Hemodynamic and morphologic adaptations of the Dural venous sinus to 7-day −6° head-down tilt and recovery: an eight-timepoint 4D flow MRI longitudinal study

Hemodynamic and morphologic adaptations of the Dural venous sinus to 7-day −6° head-down tilt and recovery: an eight-timepoint 4D flow MRI longitudinal study | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Hemodynamic and morphologic adaptations of the Dural venous sinus to 7-day −6° head-down tilt and recovery: an eight-timepoint 4D flow MRI longitudinal study Zhanxin Wu, Huanran Hou, Yan Huang, Furen Guo, Suqin Huang, Yawen Liu, and 5 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-9064673/v1 This work is licensed under a CC BY 4.0 License Status: Under Revision Version 1 posted 13 You are reading this latest preprint version Abstract Background Cephalad fluid shift during microgravity may disrupt intracranial fluid homeostasis and contribute to spaceflight-associated neuro-ocular syndrome (SANS). However, longitudinal quantitative data characterizing intracranial dural venous sinus adaptation to these fluid shifts remain limited. Methods We conducted a prospective cohort study of 38 healthy adult men undergoing 7-day − 6° head-down tilt (HDT) followed by 5-day recovery. 4D Flow MRI was acquired at eight time points (Baseline, HDT 12 h, HDT 1 d, HDT 3 d, HDT 7 d, Recovery (R) 1 d, R 3 d, and R 5 d). Hemodynamic and morphometric metrics were quantified in the superior sagittal sinus and the transverse sinuses. Time effects were tested using repeated-measures ANOVA or Friedman tests with post-hoc comparisons corrected for multiple testing. Linear mixed-effects models evaluated associations between dural venous outflow rate (DVO) and baseline physiological and biochemical variables within HDT and recovery phases. Results Venous sinuses hemodynamics and morphology changed significantly over time. Mean blood flow rate in both the superior sagittal sinus and representative transverse sinus decreased by HDT 3d and remained below baseline into recovery, while mean cross-sectional area of aforementioned sinuses showed significant reductions most clearly by HDT 7d. Indices reflecting pulsatility and resistance decreased later in HDT and persisted into recovery. DVO declined significantly by HDT 3d and remained reduced at R 1d. Arterial inflow rate (AI) progressively declined during HDT and rebounded rapidly at the onset of recovery. DVO/ AI was significantly reduced at R 1d and increased by R 5d. Inter-sinus relative pressure difference showed no significant time effect. Baseline renin ( β = 0.013, 95% CI: 0.002 to 0.024; P = 0.022) and sodium ( β = 0.240, 95% CI: 0.040 to 0.440; P = 0.019) were positively associated with DVO during HDT, whereas baseline cortisol was negatively associated with DVO during recovery ( β =−0.084, 95% CI: −0.150 to − 0.017; P = 0.014). Conclusions Short-term − 6° HDT induces time-dependent remodeling of intracranial dural venous sinus flow and geometry, with early functional changes preceding later caliber changes and a transient impairment in venous-arterial coupling during early recovery. These findings support DVO and DVO/ AI as potential imaging markers relevant to SANS research. Trial registration ChiCTR2500096128 Registration date January 17, 2025 4D Flow MRI Dural venous sinuses Head-down tilt Simulated microgravity Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Figure 6 1 Background Microgravity refers to a condition in which the effective gravitational load acting on the human body is markedly reduced, most commonly encountered during spaceflight[ 1 , 2 ]. As humanity's space exploration program continues to expand, understanding how the human body adapts to microgravity environments becomes increasingly important. Exposure to microgravity induces cephalad fluid shift, thereby disrupting the normal regulation of cerebral blood flow, cerebrospinal fluid (CSF) dynamics, and intracranial pressure (ICP)[ 2 ]. These alterations in intracranial fluid systems are thought to be closely associated with adaptive remodeling of central nervous system structure, function, and cognition, and may contribute to the development of phenotypes related to intracranial hypertension, manifested as characteristic clinical and imaging features[ 3 , 4 ]. Among these, spaceflight-associated neuro-ocular syndrome (SANS) represents the most prominent phenotype, which proposed mechanisms underlying SANS include impaired head and neck venous drainage, altered CSF absorption, and mildly but persistently elevated ICP[ 5 , 6 ]. It is noteworthy that the intracranial venous system, particularly the venous sinuses, plays a crucial role in the aforementioned changes, though the specific mechanism remains unclear. Because of the inherent constraints of conducting human research during spaceflight, the − 6° head-down tilt (HDT) bed rest model has been widely adopted as a classic ground based analog of microgravity, as it reliably reproduces sustained cephalad fluid shift[ 7 , 8 ]. Previous studies using this model have demonstrated multiple effects of cephalad fluid shift on intracranial fluid dynamics, including reduced cerebral arterial inflow, enlargement of the extracranial internal jugular vein cross-sectional area accompanied by decreased flow, restricted CSF outflow, and alterations in cerebral blood volume pulsatility[ 9 – 13 ]. Notably, Marshall-Goebel et al. further reported that during spaceflight, some astronauts exhibited venous flow stagnation or even retrograde flow in the extracranial internal jugular veins, with reported cases of venous thrombosis, highlighting the critical role of venous pathways in the physiological response to microgravity[ 14 ].Against this background, increasing attention has been directed toward the intracranial venous system, particularly the dural venous sinuses, as potential contributors to intracranial fluid regulation[ 15 ]. As the primary drainage pathways for cerebral venous blood, dural venous sinuses not only facilitate venous outflow but also, owing to their geometrically variable structure, participate in intracranial volume balance by buffering transient changes in cerebral blood and CSF volumes, and intracranial pressure. Accordingly, alterations in venous sinus hemodynamics and geometry are considered integral components of intracranial fluid regulation. Prior spaceflight research has suggested a potential role of the venous system in the development of SANS. Using magnetic resonance venography (MRV), Rosenberg et al. reported greater increases in intracranial venous sinus volume in astronauts who developed SANS and proposed that increased venous sinus compliance may represent a susceptibility factor[ 16 ]. However, whether these morphologic changes are accompanied by systematic hemodynamic adaptations remains unknown. Despite these observations, substantial knowledge gaps remain. Owing to pronounced anatomic variability of the dural venous sinuses and limitations in imaging resolution and quantitative methodology, most prior studies have focused on intracranial arteries, extracranial cervical veins, or global volumetric measures. Consequently, the hemodynamic and morphologic adaptations of the intracranial dural venous sinuses themselves under simulated microgravity, particularly their longitudinal quantitative changes, remain insufficiently characterized. This lack of direct quantitative evidence has constrained a comprehensive understanding of the role of venous sinuses within the intracranial fluid regulation network. Time-resolved three-dimensional 4D Flow MRI provides a technical means to address these limitations. This technique enables comprehensive acquisition of three-directional velocity vector fields and volumetric flow data across the entire venous sinus system within a single scan. This technique allows simultaneous quantification of key parameters, including cross-sectional area, blood flow, and total blood volume, and further enables reconstruction of relative pressure gradients across sinus segments based on the full velocity field[ 17 , 18 ]. Such integrative assessment is not achievable with conventional imaging methods. Previous studies have demonstrated the feasibility of 4D Flow MRI for assessing venous sinus hemodynamics in healthy adults, providing a technical foundation for capturing dynamic remodeling of the venous sinuses under sustained cephalad fluid shift in a controlled HDT model[ 19 ]. In this study, we aimed to characterize the time-dependent adaptive patterns of the dural venous drainage system under simulated microgravity. The study employed a 7-day − 6° HDT bed rest protocol followed by a 5-day recovery phase in a prospective cohort of healthy adults. Participants underwent 4D Flow MRI at eight time points spanning baseline, HDT exposure, and recovery, enabling longitudinal tracking of hemodynamic and morphologic adaptations of major intracranial dural venous sinuses during sustained HDT and subsequent recovery. By addressing a critical knowledge gap at the interface between venous sinus drainage and intracranial fluid regulation, our findings may provide novel imaging-based insights into microgravity-related cerebral and ocular alterations and inform monitoring and countermeasure strategies for SANS during long-duration spaceflight. 2 Methods 2.1 Study design and participants This prospective cohort study enrolled 40 healthy adult males to participate in a 7-day − 6° HDT protocol, followed by a 5-day recovery phase during which both MRI examinations and physiological monitoring were conducted. The rationale for the sample size is provided in Additional file 1: Table S1 . Inclusion criteria required male sex, age ≥ 18 years, absence of known cardiovascular, cerebrovascular, or respiratory disease, no prior intracranial surgery, and no contraindications to MRI or prolonged bed rest. Participants were not eligible for enrollment if they had a history of substance dependence, neurological or neuropsychiatric disorders, other significant mental health conditions, genetic or infectious diseases, or any clinically relevant systemic illness, particularly those involving the musculoskeletal or cardiovascular systems. Individuals taking medications known to influence bone metabolism within the previous six months, or those with a history of severe allergic reactions, malnutrition, hypertension, or major cardiac, hepatic, renal, or HIV-related disease were also excluded. Additional exclusion criteria included the presence of metallic implants or any circumstance that could interfere with MRI safety or image quality, as well as intracranial structural abnormalities such as hemorrhage, infarction, neoplasm, or vascular malformations. Subjects with anatomical variants deemed incompatible with study imaging requirements, such as a persistent trigeminal artery, were similarly excluded. Two participants were excluded because 4D flow MRI image quality was insufficient for reliable post-processing, resulting in a final sample of 38 participants (mean age ± SD: 26.7 ± 5.7 years; mean height ± SD: 171.4 ± 5.9 cm; mean weight ± SD: 66.9 ± 7.2 kg; mean BMI ± SD: 22.8 ± 2.3 kg/m²) included in the present analysis. All participants completed MRI examinations and physiological monitoring at eight time points: before HDT (Baseline), at 12 hours after HDT initiation (HDT 12h), on HDT days 1, 3, and 7 (HDT 1d, HDT 3d, HDT 7d), as well as on recovery days 1, 3, and 5 (R 1d, R 3d, R 5d) after resuming the upright posture (Fig. 1 ). 2.2 Physiological and biochemical monitoring To characterize systemic hemodynamic responses during HDT and recovery phases, physiological parameters including peripheral oxygen saturation (SpO₂), heart rate (HR), systolic blood pressure (SBP), and diastolic blood pressure (DBP) were recorded. All physiological parameters were measured in synchrony with MRI acquisitions (Baseline, HDT 12h, HDT 1d, HDT 3d, HDT 7d, R 1d, R 3d, R 5d). SpO₂ was monitored using a pulse oximeter (PM10N, Covidien, MA, USA), providing continuous, non-invasive assessment of arterial oxygen saturation. HR and blood pressure (both SBP and DBP) were measured using an automated electronic sphygmomanometer (HBP-1300, Omron, Dalian, China) while participants maintained the prescribed experimental posture to ensure methodological consistency. At each time point, three consecutive measurements were obtained after at least 5 minutes of rest, and the average of the three readings was used for analysis. Mean arterial pressure (MAP) was calculated as MAP = DBP + (SBP − DBP)/3. At each time point, venous blood samples were collected from all participants for biochemical and hormonal analyses. Endocrine hormones, including aldosterone, renin, and cortisol, were measured using chemiluminescent immunoassays. Cardiac injury biomarkers, including troponin I, myoglobin, and creatine kinase-MB (CK-MB), were determined from serum samples. Serum electrolytes (sodium, potassium, and calcium) and lipid profiles (low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, total cholesterol, and triglycerides) were analyzed using automated biochemical analyzers with standard enzymatic or ion-selective electrode methods. 2.3 HDT protocol and MRI acquisition Participants were admitted to the HDT facility one day before Baseline measurements. During the − 6° HDT phase, they remained in the HDT position continuously, including during meals and toileting. During the recovery phase, participants resumed normal condition but otherwise followed the same controlled schedule. All imaging was conducted on a 3.0 T Siemens Vida MRI scanner equipped with a 64-channel head and neck coil (HeadNeck_64_CS). 4D Flow MRI covering the intracranial arterial and venous circulation was acquired at each time point. Sequence parameters were as follows: velocity encoding (VENC) 100 cm/s, field of view (FOV) 229 × 280 mm², in-plane spatial resolution 1.59 × 1.59 mm², slice thickness 1.0 mm, repetition time (TR) 67.3 ms, echo time (TE) 3.16 ms, and flip angle 7°[ 20 , 21 ]. Prospective cardiac gating was performed using a peripheral pulse unit, and 10 cardiac phases were reconstructed per cardiac cycle to capture the temporal evolution of blood flow. All scans were obtained with participants lying supine. At Baseline and during the recovery phase, the bed was level; during the HDT phase, a customized wedge was used to maintain the − 6° head-down tilt while keeping the head and neck correctly positioned within the coil (Fig. 2 ). In addition, conventional structural MRI and three-dimensional time-of-flight magnetic resonance angiography (3D-TOF MRA) of the intracranial vessels were acquired according to routine clinical protocols and reviewed by a board-certified radiologist to exclude major intracranial vascular pathology. 