskaya E, Rumshiskaya A, Litvinova L, Nosikova I, Pechenkova E, Rukavishnikov I, Manko O, Danylichev S, Rühl RM, Kozlovskaya IB, Sunaert S, Parizel PM, Sinitsyn V, Laureys S, Sijbers J, Zu Eulenburg P, Wuyts FL. Brain ventricular volume changes induced by long-duration spaceflight. Proc Natl Acad Sci U S A 2019;116:10531-6. [Crossref] [PubMed]
22. Li J, Chen W, Wang N, Cheng G. The Influence of Microgravity to Pathology and Physiology of the Eye. Singapore: Springer; 2020:81-7.
23. Xie Y, Fu Y, Shao Y, Qu L, Yang J, Yang C, Zhou K, Li K, Xu Z, Xu D, Cao K, Tian N, Lv K, Wang L, Wang Y, Wang N, Li Y. Quantitative ultrasound image assessment of the optic nerve subarachnoid space during 90-day head-down tilt bed rest. NPJ Microgravity 2024;10:9. [Crossref] [PubMed]
24. Maleki N, Alsop DC, Dai W, Hudson C, Han JS, Fisher J, Mikulis D. The effect of hypercarbia and hyperoxia on the total blood flow to the retina as assessed by magnetic resonance imaging. Invest Ophthalmol Vis Sci 2011;52:6867-74. [Crossref] [PubMed]
25. Aubert AE, Beckers F, Verheyden B. Cardiovascular function and basics of physiology in microgravity. Acta Cardiol 2005;60:129-51. [Crossref] [PubMed]
26. Hayashi N, Ikemura T, Someya N. Effects of dynamic exercise and its intensity on ocular blood flow in humans. Eur J Appl Physiol 2011;111:2601-6. [Crossref] [PubMed]
27. Tootell RB, Hadjikhani NK, Vanduffel W, Liu AK, Mendola JD, Sereno MI, Dale AM. Functional analysis of primary visual cortex (V1) in humans. Proc Natl Acad Sci U S A 1998;95:811-7. [Crossref] [PubMed]
28. Rolls ET, Wirth S, Deco G, Huang CC, Feng J. The human posterior cingulate, retrosplenial, and medial parietal cortex effective connectome, and implications for memory and navigation. Hum Brain Mapp 2023;44:629-55. [Crossref] [PubMed]
29. Roberts DR, Collins HR, Lee JK, Taylor JA, Turner M, Zaharchuk G, Wintermark M, Antonucci MU, Mulder ER, Gerlach DA, Asemani D, McGregor HR, Seidler RD. Altered cerebral perfusion in response to chronic mild hypercapnia and head-down tilt Bed rest as an analog for Spaceflight. Neuroradiology 2021;63:1271-81. [Crossref] [PubMed]