2.4 4D Flow MRI Post-processing and Venous Sinus Hemodynamic and Morphometric Analysis 4D Flow MRI data were analyzed using cvi42 software (Circle Cardiovascular Imaging Inc., Calgary, Canada). Before data processing, regions of interest (ROIs) were manually selected on the coronal images to delineate the major intracranial dural venous sinuses. During preprocessing, static tissue and vessel masks were automatically generated, and offset correction (OC) was applied to mitigate phase-offset errors and noise, following standard 4D Flow MRI processing principles. Vessel segmentation was performed using automatic contour detection, with manual adjustments made as needed. Centerline extraction and mask threshold adjustment were employed to refine segmentation and ensure accurate delineation of the vessel walls. Analysis planes were placed orthogonal to the local vessel axis at the predefined ROI location to ensure accurate through-plane flow quantification. The position and orientation of all analysis planes were visually inspected and adjusted when needed to avoid partial-volume effects or oblique sampling. The major dural venous sinuses of interest were the superior sagittal sinus (SSS) and the bilateral transverse sinuses (TSs). The vascular annotations in this study were performed at standardized anatomical locations to ensure consistency across all participants (Fig. 3 ). The SSS was annotated at the posterior third of the sinus, with analysis planes placed 10 mm anterior to the confluence of sinuses (torcular Herophili), where the lumen is relatively straight and free from tributary junctions. The TSs were annotated near the transverse-sigmoid junction, with analysis planes placed 10 mm distal to the confluence of the superior petrosal sinus. These locations were chosen based on their anatomical significance, facilitating the accurate assessment of intracranial dural venous sinus hemodynamic and morphological changes. Given the pronounced inter-individual asymmetry of the TSs[ 22 , 23 ], TS laterality was classified at baseline using the bilateral mean blood flow ratio (Q mean,large /Q mean,small ). A ratio ≥ 1.5 was defined as TS-dominant, whereas a ratio < 1.5 was defined as co-dominant, consistent with prior dominance frameworks applying a ≥ 150% criterion[ 24 , 25 ]. For TS-dominant participants (n = 33), hemodynamic and morphometric metrics from the higher-flow TS were used as the representative transverse sinus (rTS) for longitudinal analyses. For co-dominant participants (n = 5), bilateral TS metrics were averaged to derive a single subject-level rTS value per time point[ 26 ]. TS laterality category was defined at baseline and kept constant across subsequent time points to ensure continuity in longitudinal analyses. For each venous sinus and time point, through-plane velocity and cross-sectional area were quantified across the cardiac cycle. From the resulting waveforms, the following parameters were derived: mean blood flow rate (Q mean , mL/s), maximum blood flow rate (Q max , mL/s), minimum blood flow rate (Q min , mL/s),, mean cross-sectional area (CSA mean , mm²), and relative pressure difference between the SSS ROI and the rTS ROI (ΔP SSS–rTS ). Pulsatility index (PI) and resistance index (RI) were calculated as follows: PI= (Q max − Q min )/Q mean , RI= (Q max − Q min )/Q max . For co-dominant participants, PI, RI, and ΔP SSS–rTS were computed separately for each TS and then averaged to obtain a subject-level value. For TS-dominant participants, rTS corresponded to the dominant TS. Following the approach proposed by Abdalla et al.[ 27 ], dural venous outflow rate (DVO) was calculated as the sum of Q mean in the right and left transverse sinuses (Q mean, RTS and Q mean, LTS ): DVO= Q mean, RTS + Q mean, LTS . Arterial inflow rate (AI) was calculated as the sum of mean blood flow rates in the bilateral internal carotid arteries and the basilar artery, obtained from intracranial arterial 4D Flow MRI analysis in the same cohort[ 27 ]. To characterize venous-arterial coupling, the venous-arterial flow rate ratio was computed at each time point (DVO/ AI). 2.5 Statistical analysis 4D flow MRI-derived hemodynamic parameters were exported from cvi42 (version 6.0.2) using Python (version 3.12), which was employed to automate and validate the data extraction process, ensuring accurate correspondence between ROIs, time points, and participants. Statistical analyses were performed using SPSS Statistics (version 27.0.0.0, IBM Corp., Armonk, NY, USA). The normality of all study variables was assessed using the Shapiro-Wilk test, and homogeneity of variance was tested for variables meeting the normality assumption. When analyzing the effect of time on variables, repeated measures analysis of variance (RM-ANOVA) was applied to normally distributed variables, while the Friedman test was used for non-normally distributed variables. If statistical significance was observed, Dunn's post-hoc test for multiple comparisons was applied to assess the statistical significance of differences between specific time points, and Bonferroni correction was applied to adjust P -values for multiple testing and to control the family-wise Type I error rate. Continuous variables are reported as mean ± standard deviation (SD) for approximately normally distributed data or as median with interquartile range (IQR) for non-normally distributed data. A linear mixed-effects model (LMM) was used for each baseline physiological/biochemical variable within the HDT and recovery phases. The dependent variable was repeated DVO measurements, the baseline variable was treated as a fixed effect, and a subject-specific random intercept was used to account for within-subject correlation. Fixed effects are reported as β (SE) with 95% confidence intervals (Cis). All statistical tests were two-sided and P < 0.05 was considered statistically significant. Because of scheduled scanner maintenance, 4D flow MRI data at the R 3d time point were not acquired for three participants. For these cases, missing venous sinus hemodynamic values at R 3d were imputed using the sample median for each variable to ensure the robustness and reliability of the analysis. Inter-reader reproducibility was assessed in a randomly selected 10% subset using the intraclass correlation coefficient (ICC) based on a two-way random-effects model with absolute agreement for single measurements (all ICCs > 0.90); therefore, Reader 1 measurements were used for subsequent analyses (Additional file 1: Table S2). 3 Results 3.1 Longitudinal morphological changes of intracranial venous sinuses Mean cross-sectional area (CSA mean ) showed significant time-dependent changes across the protocol. Overall testing demonstrated a significant time effect for CSA mean in the superior sagittal sinus (SSS: P = 0.009) and in the representative transverse sinus (rTS: P < 0.001) (Table. 2). Post-hoc comparisons indicated that CSA mean at HDT 7d was significantly reduced compared with Baseline in the SSS and rTS (SSS: P = 0.012; rTS: P = 0.005) (Fig. 4 ). 3.2 Changes in intracranial venous sinus hemodynamics and dural venous outflow rate Hemodynamic metrics showed significant longitudinal changes in the SSS, rTS, and combined bilateral transverse sinuses (Table. 2; Fig. 5 ; Fig. 6 ). In the SSS, Q mean , PI, and RI all showed significant time effects during HDT and recovery (PI: P = 0.002; all others: P < 0.001). Compared with baseline, Q mean was significantly reduced from HDT 3d onward (HDT 3d and HDT 7d: both P < 0.001) and remained lower than baseline during recovery (R 1d: P = 0.029; R 5d: P = 0.015). Significant reductions in PI and RI emerged at HDT 7d (PI: P = 0.015; RI: P = 0.029) and persisted at R 3d (PI: P = 0.029; RI: P = 0.015), relative to baseline (Fig. 5 ). In the rTS, Q mean , PI, and RI also demonstrated significant time effects (all P < 0.001). Relative to baseline, Q mean was significantly reduced at HDT 3d and HDT 7d ( P = 0.001 and P = 0.004, respectively) and remained lower at R 1d ( P < 0.001). Reductions in PI and RI became significant at HDT 7d (PI: P = 0.006; RI: P = 0.016) and remained significant throughout recovery (R 1d, R 3d, and R 5d: all P < 0.001), compared with baseline (Fig. 5 ). For the combined bilateral transverse sinuses, both Q mean (DVO) and V exhibited significant time effects (DVO: P = 0.002; V: P = 0.012), and the venous-arterial flow ratio (DVO/ AI) also varied over time ( P = 0.027). Based on post-hoc comparisons in Fig. 6 , DVO first reached a significant reduction at HDT 3d ( P = 0.027) and remained lower at R 1d ( P = 0.003). V was significantly decreased at R 1d ( P = 0.044). DVO/ AI was also significantly reduced at R 1d ( P = 0.013) and then increased significantly by R 5d compared with R 1d ( P = 0.025). In contrast, the relative pressure difference between the SSS ROI and the rTS ROI (ΔP SSS–rTS ) showed no significant time effect ( P = 0.169). 3.3 Associations between dural venous outflow and baseline physiological/biochemical variables In Table. 1, only the fixed-effect estimate ( β ) of each baseline variable is reported and interpreted as the association with DVO. During the HDT phase, linear mixed-effects models identified significant positive associations between DVO and baseline renin ( β = 0.013, SE = 0.006, 95% CI: 0.002 to 0.024, P = 0.022) as well as baseline sodium ( β = 0.240, SE = 0.102, 95% CI: 0.040 to 0.440, P = 0.019). No other baseline physiological or biochemical variables showed significant associations with DVO. During the recovery phase, baseline cortisol was significantly negatively associated with DVO ( β =−0.084, SE = 0.034, 95% CI: −0.150 to − 0.017, P = 0.014). All remaining baseline variables were not significantly associated with DVO during recovery. Table 1 Linear mixed-effects models assess associations between DVO and physiological/biochemical variables during head-down tilt and recovery (n = 38). Phases Variables β SE 95% CI P -values HDT phase SBP 0.001 0.011 (− 0.020, 0.023) 0.895 DBP 0.012 0.014 (− 0.016, 0.039) 0.399 MAP 0.010 0.014 (− 0.018, 0.037) 0.504 HR 0.005 0.013 (− 0.020, 0.030) 0.694 SpO 2 −0.189 0.137 (− 0.458, 0.081) 0.170 aldosterone 0.016 0.033 (− 0.048, 0.080) 0.629 renin 0.013 0.006 (0.002, 0.024) 0.022 * Cortisol 0.022 0.033 (− 0.043, 0.087) 0.509 cTnI −232.815 160.170 (− 546.749, 81.119) 0.146 myoglobin −0.014 0.013 (− 0.040, 0.012) 0.282 CK-MB −0.071 0.450 (− 0.952, 0.810) 0.874 potassium 0.640 0.505 (− 0.349, 1.629) 0.205 sodium 0.240 0.102 (0.040, 0.440) 0.019 * calcium 2.833 1.994 (− 1.075, 6.742) 0.155 LDL-C −0.004 0.432 (− 0.851, 0.843) 0.993 HDL-C −0.398 1.131 (− 2.615, 1.818) 0.725 TC 0.003 0.316 (− 0.617, 0.623) 0.993 triglycerides −0.095 0.234 (− 0.554, 0.363) 0.684 WBC 0.164 0.109 (− 0.048, 0.377) 0.130 RBC 0.462 0.563 (− 0.641, 1.565) 0.412 Hb 0.012 0.018 (− 0.024, 0.048) 0.506 phosphate 0.766 1.038 (− 1.268, 2.801) 0.460 ACTH 0.009 0.006 (− 0.002, 0.020) 0.097 R phase SBP −0.006 0.011 (− 0.027, 0.014) 0.556 DBP 0.001 0.013 (− 0.024, 0.025) 0.955 MAP −0.003 0.013 (− 0.028, 0.023) 0.836 HR −0.013 0.010 (− 0.033, 0.007) 0.198 SpO 2 −0.028 0.136 (− 0.295, 0.239) 0.838 aldosterone −0.013 0.027 (− 0.067, 0.041) 0.637 renin 0.001 0.005 (− 0.008, 0.011) 0.763 cortisol −0.084 0.034 (− 0.150, − 0.017) 0.014 * cTnI −90.979 118.652 (− 323.537, 141.579) 0.443 myoglobin 0.006 0.016 (− 0.026, 0.038) 0.716 CK-MB −0.627 0.549 (− 1.702, 0.448) 0.253 potassium 0.049 0.483 (− 0.898, 0.997) 0.919 sodium 0.099 0.103 (− 0.103, 0.300) 0.338 calcium 0.738 1.762 (− 2.716, 4.192) 0.675 LDL-C −0.420 0.409 (− 1.221, 0.381) 0.304 HDL-C 1.719 1.386 (− 0.997, 4.435) 0.215 TC −0.152 0.311 (− 0.762, 0.457) 0.624 triglycerides −0.088 0.448 (− 0.965, 0.790) 0.845 WBC 0.133 0.128 (− 0.118, 0.383) 0.299 RBC −0.452 0.584 (− 1.597, 0.693) 0.439 Hb −0.011 0.019 (− 0.048, 0.025) 0.540 phosphate 1.757 1.249 (− 0.692, 4.206) 0.160 ACTH 0.009 0.006 (− 0.004, 0.021) 0.165 Table 2 Longitudinal changes in intracranial dural venous sinus metrics during head-down tilt and recovery (n = 38) metrics Baseline HDT 12h HDT 1d HDT 3d HDT 7d R 1d R 3d R 5d P -values SSS CSA mean (mm 2 ) b 42.90(35.48,55.66) 39.63(32.65,51.39) 40.31(31.81,56.78) 37.90 ± 12.66 36.97 ± 13.16 39.15 ± 13.29 43.64 ± 13.76 40.71 ± 14.00 .009 * Q mean (mL/s) b 5.60 ± 1.24 4.82(4.20,5.73) 5.15 ± 1.78 4.25(3.26,5.28) 4.49 ± 1.52 4.71 ± 1.69 5.12 ± 1.44 4.95 ± 1.42 < .001 * PI b 0.23 ± 0.07 0.19(0.15,0.31) 0.20 ± 0.06 0.19 ± 0.05 0.18 ± 0.06 0.16(0.14,0.23) 0.18 ± 0.05 0.18 ± 0.05 .002 * RI b 0.21 ± 0.06 0.18(0.14,0.27) 0.19 ± 0.05 0.17 ± 0.04 0.16 ± 0.05 0.15(0.13,0.20) 0.16 ± 0.05 0.16 ± 0.04 < .001 * rTS CSA mean (mm 2 ) b 47.12 ± 13.28 44.81 ± 19.32 40.62(30.95,54.54) 37.60 ± 15.46 36.77 ± 16.30 34.96 ± 15.98 38.23 ± 16.94 39.65 ± 13.57 < .001 * Q mean (mL/s) b 4.92 ± 1.89 4.55 ± 1.90 4.43(3.20,4.95) 3.90 ± 1.64 3.89 ± 1.59 3.80 ± 1.77 4.30 ± 1.86 4.38 ± 1.83 < .001 * PI b 0.25(0.19,0.29) 0.23(0.17,0.35) 0.22(0.18,0.26) 0.19(0.15,0.24) 0.18(0.13,0.22) 0.19 ± 0.07 0.17(0.14,0.23) 0.17 ± 0.06 < .001 * RI b 0.22(0.17,0.26) 0.22 ± 0.08 0.20(0.17,0.23) 0.17(0.14,0.22) 0.17(0.13,0.20) 0.17 ± 0.05 0.16(0.13,0.21) 0.15 ± 0.05 < .001 * DVO (mL/s) b 5.98 ± 1.91 5.54(4.27,6.58) 5.37 ± 1.98 4.90 ± 1.67 5.01 ± 1.62 4.96 ± 1.87 5.49 ± 2.08 5.78 ± 2.18 .002 * DVO/ AI a 0.43 ± 0.12 0.40 ± 0.15 0.39 ± 0.12 0.39 ± 0.14 0.40 ± 0.13 0.36 ± 0.14 0.40 ± 0.15 0.43 ± 0.15 .027 * ΔP SSS–rTS (mmHg) b 0.26(− 0.16,0.61) 0.35(− 0.17,0.94) 0.15(− 0.33,0.54) 0.12(− 0.26,0.56) 0.26(− 0.43,0.79) 0.17(− 0.27,0.47) 0.33(− 0.09,0.66) 0.10 ± 0.77 .169 Descriptive statistics and overall time effects of intracranial dural venous sinus metrics measured at eight time points during head-down tilt (HDT) and recovery (R) (n = 38). Normally distributed data are expressed as the mean ± standard deviation (SD), and non-normally distributed data are represented as the median (interquartile range, IQR). SSS = superior sagittal sinus; rTS = representative transverse sinus; CSA mean = mean cross-sectional area; Q mean = mean blood flow rate; PI = pulsatility index; RI = resistance index; DVO = dural venous outflow rate (Q mean, RTS + Q mean, LTS ); AI = arterial inflow rate (sum of mean blood flow rates in the bilateral internal carotid arteries and the basilar artery); ΔP SSS–rTS = relative pressure between the SSS ROI and rTS ROI. Baseline indicates pre-HDT measurement. Statistical significance is noted with * ( P < 0.05). The a represents the use of repeated measures analysis of variance (RM-ANOVA); the b represents the use of Friedman test. Linear mixed-effects models were fitted separately for each physiological/biochemical variable within each phase, with dural venous outflow rate (DVO) as the dependent variable and a subject-specific random intercept to account for repeated measures. Reported values are the fixed-effect estimate ( β ), standard error (SE), and the corresponding 95% confidence interval (95% CI) for the predictor effect, together with two-sided P -values based on Wald tests. Significant associations are marked with an asterisk ( P < 0.05). DVO = dural venous outflow rate; HDT = head-down tilt; R = recovery; SBP = systolic blood pressure; DBP = diastolic blood pressure; MAP = mean arterial pressure; HR = heart rate; SpO₂ = peripheral oxygen saturation; cTnI = cardiac troponin I; CK-MB = creatine kinase-MB; LDL-C = low-density lipoprotein cholesterol; HDL-C = high-density lipoprotein cholesterol; TC = total cholesterol; WBC = white blood cell count; RBC = red blood cell count; Hb = hemoglobin; ACTH = adrenocorticotropic hormone. 4 Discussion Spaceflight and ground-based analog studies indicate that cephalad fluid shift can disturb intracranial fluid homeostasis and may contribute to the development and progression of SANS[ 5 , 28 – 30 ]. In-flight investigations have highlighted the importance of impaired head and neck venous drainage, including internal jugular vein flow stasis or retrograde flow and a potential increase in thrombosis risk. This supports venous congestion as a key component of spaceflight physiology[ 14 , 31 ]. In parallel, multiple HDT studies have reported changes in cerebral arterial inflow and CSF dynamics, underscoring that venous outflow should be interpreted within an integrated intracranial fluid system rather than as an isolated part[ 9 , 32 ]. Building on this framework, our study further provides evidence at the level of intracranial dural venous sinuses that short-term HDT exposure and subsequent recovery are accompanied by quantifiable morphological and hemodynamic remodeling. In our post-hoc comparisons, venous flow metrics (Q mean in the SSS and rTS, as well as DVO) showed significant reductions by HDT 3d, whereas significant decreases in CSA mean were primarily observed at HDT 7d. The aforementioned difference suggests that early changes may be dominated by functional adaptation, such as redistribution of venous drainage and changes in the transmural pressure environment, while more readily detectable geometric changes become apparent later. This is consistent with previous microgravity studies. A phase-contrast MRI study demonstrated that internal jugular vein velocity decreased and total jugular venous outflow was significantly reduced after 4.5 h of − 12° HDT compared with baseline[ 11 ]. Meanwhile, Nimpal et al. conducted a ~ 2-h − 10° HDT study and found no group-level volumetric change in major dural sinus masks. They further noted that measurable sinus enlargement is unlikely in an acute setting, whereas dural sinus expansion has been documented after weeks of microgravity exposure, particularly among astronauts who develop SANS[ 16 , 33 ]. Accordingly, flow measures may serve as earlier and potentially more sensitive metrics of venous adaptation related to HDT. During HDT, we observed reduced dural venous flow rate accompanied by decreased cross-sectional area and reductions in indicators of pulsatility and resistance, whereas the ΔP SSS–rTS did not change significantly. The findings suggest that the observed changes may not be primarily attributable to a significant increase in local resistance at the measured segment, but may instead reflect system level regulation, including redistribution of venous return pathways such as through bypass drainage via the vertebral venous plexus, changes in downstream drainage conditions, or shifts in intracranial and extracranial pressure environments that modify overall compliance[ 34 – 37 ]. In astronauts, MRV studies have reported increased dural venous sinus volume in individuals with SANS after spaceflight, commonly interpreted as reflecting abnormal venous compliance or susceptibility to venous congestion[ 16 ]. Differences between those in-flight observations and our findings may relate to exposure duration and cumulative adaptation, the use of a healthy cohort undergoing short-term HDT without SANS clinical endpoints, and the distinct dimensions captured by MRV-derived sinus volume versus localized segmental cross-sectional area. Importantly, dural sinus caliber is highly sensitive to subtle changes in transmural pressure, surrounding tissue and ICP. Therefore, a smaller caliber does not imply fixed stenosis and may instead represent reversible extrinsic compression or compliance-related adaptation associated with reduced transmural pressure[ 37 , 38 ]. Future studies integrating 4D Flow MRI with direct ICP measurement, together with CSF dynamics and ocular endpoints, will be critical to more tightly link venous sinus changes to mechanistic outcomes[ 28 ]. Because venous return is highly posture dependent and strongly influenced by central blood volume regulation, DVO may better capture system-level intracranial hemodynamic status than any single-segment metric[ 34 , 35 ]. The reduction in DVO during HDT that persisted into early recovery, suggests that venous adaptation and recovery may lag behind postural change[ 39 , 40 ]. Due to the predominant role of the internal jugular vein in venous return during supine positioning and the increased contribution of the vertebral venous system during upright positioning, HDT and the readaptation phase may trigger redistribution of return pathways and alterations in downstream conditions, thereby causing a transient reduction in DVO. The Monro-Kellie doctrine further emphasizes that intracranial blood volume is highly dynamic and that even transient mismatches between arterial inflow and venous outflow can rapidly alter intracranial blood volume distribution and the pressure environment, positioning venous pathways as important determinants of intracranial compliance[ 15 ]. The transient decrease in the early recovery phase followed by a rebound in DVO/ AI may reflect the faster arterial recovery relative to venous recovery, potentially associated with reduced orthostatic tolerance and autonomic regulation following HDT[ 40 , 41 ]. Together with in-flight evidence of abnormal head and neck venous drainage and venous sinus structural changes related to SANS, these findings support DVO and DVO/ AI as candidate imaging markers of intracranial hemodynamic balance under cephalad fluid shift, which we plan to further integrate comprehensive analysis of the arterial-venous system and microcirculation. We also found that baseline renin and sodium were positively associated with DVO during HDT, whereas baseline cortisol was negatively associated with DVO during recovery. This pattern suggests that differences across participants in venous outflow rate during HDT may be more closely related to volume regulation mediated by the renin–angiotensin–aldosterone system (RAAS)[ 42 ]. Prior studies have demonstrated that the RAAS plays a pivotal role in cephalad fluid shift, early diuresis, and plasma volume reduction during HDT, which also leads to a new steady state within days[ 43 ]. This may affect the filling state and return distribution of the venous system, manifesting as DVO differences. In contrast, the recovery phase represents a readaptation after postural restoration. Cortisol can increase vascular responsiveness to catecholamines and alter vascular reactivity[ 44 ]. The longer-duration HDT studies suggest that cortisol rhythmicity may be more active during recovery[ 45 , 46 ]. These mechanisms may help explain why higher baseline cortisol was associated with slower early recovery of DVO. Nevertheless, given the large number of biomarkers screened, these associations should be considered exploratory rather than causal. If replicated, such baseline factors may help explain inter-individual heterogeneity in venous adaptation and provide clues for research on individualized countermeasures targeting fluid-electrolyte regulation or neuroendocrine stress responses. Several limitations should be noted. First, the cohort comprised healthy adult men, limiting generalizability across sex and age. Second, constrained by imaging resolution and coverage, we focused primarily on larger dural venous sinuses and did not systematically assess smaller venous pathways or extracranial drainage routes. Third, although defining DVO as the sum of mean blood flow rates in the bilateral transverse sinuses captures changes in the primary outflow pathways, it does not fully represent total cranial venous outflow. Fourth, despite incorporating arterial metrics for coupling analyses, there remains a lack of concurrent evidence linking cerebral microperfusion, CSF dynamics, and ocular endpoints. 5 Conclusions In this prospective 7-day − 6° head-down tilt (HDT) study using longitudinal 4D Flow MRI, major intracranial dural venous sinuses exhibited time-dependent hemodynamic and morphometric remodeling under simulated microgravity. Venous flow reductions were evident by HDT day 3, whereas measurable caliber reductions were most prominent by HDT day 7. Dural venous outflow rate (DVO) remained depressed into early recovery, accompanied by a transient reduction in venous–arterial coupling that subsequently rebounded. Mixed-effects analyses further suggested that higher baseline renin and sodium were associated with increased DVO during HDT, whereas higher baseline cortisol was inversely associated with DVO during recovery. Taken together, these findings support the concept that the dural venous sinuses acts as dynamic components of intracranial fluid regulation under sustained cephalad fluid shift and identify DVO and venous-arterial flow rate ratio (DVO/ AI) as potential imaging markers for monitoring adaptation and recovery in the context of spaceflight-associated neuro-ocular syndrome research. Abbreviations ACTH: adrenocorticotropic hormone AI: arterial inflow rate BMI: body mass index CK-MB: creatine kinase-MB CSF: cerebrospinal fluid CSA mean : mean cross-sectional area cTnI: cardiac troponin I DVO: dural venous outflow rate DVO/ AI: venous-arterial flow rate ratio DBP: diastolic blood pressure FOV: field of view HDT: head-down tilt Hb: hemoglobin HDL-C: high-density lipoprotein cholesterol HIV: human immunodeficiency virus HR: heart rate ICC: intraclass correlation coefficient ICP: intracranial pressure IQR: interquartile range LDL-C: low-density lipoprotein cholesterol LTS: left transverse sinus LVEF: left ventricular ejection fraction MAP: mean arterial pressure MRA: magnetic resonance angiography MRI: magnetic resonance imaging MRV: magnetic resonance venography OC: offset correction PI: pulsatility index Q mean : mean blood flow rate Q max : maximum blood flow rate Q min : minimum blood flow rate R: recovery RAAS: renin–angiotensin–aldosterone system RBC: red blood cell count RI: resistance index ROI: region of interest rTS: representative transverse sinus RTS: right transverse sinus SANS: spaceflight-associated neuro-ocular syndrome SBP: systolic blood pressure SD: standard deviation SE: standard error SpO₂: peripheral oxygen saturation SSS: superior sagittal sinus TC: total cholesterol TE: echo time TR: repetition time TS: transverse sinus VENC: velocity encoding WBC: white blood cell count ΔP SSS – rTS : relative pressure difference between the superior sagittal sinus ROI and representative transverse sinus ROI Declarations Ethics approval and consent to participate All participants provided written informed consent prior to enrollment. The study protocol was approved by the Research Ethics Committee of Beijing Friendship Hospital, Capital Medical University (approval number: 2024-P2-069-04) and complied with the Declaration of Helsinki. The trial was registered in the Chinese Clinical Trial Registry (ChiCTR2500096128; registration date: January 17, 2025). Consent for publication Not applicable. Availability of data and materials The data supporting the findings of this study are available from the corresponding authors upon request. Competing interests There are no competing interests in this study. Funding This study was supported by the Space Medical Experiment Project of China Manned Space Program (No. HYZHXMH01005), Beijing Hospitals Authority Innovation Studio of Young Staff Funding Support (No.202302) and Beijing Scholar 2015. Authors’ Contributions ZXW was responsible for experiment execution, data analysis, and manuscript drafting. HRH provided substantial guidance in manuscript preparation and data analysis, and supervised data quality control. HRH, YH, FRG, and SQH participated in MRI scanning and data acquisition. YWL and RW contributed to critical guidance on data analysis. Jumatay Biekan, as a CVI 42 software engineer, provided technical support for software-based flow analysis. PFZ, PLR, and ZCW as corresponding authors, contributed to study conception and design, overall supervision, and critical revision of the manuscript. All authors read and approved the final manuscript. Acknowledgements The authors would like to thank the medical staff of Beijing Friendship Hospital, Capital Medical University, for their support and assistance in this study. We would like to express our sincere gratitude to Dr. Yu Tian for his invaluable support and guidance throughout this experiment. We are also grateful to all the volunteers who generously participated in the research. 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Supplementary Files Additionalfile1.docx Supplementary Information Additional file 1. Table S1. Sample sizes of prior HDT or HDTBR studies assessing venous hemodynamics. Table S2. Inter-observer reliability for superior sagittal sinus (SSS) measurements (n=30). 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13:55:16","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-9064673/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-9064673/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":107482837,"identity":"c682b903-e763-4543-8581-47929588981d","added_by":"auto","created_at":"2026-04-22 02:25:06","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":159320,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eParticipant Enrollment Flowchart in −6° head-down tilt study\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-9064673/v1/3a2d3bba048b1e4ba7604d67.png"},{"id":107245736,"identity":"19b36c7c-0335-45bb-abd9-1c835f081a14","added_by":"auto","created_at":"2026-04-19 08:06:34","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":169629,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eHDT protocol and assessment timeline\u003c/strong\u003e (a) −6° head-down tilt (HDT) and recovery (R) schedule with eight time points; (b) Assessments at each visit; (c) MRI setup in the −6° HDT position using a posture-support cushion.\u003c/p\u003e","description":"","filename":"2.png","url":"https://assets-eu.researchsquare.com/files/rs-9064673/v1/fb97270484b262d50e8bbb4f.png"},{"id":107482845,"identity":"b398e634-7fc5-4359-9e10-0ad5b932dc0a","added_by":"auto","created_at":"2026-04-22 02:25:08","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":171195,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eMeasurement planes and streamline visualization of dural venous sinuses using CVI 42\u003c/strong\u003e (a) Target venous sinuses and measurement planes: Schematic of the superior sagittal sinus, bilateral transverse sinuses, and bilateral sigmoid sinuses, with predefined analysis planes (P1~P3) placed at standard distances. P1 was annotated at the posterior third of the sinus, 10 mm anterior to the confluence of sinuses. P2 and P3 were annotated at the proximal transverse segments, 10 mm distal to the confluence of the superior petrosal sinus. Each plane was positioned perpendicular to the local vessel axis. (b) Magnitude image: region of interest (ROI) and analysis plane at the superior sagittal sinus. (c) velocity map: corresponding velocity-encoded image at the same location. (d) orthogonal view: positioning the analysis plane perpendicular to the vessel course. (e) oblique view: confirmation of perpendicular orientation and ROI location.\u003c/p\u003e","description":"","filename":"3.png","url":"https://assets-eu.researchsquare.com/files/rs-9064673/v1/84b2507efb691eeda50f16c8.png"},{"id":107245738,"identity":"ab1a6c09-e3cb-406c-9788-0700bddc216a","added_by":"auto","created_at":"2026-04-19 08:06:34","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":56507,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eLongitudinal changes in mean cross-sectional area (CSA\u003c/strong\u003e\u003csub\u003e\u003cstrong\u003emean\u003c/strong\u003e\u003c/sub\u003e\u003cstrong\u003e, mm²) of dural venous sinuses during head-down tilt and recovery\u003c/strong\u003e (a) the superior sagittal sinus (SSS) and (b) the representative transverse sinus (rTS). Data are shown for eight time points: Baseline, HDT 12h, HDT 1d, HDT 3d, HDT 7d, R 1d, R 3d, and R 5d. *\u003cem\u003eP\u003c/em\u003e \u0026lt; 0.05. **\u003cem\u003eP\u003c/em\u003e \u0026lt; 0.01. ***\u003cem\u003eP\u003c/em\u003e \u0026lt; 0.001. The x-axis spacing indicates the order of measurements rather than equal time intervals.\u003c/p\u003e","description":"","filename":"4.png","url":"https://assets-eu.researchsquare.com/files/rs-9064673/v1/faa7b5db7ae349903c5ee8da.png"},{"id":107245740,"identity":"79e18375-4832-40e2-a64a-718ce90c4a88","added_by":"auto","created_at":"2026-04-19 08:06:35","extension":"png","order_by":5,"title":"Figure 5","display":"","copyAsset":false,"role":"figure","size":114657,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eLongitudinal changes in hemodynamic metrics derived from 4D Flow MRI during head-down tilt (HDT) and recovery (R)\u003c/strong\u003e Panels (a~c) show metrics for the superior sagittal sinus (SSS): (a) mean blood flow rate (Q\u003csub\u003emean\u003c/sub\u003e), (b) pulsatility index (PI), and (c) resistance index (RI). Panels (d~f) show the corresponding metrics for the representative transverse sinus (rTS). *\u003cem\u003eP\u003c/em\u003e \u0026lt; 0.05. **\u003cem\u003eP\u003c/em\u003e \u0026lt; 0.01. ***\u003cem\u003eP\u003c/em\u003e \u0026lt; 0.001. The x-axis spacing indicates the order of measurements rather than equal time intervals.\u003c/p\u003e","description":"","filename":"5.png","url":"https://assets-eu.researchsquare.com/files/rs-9064673/v1/0f341620d2b6e3050026de64.png"},{"id":107483135,"identity":"5b357dae-90f9-4468-968a-98a3ed178bc8","added_by":"auto","created_at":"2026-04-22 02:26:29","extension":"png","order_by":6,"title":"Figure 6","display":"","copyAsset":false,"role":"figure","size":46336,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eLongitudinal changes in dural venous outflow rate and venous-arterial coupling\u003c/strong\u003e (a) dural venous outflow rate (DVO), calculated as the sum of mean blood flow rates in the bilateral transverse sinuses and (b) venous-arterial flow rate ratio (DVO/ AI). Measurements were obtained at eight time points during head-down tilt (HDT) and recovery (R). *\u003cem\u003eP\u003c/em\u003e \u0026lt; 0.05. **\u003cem\u003eP\u003c/em\u003e\u0026lt; 0.01. ***\u003cem\u003eP\u003c/em\u003e \u0026lt; 0.001. The x-axis spacing indicates the order of measurements, not equal time intervals.\u003c/p\u003e","description":"","filename":"6.png","url":"https://assets-eu.researchsquare.com/files/rs-9064673/v1/e11513508b10342bdba24928.png"},{"id":107486849,"identity":"5b7ac6e9-7841-47dc-8513-6a6101f394a1","added_by":"auto","created_at":"2026-04-22 02:39:05","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1365759,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-9064673/v1/241a4d6f-a68b-4753-90e6-a8664be43a29.pdf"},{"id":107245735,"identity":"c34dbae3-5b1b-4fd7-a89a-ae1e2c48daeb","added_by":"auto","created_at":"2026-04-19 08:06:34","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":28322,"visible":true,"origin":"","legend":"\u003cp\u003eSupplementary Information\u003c/p\u003e\n\u003cp\u003eAdditional file 1. \u003cstrong\u003eTable S1.\u003c/strong\u003e Sample sizes of prior HDT or HDTBR studies assessing venous hemodynamics. \u003cstrong\u003eTable S2.\u003c/strong\u003e Inter-observer reliability for superior sagittal sinus (SSS) measurements (n=30).\u003c/p\u003e","description":"","filename":"Additionalfile1.docx","url":"https://assets-eu.researchsquare.com/files/rs-9064673/v1/f1897e928d463ce08cc54249.docx"}],"financialInterests":"No competing interests reported.","formattedTitle":"Hemodynamic and morphologic adaptations of the Dural venous sinus to 7-day −6° head-down tilt and recovery: an eight-timepoint 4D flow MRI longitudinal study","fulltext":[{"header":"1 Background","content":"\u003cp\u003eMicrogravity refers to a condition in which the effective gravitational load acting on the human body is markedly reduced, most commonly encountered during spaceflight[\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. As humanity's space exploration program continues to expand, understanding how the human body adapts to microgravity environments becomes increasingly important. Exposure to microgravity induces cephalad fluid shift, thereby disrupting the normal regulation of cerebral blood flow, cerebrospinal fluid (CSF) dynamics, and intracranial pressure (ICP)[\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. These alterations in intracranial fluid systems are thought to be closely associated with adaptive remodeling of central nervous system structure, function, and cognition, and may contribute to the development of phenotypes related to intracranial hypertension, manifested as characteristic clinical and imaging features[\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. Among these, spaceflight-associated neuro-ocular syndrome (SANS) represents the most prominent phenotype, which proposed mechanisms underlying SANS include impaired head and neck venous drainage, altered CSF absorption, and mildly but persistently elevated ICP[\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e, \u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. It is noteworthy that the intracranial venous system, particularly the venous sinuses, plays a crucial role in the aforementioned changes, though the specific mechanism remains unclear.\u003c/p\u003e \u003cp\u003eBecause of the inherent constraints of conducting human research during spaceflight, the \u0026minus;\u0026thinsp;6\u0026deg; head-down tilt (HDT) bed rest model has been widely adopted as a classic ground based analog of microgravity, as it reliably reproduces sustained cephalad fluid shift[\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e, \u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]. Previous studies using this model have demonstrated multiple effects of cephalad fluid shift on intracranial fluid dynamics, including reduced cerebral arterial inflow, enlargement of the extracranial internal jugular vein cross-sectional area accompanied by decreased flow, restricted CSF outflow, and alterations in cerebral blood volume pulsatility[\u003cspan additionalcitationids=\"CR10 CR11 CR12\" citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]. Notably, Marshall-Goebel et al. further reported that during spaceflight, some astronauts exhibited venous flow stagnation or even retrograde flow in the extracranial internal jugular veins, with reported cases of venous thrombosis, highlighting the critical role of venous pathways in the physiological response to microgravity[\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e].Against this background, increasing attention has been directed toward the intracranial venous system, particularly the dural venous sinuses, as potential contributors to intracranial fluid regulation[\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]. As the primary drainage pathways for cerebral venous blood, dural venous sinuses not only facilitate venous outflow but also, owing to their geometrically variable structure, participate in intracranial volume balance by buffering transient changes in cerebral blood and CSF volumes, and intracranial pressure. Accordingly, alterations in venous sinus hemodynamics and geometry are considered integral components of intracranial fluid regulation. Prior spaceflight research has suggested a potential role of the venous system in the development of SANS. Using magnetic resonance venography (MRV), Rosenberg et al. reported greater increases in intracranial venous sinus volume in astronauts who developed SANS and proposed that increased venous sinus compliance may represent a susceptibility factor[\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]. However, whether these morphologic changes are accompanied by systematic hemodynamic adaptations remains unknown.\u003c/p\u003e \u003cp\u003eDespite these observations, substantial knowledge gaps remain. Owing to pronounced anatomic variability of the dural venous sinuses and limitations in imaging resolution and quantitative methodology, most prior studies have focused on intracranial arteries, extracranial cervical veins, or global volumetric measures. Consequently, the hemodynamic and morphologic adaptations of the intracranial dural venous sinuses themselves under simulated microgravity, particularly their longitudinal quantitative changes, remain insufficiently characterized. This lack of direct quantitative evidence has constrained a comprehensive understanding of the role of venous sinuses within the intracranial fluid regulation network. Time-resolved three-dimensional 4D Flow MRI provides a technical means to address these limitations. This technique enables comprehensive acquisition of three-directional velocity vector fields and volumetric flow data across the entire venous sinus system within a single scan. This technique allows simultaneous quantification of key parameters, including cross-sectional area, blood flow, and total blood volume, and further enables reconstruction of relative pressure gradients across sinus segments based on the full velocity field[\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e, \u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e]. Such integrative assessment is not achievable with conventional imaging methods. Previous studies have demonstrated the feasibility of 4D Flow MRI for assessing venous sinus hemodynamics in healthy adults, providing a technical foundation for capturing dynamic remodeling of the venous sinuses under sustained cephalad fluid shift in a controlled HDT model[\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eIn this study, we aimed to characterize the time-dependent adaptive patterns of the dural venous drainage system under simulated microgravity. The study employed a 7-day\u0026thinsp;\u0026minus;\u0026thinsp;6\u0026deg; HDT bed rest protocol followed by a 5-day recovery phase in a prospective cohort of healthy adults. Participants underwent 4D Flow MRI at eight time points spanning baseline, HDT exposure, and recovery, enabling longitudinal tracking of hemodynamic and morphologic adaptations of major intracranial dural venous sinuses during sustained HDT and subsequent recovery. By addressing a critical knowledge gap at the interface between venous sinus drainage and intracranial fluid regulation, our findings may provide novel imaging-based insights into microgravity-related cerebral and ocular alterations and inform monitoring and countermeasure strategies for SANS during long-duration spaceflight.\u003c/p\u003e"},{"header":"2 Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003e2.1 Study design and participants\u003c/h2\u003e \u003cp\u003eThis prospective cohort study enrolled 40 healthy adult males to participate in a 7-day\u0026thinsp;\u0026minus;\u0026thinsp;6\u0026deg; HDT protocol, followed by a 5-day recovery phase during which both MRI examinations and physiological monitoring were conducted. The rationale for the sample size is provided in Additional file 1: Table \u003cspan refid=\"MOESM1\" class=\"InternalRef\"\u003eS1\u003c/span\u003e. Inclusion criteria required male sex, age\u0026thinsp;\u0026ge;\u0026thinsp;18 years, absence of known cardiovascular, cerebrovascular, or respiratory disease, no prior intracranial surgery, and no contraindications to MRI or prolonged bed rest. Participants were not eligible for enrollment if they had a history of substance dependence, neurological or neuropsychiatric disorders, other significant mental health conditions, genetic or infectious diseases, or any clinically relevant systemic illness, particularly those involving the musculoskeletal or cardiovascular systems. Individuals taking medications known to influence bone metabolism within the previous six months, or those with a history of severe allergic reactions, malnutrition, hypertension, or major cardiac, hepatic, renal, or HIV-related disease were also excluded. Additional exclusion criteria included the presence of metallic implants or any circumstance that could interfere with MRI safety or image quality, as well as intracranial structural abnormalities such as hemorrhage, infarction, neoplasm, or vascular malformations. Subjects with anatomical variants deemed incompatible with study imaging requirements, such as a persistent trigeminal artery, were similarly excluded. Two participants were excluded because 4D flow MRI image quality was insufficient for reliable post-processing, resulting in a final sample of 38 participants (mean age\u0026thinsp;\u0026plusmn;\u0026thinsp;SD: 26.7\u0026thinsp;\u0026plusmn;\u0026thinsp;5.7 years; mean height\u0026thinsp;\u0026plusmn;\u0026thinsp;SD: 171.4\u0026thinsp;\u0026plusmn;\u0026thinsp;5.9 cm; mean weight\u0026thinsp;\u0026plusmn;\u0026thinsp;SD: 66.9\u0026thinsp;\u0026plusmn;\u0026thinsp;7.2 kg; mean BMI\u0026thinsp;\u0026plusmn;\u0026thinsp;SD: 22.8\u0026thinsp;\u0026plusmn;\u0026thinsp;2.3 kg/m\u0026sup2;) included in the present analysis. All participants completed MRI examinations and physiological monitoring at eight time points: before HDT (Baseline), at 12 hours after HDT initiation (HDT 12h), on HDT days 1, 3, and 7 (HDT 1d, HDT 3d, HDT 7d), as well as on recovery days 1, 3, and 5 (R 1d, R 3d, R 5d) after resuming the upright posture (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003ch2\u003e2.2 Physiological and biochemical monitoring\u003c/h2\u003e \u003cp\u003eTo characterize systemic hemodynamic responses during HDT and recovery phases, physiological parameters including peripheral oxygen saturation (SpO₂), heart rate (HR), systolic blood pressure (SBP), and diastolic blood pressure (DBP) were recorded. All physiological parameters were measured in synchrony with MRI acquisitions (Baseline, HDT 12h, HDT 1d, HDT 3d, HDT 7d, R 1d, R 3d, R 5d). SpO₂ was monitored using a pulse oximeter (PM10N, Covidien, MA, USA), providing continuous, non-invasive assessment of arterial oxygen saturation. HR and blood pressure (both SBP and DBP) were measured using an automated electronic sphygmomanometer (HBP-1300, Omron, Dalian, China) while participants maintained the prescribed experimental posture to ensure methodological consistency. At each time point, three consecutive measurements were obtained after at least 5 minutes of rest, and the average of the three readings was used for analysis. Mean arterial pressure (MAP) was calculated as MAP\u0026thinsp;=\u0026thinsp;DBP + (SBP\u0026thinsp;\u0026minus;\u0026thinsp;DBP)/3.\u003c/p\u003e \u003cp\u003eAt each time point, venous blood samples were collected from all participants for biochemical and hormonal analyses. Endocrine hormones, including aldosterone, renin, and cortisol, were measured using chemiluminescent immunoassays. Cardiac injury biomarkers, including troponin I, myoglobin, and creatine kinase-MB (CK-MB), were determined from serum samples. Serum electrolytes (sodium, potassium, and calcium) and lipid profiles (low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, total cholesterol, and triglycerides) were analyzed using automated biochemical analyzers with standard enzymatic or ion-selective electrode methods.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec5\" class=\"Section2\"\u003e \u003ch2\u003e2.3 HDT protocol and MRI acquisition\u003c/h2\u003e \u003cp\u003eParticipants were admitted to the HDT facility one day before Baseline measurements. During the \u0026minus;\u0026thinsp;6\u0026deg; HDT phase, they remained in the HDT position continuously, including during meals and toileting. During the recovery phase, participants resumed normal condition but otherwise followed the same controlled schedule. All imaging was conducted on a 3.0 T Siemens Vida MRI scanner equipped with a 64-channel head and neck coil (HeadNeck_64_CS). 4D Flow MRI covering the intracranial arterial and venous circulation was acquired at each time point. Sequence parameters were as follows: velocity encoding (VENC) 100 cm/s, field of view (FOV) 229 \u0026times; 280 mm\u0026sup2;, in-plane spatial resolution 1.59 \u0026times; 1.59 mm\u0026sup2;, slice thickness 1.0 mm, repetition time (TR) 67.3 ms, echo time (TE) 3.16 ms, and flip angle 7\u0026deg;[\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e, \u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e]. Prospective cardiac gating was performed using a peripheral pulse unit, and 10 cardiac phases were reconstructed per cardiac cycle to capture the temporal evolution of blood flow. All scans were obtained with participants lying supine. At Baseline and during the recovery phase, the bed was level; during the HDT phase, a customized wedge was used to maintain the \u0026minus;\u0026thinsp;6\u0026deg; head-down tilt while keeping the head and neck correctly positioned within the coil (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e). In addition, conventional structural MRI and three-dimensional time-of-flight magnetic resonance angiography (3D-TOF MRA) of the intracranial vessels were acquired according to routine clinical protocols and reviewed by a board-certified radiologist to exclude major intracranial vascular pathology.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec6\" class=\"Section2\"\u003e \u003ch2\u003e2.4 4D Flow MRI Post-processing and Venous Sinus Hemodynamic and Morphometric Analysis\u003c/h2\u003e \u003cp\u003e4D Flow MRI data were analyzed using cvi42 software (Circle Cardiovascular Imaging Inc., Calgary, Canada). Before data processing, regions of interest (ROIs) were manually selected on the coronal images to delineate the major intracranial dural venous sinuses. During preprocessing, static tissue and vessel masks were automatically generated, and offset correction (OC) was applied to mitigate phase-offset errors and noise, following standard 4D Flow MRI processing principles. Vessel segmentation was performed using automatic contour detection, with manual adjustments made as needed. Centerline extraction and mask threshold adjustment were employed to refine segmentation and ensure accurate delineation of the vessel walls. Analysis planes were placed orthogonal to the local vessel axis at the predefined ROI location to ensure accurate through-plane flow quantification. The position and orientation of all analysis planes were visually inspected and adjusted when needed to avoid partial-volume effects or oblique sampling.\u003c/p\u003e \u003cp\u003eThe major dural venous sinuses of interest were the superior sagittal sinus (SSS) and the bilateral transverse sinuses (TSs). The vascular annotations in this study were performed at standardized anatomical locations to ensure consistency across all participants (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e). The SSS was annotated at the posterior third of the sinus, with analysis planes placed 10 mm anterior to the confluence of sinuses (torcular Herophili), where the lumen is relatively straight and free from tributary junctions. The TSs were annotated near the transverse-sigmoid junction, with analysis planes placed 10 mm distal to the confluence of the superior petrosal sinus. These locations were chosen based on their anatomical significance, facilitating the accurate assessment of intracranial dural venous sinus hemodynamic and morphological changes.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eGiven the pronounced inter-individual asymmetry of the TSs[\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e, \u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e], TS laterality was classified at baseline using the bilateral mean blood flow ratio (Q\u003csub\u003emean,large\u003c/sub\u003e/Q\u003csub\u003emean,small\u003c/sub\u003e). A ratio\u0026thinsp;\u0026ge;\u0026thinsp;1.5 was defined as TS-dominant, whereas a ratio\u0026thinsp;\u0026lt;\u0026thinsp;1.5 was defined as co-dominant, consistent with prior dominance frameworks applying a\u0026thinsp;\u0026ge;\u0026thinsp;150% criterion[\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e, \u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e]. For TS-dominant participants (n\u0026thinsp;=\u0026thinsp;33), hemodynamic and morphometric metrics from the higher-flow TS were used as the representative transverse sinus (rTS) for longitudinal analyses. For co-dominant participants (n\u0026thinsp;=\u0026thinsp;5), bilateral TS metrics were averaged to derive a single subject-level rTS value per time point[\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e]. TS laterality category was defined at baseline and kept constant across subsequent time points to ensure continuity in longitudinal analyses.\u003c/p\u003e \u003cp\u003eFor each venous sinus and time point, through-plane velocity and cross-sectional area were quantified across the cardiac cycle. From the resulting waveforms, the following parameters were derived: mean blood flow rate (Q\u003csub\u003emean\u003c/sub\u003e, mL/s), maximum blood flow rate (Q\u003csub\u003emax\u003c/sub\u003e, mL/s), minimum blood flow rate (Q\u003csub\u003emin\u003c/sub\u003e, mL/s),, mean cross-sectional area (CSA\u003csub\u003emean\u003c/sub\u003e, mm\u0026sup2;), and relative pressure difference between the SSS ROI and the rTS ROI (ΔP\u003csub\u003eSSS\u0026ndash;rTS\u003c/sub\u003e). Pulsatility index (PI) and resistance index (RI) were calculated as follows: PI= (Q\u003csub\u003emax\u003c/sub\u003e \u0026minus; Q\u003csub\u003emin\u003c/sub\u003e)/Q\u003csub\u003emean\u003c/sub\u003e, RI= (Q\u003csub\u003emax\u003c/sub\u003e \u0026minus; Q\u003csub\u003emin\u003c/sub\u003e)/Q\u003csub\u003emax\u003c/sub\u003e. For co-dominant participants, PI, RI, and ΔP\u003csub\u003eSSS\u0026ndash;rTS\u003c/sub\u003e were computed separately for each TS and then averaged to obtain a subject-level value. For TS-dominant participants, rTS corresponded to the dominant TS. Following the approach proposed by Abdalla et al.[\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e], dural venous outflow rate (DVO) was calculated as the sum of Q\u003csub\u003emean\u003c/sub\u003e in the right and left transverse sinuses (Q\u003csub\u003emean, RTS\u003c/sub\u003e and Q\u003csub\u003emean, LTS\u003c/sub\u003e): DVO= Q\u003csub\u003emean, RTS\u003c/sub\u003e + Q\u003csub\u003emean, LTS\u003c/sub\u003e. Arterial inflow rate (AI) was calculated as the sum of mean blood flow rates in the bilateral internal carotid arteries and the basilar artery, obtained from intracranial arterial 4D Flow MRI analysis in the same cohort[\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e]. To characterize venous-arterial coupling, the venous-arterial flow rate ratio was computed at each time point (DVO/ AI).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec7\" class=\"Section2\"\u003e \u003ch2\u003e2.5 Statistical analysis\u003c/h2\u003e \u003cp\u003e 4D flow MRI-derived hemodynamic parameters were exported from cvi42 (version 6.0.2) using Python (version 3.12), which was employed to automate and validate the data extraction process, ensuring accurate correspondence between ROIs, time points, and participants. Statistical analyses were performed using SPSS Statistics (version 27.0.0.0, IBM Corp., Armonk, NY, USA). The normality of all study variables was assessed using the Shapiro-Wilk test, and homogeneity of variance was tested for variables meeting the normality assumption. When analyzing the effect of time on variables, repeated measures analysis of variance (RM-ANOVA) was applied to normally distributed variables, while the Friedman test was used for non-normally distributed variables. If statistical significance was observed, Dunn's post-hoc test for multiple comparisons was applied to assess the statistical significance of differences between specific time points, and Bonferroni correction was applied to adjust \u003cem\u003eP\u003c/em\u003e-values for multiple testing and to control the family-wise Type I error rate. Continuous variables are reported as mean\u0026thinsp;\u0026plusmn;\u0026thinsp;standard deviation (SD) for approximately normally distributed data or as median with interquartile range (IQR) for non-normally distributed data. A linear mixed-effects model (LMM) was used for each baseline physiological/biochemical variable within the HDT and recovery phases. The dependent variable was repeated DVO measurements, the baseline variable was treated as a fixed effect, and a subject-specific random intercept was used to account for within-subject correlation. Fixed effects are reported as \u003cem\u003eβ\u003c/em\u003e (SE) with 95% confidence intervals (Cis). All statistical tests were two-sided and \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.05 was considered statistically significant.\u003c/p\u003e \u003cp\u003eBecause of scheduled scanner maintenance, 4D flow MRI data at the R 3d time point were not acquired for three participants. For these cases, missing venous sinus hemodynamic values at R 3d were imputed using the sample median for each variable to ensure the robustness and reliability of the analysis.\u003c/p\u003e \u003cp\u003eInter-reader reproducibility was assessed in a randomly selected 10% subset using the intraclass correlation coefficient (ICC) based on a two-way random-effects model with absolute agreement for single measurements (all ICCs\u0026thinsp;\u0026gt;\u0026thinsp;0.90); therefore, Reader 1 measurements were used for subsequent analyses (Additional file 1: Table S2).\u003c/p\u003e \u003c/div\u003e"},{"header":"3 Results","content":"\u003cdiv id=\"Sec9\" class=\"Section2\"\u003e \u003ch2\u003e3.1 Longitudinal morphological changes of intracranial venous sinuses\u003c/h2\u003e \u003cp\u003eMean cross-sectional area (CSA\u003csub\u003emean\u003c/sub\u003e) showed significant time-dependent changes across the protocol. Overall testing demonstrated a significant time effect for CSA\u003csub\u003emean\u003c/sub\u003e in the superior sagittal sinus (SSS: \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.009) and in the representative transverse sinus (rTS: \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001) (Table. 2). Post-hoc comparisons indicated that CSA\u003csub\u003emean\u003c/sub\u003e at HDT 7d was significantly reduced compared with Baseline in the SSS and rTS (SSS: \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.012; rTS: \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.005) (Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec10\" class=\"Section2\"\u003e \u003ch2\u003e3.2 Changes in intracranial venous sinus hemodynamics and dural venous outflow rate\u003c/h2\u003e \u003cp\u003eHemodynamic metrics showed significant longitudinal changes in the SSS, rTS, and combined bilateral transverse sinuses (Table. 2; Fig.\u0026nbsp;\u003cspan refid=\"Fig5\" class=\"InternalRef\"\u003e5\u003c/span\u003e; Fig.\u0026nbsp;\u003cspan refid=\"Fig6\" class=\"InternalRef\"\u003e6\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eIn the SSS, Q\u003csub\u003emean\u003c/sub\u003e, PI, and RI all showed significant time effects during HDT and recovery (PI: \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.002; all others: \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001). Compared with baseline, Q\u003csub\u003emean\u003c/sub\u003e was significantly reduced from HDT 3d onward (HDT 3d and HDT 7d: both \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001) and remained lower than baseline during recovery (R 1d: \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.029; R 5d: \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.015). Significant reductions in PI and RI emerged at HDT 7d (PI: \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.015; RI: \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.029) and persisted at R 3d (PI: \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.029; RI: \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.015), relative to baseline (Fig.\u0026nbsp;\u003cspan refid=\"Fig5\" class=\"InternalRef\"\u003e5\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eIn the rTS, Q\u003csub\u003emean\u003c/sub\u003e, PI, and RI also demonstrated significant time effects (all \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001). Relative to baseline, Q\u003csub\u003emean\u003c/sub\u003e was significantly reduced at HDT 3d and HDT 7d (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.001 and \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.004, respectively) and remained lower at R 1d (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001). Reductions in PI and RI became significant at HDT 7d (PI: \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.006; RI: \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.016) and remained significant throughout recovery (R 1d, R 3d, and R 5d: all \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001), compared with baseline (Fig.\u0026nbsp;\u003cspan refid=\"Fig5\" class=\"InternalRef\"\u003e5\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eFor the combined bilateral transverse sinuses, both Q\u003csub\u003emean\u003c/sub\u003e (DVO) and V exhibited significant time effects (DVO: \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.002; V: \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.012), and the venous-arterial flow ratio (DVO/ AI) also varied over time (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.027). Based on post-hoc comparisons in Fig.\u0026nbsp;\u003cspan refid=\"Fig6\" class=\"InternalRef\"\u003e6\u003c/span\u003e, DVO first reached a significant reduction at HDT 3d (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.027) and remained lower at R 1d (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.003). V was significantly decreased at R 1d (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.044). DVO/ AI was also significantly reduced at R 1d (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.013) and then increased significantly by R 5d compared with R 1d (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.025).\u003c/p\u003e \u003cp\u003eIn contrast, the relative pressure difference between the SSS ROI and the rTS ROI (ΔP\u003csub\u003eSSS\u0026ndash;rTS\u003c/sub\u003e) showed no significant time effect (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.169).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec11\" class=\"Section2\"\u003e \u003ch2\u003e3.3 Associations between dural venous outflow and baseline physiological/biochemical variables\u003c/h2\u003e \u003cp\u003eIn Table. 1, only the fixed-effect estimate (\u003cem\u003eβ\u003c/em\u003e) of each baseline variable is reported and interpreted as the association with DVO. During the HDT phase, linear mixed-effects models identified significant positive associations between DVO and baseline renin (\u003cem\u003eβ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.013, SE\u0026thinsp;=\u0026thinsp;0.006, 95% CI: 0.002 to 0.024, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.022) as well as baseline sodium (\u003cem\u003eβ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.240, SE\u0026thinsp;=\u0026thinsp;0.102, 95% CI: 0.040 to 0.440, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.019). No other baseline physiological or biochemical variables showed significant associations with DVO. During the recovery phase, baseline cortisol was significantly negatively associated with DVO (\u003cem\u003eβ\u003c/em\u003e=\u0026minus;0.084, SE\u0026thinsp;=\u0026thinsp;0.034, 95% CI: \u0026minus;0.150 to \u0026minus;\u0026thinsp;0.017, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.014). All remaining baseline variables were not significantly associated with DVO during recovery.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eLinear mixed-effects models assess associations between DVO and physiological/biochemical variables during head-down tilt and recovery (n\u0026thinsp;=\u0026thinsp;38).\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"6\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePhases\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eVariables\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u003cem\u003eβ\u003c/em\u003e\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eSE\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003e95% CI\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e \u003cp\u003e\u003cem\u003eP\u003c/em\u003e-values\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\" morerows=\"22\" rowspan=\"23\"\u003e \u003cp\u003eHDT phase\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eSBP\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.001\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.011\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e(\u0026minus;\u0026thinsp;0.020, 0.023)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.895\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eDBP\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.012\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.014\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e(\u0026minus;\u0026thinsp;0.016, 0.039)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.399\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eMAP\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.010\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.014\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e(\u0026minus;\u0026thinsp;0.018, 0.037)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.504\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eHR\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.005\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.013\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e(\u0026minus;\u0026thinsp;0.020, 0.030)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.694\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eSpO\u003csub\u003e2\u003c/sub\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e\u0026minus;0.189\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.137\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e(\u0026minus;\u0026thinsp;0.458, 0.081)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.170\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003ealdosterone\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.016\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.033\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e(\u0026minus;\u0026thinsp;0.048, 0.080)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.629\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003erenin\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.013\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.006\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e(0.002, 0.024)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.022 *\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eCortisol\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.022\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.033\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e(\u0026minus;\u0026thinsp;0.043, 0.087)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.509\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003ecTnI\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e\u0026minus;232.815\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e160.170\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e(\u0026minus;\u0026thinsp;546.749, 81.119)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.146\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003emyoglobin\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e\u0026minus;0.014\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.013\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e(\u0026minus;\u0026thinsp;0.040, 0.012)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.282\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eCK-MB\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e\u0026minus;0.071\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.450\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e(\u0026minus;\u0026thinsp;0.952, 0.810)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.874\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003epotassium\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.640\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.505\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e(\u0026minus;\u0026thinsp;0.349, 1.629)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.205\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003esodium\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.240\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.102\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e(0.040, 0.440)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.019 *\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003ecalcium\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e2.833\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e1.994\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e(\u0026minus;\u0026thinsp;1.075, 6.742)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.155\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eLDL-C\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e\u0026minus;0.004\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.432\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e(\u0026minus;\u0026thinsp;0.851, 0.843)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.993\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eHDL-C\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e\u0026minus;0.398\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e1.131\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e(\u0026minus;\u0026thinsp;2.615, 1.818)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.725\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eTC\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.003\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.316\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e(\u0026minus;\u0026thinsp;0.617, 0.623)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.993\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003etriglycerides\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e\u0026minus;0.095\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.234\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e(\u0026minus;\u0026thinsp;0.554, 0.363)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.684\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eWBC\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.164\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.109\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e(\u0026minus;\u0026thinsp;0.048, 0.377)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.130\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eRBC\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.462\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.563\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e(\u0026minus;\u0026thinsp;0.641, 1.565)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.412\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eHb\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.012\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.018\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e(\u0026minus;\u0026thinsp;0.024, 0.048)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.506\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003ephosphate\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.766\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e1.038\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e(\u0026minus;\u0026thinsp;1.268, 2.801)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.460\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eACTH\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.009\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.006\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e(\u0026minus;\u0026thinsp;0.002, 0.020)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.097\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\" morerows=\"22\" rowspan=\"23\"\u003e \u003cp\u003eR phase\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eSBP\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e\u0026minus;0.006\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.011\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e(\u0026minus;\u0026thinsp;0.027, 0.014)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.556\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eDBP\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.001\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.013\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e(\u0026minus;\u0026thinsp;0.024, 0.025)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.955\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eMAP\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e\u0026minus;0.003\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.013\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e(\u0026minus;\u0026thinsp;0.028, 0.023)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.836\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eHR\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e\u0026minus;0.013\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.010\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e(\u0026minus;\u0026thinsp;0.033, 0.007)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.198\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eSpO\u003csub\u003e2\u003c/sub\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e\u0026minus;0.028\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.136\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e(\u0026minus;\u0026thinsp;0.295, 0.239)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.838\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003ealdosterone\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e\u0026minus;0.013\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.027\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e(\u0026minus;\u0026thinsp;0.067, 0.041)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.637\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003erenin\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.001\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.005\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e(\u0026minus;\u0026thinsp;0.008, 0.011)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.763\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003ecortisol\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e\u0026minus;0.084\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.034\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e(\u0026minus;\u0026thinsp;0.150, \u0026minus;\u0026thinsp;0.017)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.014 *\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003ecTnI\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e\u0026minus;90.979\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e118.652\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e(\u0026minus;\u0026thinsp;323.537, 141.579)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.443\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003emyoglobin\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.006\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.016\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e(\u0026minus;\u0026thinsp;0.026, 0.038)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.716\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eCK-MB\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e\u0026minus;0.627\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.549\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e(\u0026minus;\u0026thinsp;1.702, 0.448)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.253\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003epotassium\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.049\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.483\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e(\u0026minus;\u0026thinsp;0.898, 0.997)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.919\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003esodium\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.099\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.103\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e(\u0026minus;\u0026thinsp;0.103, 0.300)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.338\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003ecalcium\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.738\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e1.762\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e(\u0026minus;\u0026thinsp;2.716, 4.192)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.675\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eLDL-C\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e\u0026minus;0.420\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.409\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e(\u0026minus;\u0026thinsp;1.221, 0.381)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.304\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eHDL-C\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e1.719\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e1.386\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e(\u0026minus;\u0026thinsp;0.997, 4.435)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.215\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eTC\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e\u0026minus;0.152\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.311\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e(\u0026minus;\u0026thinsp;0.762, 0.457)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.624\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003etriglycerides\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e\u0026minus;0.088\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.448\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e(\u0026minus;\u0026thinsp;0.965, 0.790)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.845\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eWBC\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.133\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.128\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e(\u0026minus;\u0026thinsp;0.118, 0.383)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.299\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eRBC\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e\u0026minus;0.452\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.584\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e(\u0026minus;\u0026thinsp;1.597, 0.693)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.439\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eHb\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e\u0026minus;0.011\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.019\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e(\u0026minus;\u0026thinsp;0.048, 0.025)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.540\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003ephosphate\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e1.757\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e1.249\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e(\u0026minus;\u0026thinsp;0.692, 4.206)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.160\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eACTH\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.009\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.006\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e(\u0026minus;\u0026thinsp;0.004, 0.021)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.165\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eLongitudinal changes in intracranial dural venous sinus metrics during head-down tilt and recovery (n\u0026thinsp;=\u0026thinsp;38)\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"10\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c8\" colnum=\"8\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\"\u0026plusmn;\" class=\"colspec\" colname=\"c9\" colnum=\"9\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c10\" colnum=\"10\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003emetrics\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eBaseline\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eHDT 12h\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eHDT 1d\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eHDT 3d\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e \u003cp\u003eHDT 7d\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c7\"\u003e \u003cp\u003eR 1d\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c8\"\u003e \u003cp\u003eR 3d\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c9\"\u003e \u003cp\u003eR 5d\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c10\"\u003e \u003cp\u003e\u003cem\u003eP\u003c/em\u003e-values\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSSS\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCSA\u003csub\u003emean\u003c/sub\u003e (mm\u003csup\u003e2\u003c/sup\u003e) \u003csup\u003eb\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e42.90(35.48,55.66)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e39.63(32.65,51.39)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e40.31(31.81,56.78)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e37.90\u0026thinsp;\u0026plusmn;\u0026thinsp;12.66\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e36.97\u0026thinsp;\u0026plusmn;\u0026thinsp;13.16\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e39.15\u0026thinsp;\u0026plusmn;\u0026thinsp;13.29\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e43.64\u0026thinsp;\u0026plusmn;\u0026thinsp;13.76\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c9\"\u003e \u003cp\u003e40.71\u0026thinsp;\u0026plusmn;\u0026thinsp;14.00\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e.009\u003csup\u003e*\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eQ\u003csub\u003emean\u003c/sub\u003e (mL/s) \u003csup\u003eb\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e5.60\u0026thinsp;\u0026plusmn;\u0026thinsp;1.24\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e4.82(4.20,5.73)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e5.15\u0026thinsp;\u0026plusmn;\u0026thinsp;1.78\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e4.25(3.26,5.28)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e4.49\u0026thinsp;\u0026plusmn;\u0026thinsp;1.52\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e4.71\u0026thinsp;\u0026plusmn;\u0026thinsp;1.69\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e5.12\u0026thinsp;\u0026plusmn;\u0026thinsp;1.44\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c9\"\u003e \u003cp\u003e4.95\u0026thinsp;\u0026plusmn;\u0026thinsp;1.42\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;.001 \u003csup\u003e*\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePI \u003csup\u003eb\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e0.23\u0026thinsp;\u0026plusmn;\u0026thinsp;0.07\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.19(0.15,0.31)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.20\u0026thinsp;\u0026plusmn;\u0026thinsp;0.06\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.19\u0026thinsp;\u0026plusmn;\u0026thinsp;0.05\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.18\u0026thinsp;\u0026plusmn;\u0026thinsp;0.06\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.16(0.14,0.23)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e0.18\u0026thinsp;\u0026plusmn;\u0026thinsp;0.05\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c9\"\u003e \u003cp\u003e0.18\u0026thinsp;\u0026plusmn;\u0026thinsp;0.05\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e.002 \u003csup\u003e*\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eRI \u003csup\u003eb\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e0.21\u0026thinsp;\u0026plusmn;\u0026thinsp;0.06\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.18(0.14,0.27)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.19\u0026thinsp;\u0026plusmn;\u0026thinsp;0.05\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.17\u0026thinsp;\u0026plusmn;\u0026thinsp;0.04\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.16\u0026thinsp;\u0026plusmn;\u0026thinsp;0.05\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.15(0.13,0.20)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e0.16\u0026thinsp;\u0026plusmn;\u0026thinsp;0.05\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c9\"\u003e \u003cp\u003e0.16\u0026thinsp;\u0026plusmn;\u0026thinsp;0.04\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;.001 \u003csup\u003e*\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003erTS\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCSA\u003csub\u003emean\u003c/sub\u003e (mm\u003csup\u003e2\u003c/sup\u003e) \u003csup\u003eb\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e47.12\u0026thinsp;\u0026plusmn;\u0026thinsp;13.28\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e44.81\u0026thinsp;\u0026plusmn;\u0026thinsp;19.32\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e40.62(30.95,54.54)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e37.60\u0026thinsp;\u0026plusmn;\u0026thinsp;15.46\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e36.77\u0026thinsp;\u0026plusmn;\u0026thinsp;16.30\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e34.96\u0026thinsp;\u0026plusmn;\u0026thinsp;15.98\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e38.23\u0026thinsp;\u0026plusmn;\u0026thinsp;16.94\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c9\"\u003e \u003cp\u003e39.65\u0026thinsp;\u0026plusmn;\u0026thinsp;13.57\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;.001\u003csup\u003e*\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eQ\u003csub\u003emean\u003c/sub\u003e (mL/s) \u003csup\u003eb\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e4.92\u0026thinsp;\u0026plusmn;\u0026thinsp;1.89\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e4.55\u0026thinsp;\u0026plusmn;\u0026thinsp;1.90\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e4.43(3.20,4.95)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e3.90\u0026thinsp;\u0026plusmn;\u0026thinsp;1.64\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e3.89\u0026thinsp;\u0026plusmn;\u0026thinsp;1.59\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e3.80\u0026thinsp;\u0026plusmn;\u0026thinsp;1.77\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e4.30\u0026thinsp;\u0026plusmn;\u0026thinsp;1.86\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c9\"\u003e \u003cp\u003e4.38\u0026thinsp;\u0026plusmn;\u0026thinsp;1.83\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;.001 \u003csup\u003e*\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePI \u003csup\u003eb\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e0.25(0.19,0.29)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.23(0.17,0.35)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.22(0.18,0.26)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.19(0.15,0.24)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.18(0.13,0.22)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.19\u0026thinsp;\u0026plusmn;\u0026thinsp;0.07\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e0.17(0.14,0.23)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c9\"\u003e \u003cp\u003e0.17\u0026thinsp;\u0026plusmn;\u0026thinsp;0.06\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;.001 \u003csup\u003e*\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eRI \u003csup\u003eb\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e0.22(0.17,0.26)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.22\u0026thinsp;\u0026plusmn;\u0026thinsp;0.08\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.20(0.17,0.23)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.17(0.14,0.22)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.17(0.13,0.20)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.17\u0026thinsp;\u0026plusmn;\u0026thinsp;0.05\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e0.16(0.13,0.21)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c9\"\u003e \u003cp\u003e0.15\u0026thinsp;\u0026plusmn;\u0026thinsp;0.05\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;.001 \u003csup\u003e*\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDVO (mL/s) \u003csup\u003eb\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e5.98\u0026thinsp;\u0026plusmn;\u0026thinsp;1.91\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e5.54(4.27,6.58)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e5.37\u0026thinsp;\u0026plusmn;\u0026thinsp;1.98\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e4.90\u0026thinsp;\u0026plusmn;\u0026thinsp;1.67\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e5.01\u0026thinsp;\u0026plusmn;\u0026thinsp;1.62\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e4.96\u0026thinsp;\u0026plusmn;\u0026thinsp;1.87\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e5.49\u0026thinsp;\u0026plusmn;\u0026thinsp;2.08\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c9\"\u003e \u003cp\u003e5.78\u0026thinsp;\u0026plusmn;\u0026thinsp;2.18\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e.002 \u003csup\u003e*\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDVO/ AI \u003csup\u003ea\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e0.43\u0026thinsp;\u0026plusmn;\u0026thinsp;0.12\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.40\u0026thinsp;\u0026plusmn;\u0026thinsp;0.15\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.39\u0026thinsp;\u0026plusmn;\u0026thinsp;0.12\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.39\u0026thinsp;\u0026plusmn;\u0026thinsp;0.14\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.40\u0026thinsp;\u0026plusmn;\u0026thinsp;0.13\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.36\u0026thinsp;\u0026plusmn;\u0026thinsp;0.14\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e0.40\u0026thinsp;\u0026plusmn;\u0026thinsp;0.15\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c9\"\u003e \u003cp\u003e0.43\u0026thinsp;\u0026plusmn;\u0026thinsp;0.15\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e.027 \u003csup\u003e*\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eΔP\u003csub\u003eSSS\u0026ndash;rTS\u003c/sub\u003e (mmHg) \u003csup\u003eb\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e0.26(\u0026minus;\u0026thinsp;0.16,0.61)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.35(\u0026minus;\u0026thinsp;0.17,0.94)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.15(\u0026minus;\u0026thinsp;0.33,0.54)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.12(\u0026minus;\u0026thinsp;0.26,0.56)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.26(\u0026minus;\u0026thinsp;0.43,0.79)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.17(\u0026minus;\u0026thinsp;0.27,0.47)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e0.33(\u0026minus;\u0026thinsp;0.09,0.66)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c9\"\u003e \u003cp\u003e0.10\u0026thinsp;\u0026plusmn;\u0026thinsp;0.77\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e.169\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"10\"\u003eDescriptive statistics and overall time effects of intracranial dural venous sinus metrics measured at eight time points during head-down tilt (HDT) and recovery (R) (n\u0026thinsp;=\u0026thinsp;38). Normally distributed data are expressed as the mean\u0026thinsp;\u0026plusmn;\u0026thinsp;standard deviation (SD), and non-normally distributed data are represented as the median (interquartile range, IQR). SSS\u0026thinsp;=\u0026thinsp;superior sagittal sinus; rTS\u0026thinsp;=\u0026thinsp;representative transverse sinus; CSA\u003csub\u003emean\u003c/sub\u003e = mean cross-sectional area; Q\u003csub\u003emean\u003c/sub\u003e = mean blood flow rate; PI\u0026thinsp;=\u0026thinsp;pulsatility index; RI\u0026thinsp;=\u0026thinsp;resistance index; DVO\u0026thinsp;=\u0026thinsp;dural venous outflow rate (Q\u003csub\u003emean, RTS\u003c/sub\u003e + Q\u003csub\u003emean, LTS\u003c/sub\u003e); AI\u0026thinsp;=\u0026thinsp;arterial inflow rate (sum of mean blood flow rates in the bilateral internal carotid arteries and the basilar artery); ΔP\u003csub\u003eSSS\u0026ndash;rTS\u003c/sub\u003e = relative pressure between the SSS ROI and rTS ROI. Baseline indicates pre-HDT measurement. Statistical significance is noted with \u003csup\u003e*\u003c/sup\u003e (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.05). The \u003csup\u003ea\u003c/sup\u003e represents the use of repeated measures analysis of variance (RM-ANOVA); the \u003csup\u003eb\u003c/sup\u003e represents the use of Friedman test.\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eLinear mixed-effects models were fitted separately for each physiological/biochemical variable within each phase, with dural venous outflow rate (DVO) as the dependent variable and a subject-specific random intercept to account for repeated measures. Reported values are the fixed-effect estimate (\u003cem\u003eβ\u003c/em\u003e), standard error (SE), and the corresponding 95% confidence interval (95% CI) for the predictor effect, together with two-sided \u003cem\u003eP\u003c/em\u003e-values based on Wald tests. Significant associations are marked with an asterisk (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.05). DVO\u0026thinsp;=\u0026thinsp;dural venous outflow rate; HDT\u0026thinsp;=\u0026thinsp;head-down tilt; R\u0026thinsp;=\u0026thinsp;recovery; SBP\u0026thinsp;=\u0026thinsp;systolic blood pressure; DBP\u0026thinsp;=\u0026thinsp;diastolic blood pressure; MAP\u0026thinsp;=\u0026thinsp;mean arterial pressure; HR\u0026thinsp;=\u0026thinsp;heart rate; SpO₂ = peripheral oxygen saturation; cTnI\u0026thinsp;=\u0026thinsp;cardiac troponin I; CK-MB\u0026thinsp;=\u0026thinsp;creatine kinase-MB; LDL-C\u0026thinsp;=\u0026thinsp;low-density lipoprotein cholesterol; HDL-C\u0026thinsp;=\u0026thinsp;high-density lipoprotein cholesterol; TC\u0026thinsp;=\u0026thinsp;total cholesterol; WBC\u0026thinsp;=\u0026thinsp;white blood cell count; RBC\u0026thinsp;=\u0026thinsp;red blood cell count; Hb\u0026thinsp;=\u0026thinsp;hemoglobin; ACTH\u0026thinsp;=\u0026thinsp;adrenocorticotropic hormone.\u003c/p\u003e \u003c/div\u003e"},{"header":"4 Discussion","content":"\u003cp\u003eSpaceflight and ground-based analog studies indicate that cephalad fluid shift can disturb intracranial fluid homeostasis and may contribute to the development and progression of SANS[\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e, \u003cspan additionalcitationids=\"CR29\" citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e]. In-flight investigations have highlighted the importance of impaired head and neck venous drainage, including internal jugular vein flow stasis or retrograde flow and a potential increase in thrombosis risk. This supports venous congestion as a key component of spaceflight physiology[\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e, \u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e]. In parallel, multiple HDT studies have reported changes in cerebral arterial inflow and CSF dynamics, underscoring that venous outflow should be interpreted within an integrated intracranial fluid system rather than as an isolated part[\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e, \u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e]. Building on this framework, our study further provides evidence at the level of intracranial dural venous sinuses that short-term HDT exposure and subsequent recovery are accompanied by quantifiable morphological and hemodynamic remodeling. In our post-hoc comparisons, venous flow metrics (Q\u003csub\u003emean\u003c/sub\u003e in the SSS and rTS, as well as DVO) showed significant reductions by HDT 3d, whereas significant decreases in CSA\u003csub\u003emean\u003c/sub\u003e were primarily observed at HDT 7d.\u003c/p\u003e \u003cp\u003eThe aforementioned difference suggests that early changes may be dominated by functional adaptation, such as redistribution of venous drainage and changes in the transmural pressure environment, while more readily detectable geometric changes become apparent later. This is consistent with previous microgravity studies. A phase-contrast MRI study demonstrated that internal jugular vein velocity decreased and total jugular venous outflow was significantly reduced after 4.5 h of \u0026minus;\u0026thinsp;12\u0026deg; HDT compared with baseline[\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]. Meanwhile, Nimpal et al. conducted a\u0026thinsp;~\u0026thinsp;2-h\u0026thinsp;\u0026minus;\u0026thinsp;10\u0026deg; HDT study and found no group-level volumetric change in major dural sinus masks. They further noted that measurable sinus enlargement is unlikely in an acute setting, whereas dural sinus expansion has been documented after weeks of microgravity exposure, particularly among astronauts who develop SANS[\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e, \u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e]. Accordingly, flow measures may serve as earlier and potentially more sensitive metrics of venous adaptation related to HDT.\u003c/p\u003e \u003cp\u003eDuring HDT, we observed reduced dural venous flow rate accompanied by decreased cross-sectional area and reductions in indicators of pulsatility and resistance, whereas the ΔP\u003csub\u003eSSS\u0026ndash;rTS\u003c/sub\u003e did not change significantly. The findings suggest that the observed changes may not be primarily attributable to a significant increase in local resistance at the measured segment, but may instead reflect system level regulation, including redistribution of venous return pathways such as through bypass drainage via the vertebral venous plexus, changes in downstream drainage conditions, or shifts in intracranial and extracranial pressure environments that modify overall compliance[\u003cspan additionalcitationids=\"CR35 CR36\" citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e]. In astronauts, MRV studies have reported increased dural venous sinus volume in individuals with SANS after spaceflight, commonly interpreted as reflecting abnormal venous compliance or susceptibility to venous congestion[\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]. Differences between those in-flight observations and our findings may relate to exposure duration and cumulative adaptation, the use of a healthy cohort undergoing short-term HDT without SANS clinical endpoints, and the distinct dimensions captured by MRV-derived sinus volume versus localized segmental cross-sectional area. Importantly, dural sinus caliber is highly sensitive to subtle changes in transmural pressure, surrounding tissue and ICP. Therefore, a smaller caliber does not imply fixed stenosis and may instead represent reversible extrinsic compression or compliance-related adaptation associated with reduced transmural pressure[\u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e, \u003cspan citationid=\"CR38\" class=\"CitationRef\"\u003e38\u003c/span\u003e]. Future studies integrating 4D Flow MRI with direct ICP measurement, together with CSF dynamics and ocular endpoints, will be critical to more tightly link venous sinus changes to mechanistic outcomes[\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eBecause venous return is highly posture dependent and strongly influenced by central blood volume regulation, DVO may better capture system-level intracranial hemodynamic status than any single-segment metric[\u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e, \u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e]. The reduction in DVO during HDT that persisted into early recovery, suggests that venous adaptation and recovery may lag behind postural change[\u003cspan citationid=\"CR39\" class=\"CitationRef\"\u003e39\u003c/span\u003e, \u003cspan citationid=\"CR40\" class=\"CitationRef\"\u003e40\u003c/span\u003e]. Due to the predominant role of the internal jugular vein in venous return during supine positioning and the increased contribution of the vertebral venous system during upright positioning, HDT and the readaptation phase may trigger redistribution of return pathways and alterations in downstream conditions, thereby causing a transient reduction in DVO. The Monro-Kellie doctrine further emphasizes that intracranial blood volume is highly dynamic and that even transient mismatches between arterial inflow and venous outflow can rapidly alter intracranial blood volume distribution and the pressure environment, positioning venous pathways as important determinants of intracranial compliance[\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]. The transient decrease in the early recovery phase followed by a rebound in DVO/ AI may reflect the faster arterial recovery relative to venous recovery, potentially associated with reduced orthostatic tolerance and autonomic regulation following HDT[\u003cspan citationid=\"CR40\" class=\"CitationRef\"\u003e40\u003c/span\u003e, \u003cspan citationid=\"CR41\" class=\"CitationRef\"\u003e41\u003c/span\u003e]. Together with in-flight evidence of abnormal head and neck venous drainage and venous sinus structural changes related to SANS, these findings support DVO and DVO/ AI as candidate imaging markers of intracranial hemodynamic balance under cephalad fluid shift, which we plan to further integrate comprehensive analysis of the arterial-venous system and microcirculation.\u003c/p\u003e \u003cp\u003eWe also found that baseline renin and sodium were positively associated with DVO during HDT, whereas baseline cortisol was negatively associated with DVO during recovery. This pattern suggests that differences across participants in venous outflow rate during HDT may be more closely related to volume regulation mediated by the renin\u0026ndash;angiotensin\u0026ndash;aldosterone system (RAAS)[\u003cspan citationid=\"CR42\" class=\"CitationRef\"\u003e42\u003c/span\u003e]. Prior studies have demonstrated that the RAAS plays a pivotal role in cephalad fluid shift, early diuresis, and plasma volume reduction during HDT, which also leads to a new steady state within days[\u003cspan citationid=\"CR43\" class=\"CitationRef\"\u003e43\u003c/span\u003e]. This may affect the filling state and return distribution of the venous system, manifesting as DVO differences. In contrast, the recovery phase represents a readaptation after postural restoration. Cortisol can increase vascular responsiveness to catecholamines and alter vascular reactivity[\u003cspan citationid=\"CR44\" class=\"CitationRef\"\u003e44\u003c/span\u003e]. The longer-duration HDT studies suggest that cortisol rhythmicity may be more active during recovery[\u003cspan citationid=\"CR45\" class=\"CitationRef\"\u003e45\u003c/span\u003e, \u003cspan citationid=\"CR46\" class=\"CitationRef\"\u003e46\u003c/span\u003e]. These mechanisms may help explain why higher baseline cortisol was associated with slower early recovery of DVO. Nevertheless, given the large number of biomarkers screened, these associations should be considered exploratory rather than causal. If replicated, such baseline factors may help explain inter-individual heterogeneity in venous adaptation and provide clues for research on individualized countermeasures targeting fluid-electrolyte regulation or neuroendocrine stress responses.\u003c/p\u003e \u003cp\u003eSeveral limitations should be noted. First, the cohort comprised healthy adult men, limiting generalizability across sex and age. Second, constrained by imaging resolution and coverage, we focused primarily on larger dural venous sinuses and did not systematically assess smaller venous pathways or extracranial drainage routes. Third, although defining DVO as the sum of mean blood flow rates in the bilateral transverse sinuses captures changes in the primary outflow pathways, it does not fully represent total cranial venous outflow. Fourth, despite incorporating arterial metrics for coupling analyses, there remains a lack of concurrent evidence linking cerebral microperfusion, CSF dynamics, and ocular endpoints.\u003c/p\u003e"},{"header":"5 Conclusions","content":"\u003cp\u003eIn this prospective 7-day\u0026thinsp;\u0026minus;\u0026thinsp;6\u0026deg; head-down tilt (HDT) study using longitudinal 4D Flow MRI, major intracranial dural venous sinuses exhibited time-dependent hemodynamic and morphometric remodeling under simulated microgravity. Venous flow reductions were evident by HDT day 3, whereas measurable caliber reductions were most prominent by HDT day 7. Dural venous outflow rate (DVO) remained depressed into early recovery, accompanied by a transient reduction in venous\u0026ndash;arterial coupling that subsequently rebounded. Mixed-effects analyses further suggested that higher baseline renin and sodium were associated with increased DVO during HDT, whereas higher baseline cortisol was inversely associated with DVO during recovery. Taken together, these findings support the concept that the dural venous sinuses acts as dynamic components of intracranial fluid regulation under sustained cephalad fluid shift and identify DVO and venous-arterial flow rate ratio (DVO/ AI) as potential imaging markers for monitoring adaptation and recovery in the context of spaceflight-associated neuro-ocular syndrome research.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cp\u003eACTH: adrenocorticotropic hormone\u003c/p\u003e\n\u003cp\u003eAI: arterial inflow rate\u003c/p\u003e\n\u003cp\u003eBMI: body mass index\u003c/p\u003e\n\u003cp\u003eCK-MB: creatine kinase-MB\u003c/p\u003e\n\u003cp\u003eCSF: cerebrospinal fluid\u003c/p\u003e\n\u003cp\u003eCSA\u003csub\u003emean\u003c/sub\u003e: mean cross-sectional area\u003c/p\u003e\n\u003cp\u003ecTnI: cardiac troponin I\u003c/p\u003e\n\u003cp\u003eDVO: dural venous outflow rate\u003c/p\u003e\n\u003cp\u003eDVO/ AI: venous-arterial flow rate ratio\u003c/p\u003e\n\u003cp\u003eDBP: diastolic blood pressure\u003c/p\u003e\n\u003cp\u003eFOV: field of view\u003c/p\u003e\n\u003cp\u003eHDT: head-down tilt\u003c/p\u003e\n\u003cp\u003eHb: hemoglobin\u003c/p\u003e\n\u003cp\u003eHDL-C: high-density lipoprotein cholesterol\u003c/p\u003e\n\u003cp\u003eHIV: human immunodeficiency virus\u003c/p\u003e\n\u003cp\u003eHR: heart rate\u003c/p\u003e\n\u003cp\u003eICC: intraclass correlation coefficient\u003c/p\u003e\n\u003cp\u003eICP: intracranial pressure\u003c/p\u003e\n\u003cp\u003eIQR: interquartile range\u003c/p\u003e\n\u003cp\u003eLDL-C: low-density lipoprotein cholesterol\u003c/p\u003e\n\u003cp\u003eLTS: left transverse sinus\u003c/p\u003e\n\u003cp\u003eLVEF: left ventricular ejection fraction\u003c/p\u003e\n\u003cp\u003eMAP: mean arterial pressure\u003c/p\u003e\n\u003cp\u003eMRA: magnetic resonance angiography\u003c/p\u003e\n\u003cp\u003eMRI: magnetic resonance imaging\u003c/p\u003e\n\u003cp\u003eMRV: magnetic resonance venography\u003c/p\u003e\n\u003cp\u003eOC: offset correction\u003c/p\u003e\n\u003cp\u003ePI: pulsatility index\u003c/p\u003e\n\u003cp\u003eQ\u003csub\u003emean\u003c/sub\u003e: mean blood flow rate\u003c/p\u003e\n\u003cp\u003eQ\u003csub\u003emax\u003c/sub\u003e: maximum blood flow rate\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eQ\u003csub\u003emin\u003c/sub\u003e: minimum blood flow rate\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eR: recovery\u003c/p\u003e\n\u003cp\u003eRAAS: renin\u0026ndash;angiotensin\u0026ndash;aldosterone system\u003c/p\u003e\n\u003cp\u003eRBC: red blood cell count\u003c/p\u003e\n\u003cp\u003eRI: resistance index\u003c/p\u003e\n\u003cp\u003eROI: region of interest\u003c/p\u003e\n\u003cp\u003erTS: representative transverse sinus\u003c/p\u003e\n\u003cp\u003eRTS: right transverse sinus\u003c/p\u003e\n\u003cp\u003eSANS: spaceflight-associated neuro-ocular syndrome\u003c/p\u003e\n\u003cp\u003eSBP: systolic blood pressure\u003c/p\u003e\n\u003cp\u003eSD: standard deviation\u003c/p\u003e\n\u003cp\u003eSE: standard error\u003c/p\u003e\n\u003cp\u003eSpO₂: peripheral oxygen saturation\u003c/p\u003e\n\u003cp\u003eSSS: superior sagittal sinus\u003c/p\u003e\n\u003cp\u003eTC: total cholesterol\u003c/p\u003e\n\u003cp\u003eTE: echo time\u003c/p\u003e\n\u003cp\u003eTR: repetition time\u003c/p\u003e\n\u003cp\u003eTS: transverse sinus\u003c/p\u003e\n\u003cp\u003eVENC: velocity encoding\u003c/p\u003e\n\u003cp\u003eWBC: white blood cell count\u003c/p\u003e\n\u003cp\u003e\u0026Delta;P\u003csub\u003eSSS\u003c/sub\u003e\u003csub\u003e\u0026ndash;\u003c/sub\u003e\u003csub\u003erTS\u003c/sub\u003e: relative pressure difference between the superior sagittal sinus ROI and representative transverse sinus ROI\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll participants provided written informed consent prior to enrollment. The study protocol was approved by the Research Ethics Committee of Beijing Friendship Hospital, Capital Medical University (approval number: 2024-P2-069-04) and complied with the Declaration of Helsinki. The trial was registered in the Chinese Clinical Trial Registry (ChiCTR2500096128; registration date: January 17, 2025).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and materials\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe data supporting the findings of this study are available from the corresponding authors upon request.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThere are no competing interests in this study.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study was supported by the Space Medical Experiment Project of China Manned Space Program (No. HYZHXMH01005), Beijing Hospitals Authority Innovation Studio of Young Staff Funding Support (No.202302) and Beijing Scholar 2015.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors\u0026rsquo; Contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eZXW was responsible for experiment execution, data analysis, and manuscript drafting. HRH provided substantial guidance in manuscript preparation and data analysis, and supervised data quality control. HRH, YH, FRG, and SQH participated in MRI scanning and data acquisition. YWL and RW contributed to critical guidance on data analysis. Jumatay Biekan, as a CVI 42 software engineer, provided technical support for software-based flow analysis. PFZ, PLR, and ZCW as corresponding authors, contributed to study conception and design, overall supervision, and critical revision of the manuscript. All authors read and approved the final manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgements\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors would like to thank the medical staff of Beijing Friendship Hospital, Capital Medical University, for their support and assistance in this study. We would like to express our sincere gratitude to Dr. Yu Tian for his invaluable support and guidance throughout this experiment. We are also grateful to all the volunteers who generously participated in the research. In addition, we appreciate the technical assistance provided by the CVI 42 software team.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eSeidler RD, Mao XW, Tays GD, Wang T, Zu Eulenburg P. Effects of spaceflight on the brain. Lancet Neurol. 2024;23(8):826\u0026ndash;35. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1016/S1474-4422\u003c/span\u003e\u003cspan address=\"10.1016/S1474-4422\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e. )00224-2 PubMed PMID: 38945144.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKramer LA, Hasan KM, Stenger MB, Sargsyan A, Laurie SS, Otto C, et al. Intracranial Effects of Microgravity: A Prospective Longitudinal MRI Study. 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PLoS ONE. 2012;7(10):e47984. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1371/journal.pone.0047984\u003c/span\u003e\u003cspan address=\"10.1371/journal.pone.0047984\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"fluids-and-barriers-of-the-cns","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"fbcn","sideBox":"Learn more about [Fluids and Barriers of the CNS](http://fluidsbarrierscns.biomedcentral.com/)","snPcode":"12987","submissionUrl":"https://submission.nature.com/new-submission/12987/3","title":"Fluids and Barriers of the CNS","twitterHandle":"@BioMedCentral","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"4D Flow MRI, Dural venous sinuses, Head-down tilt, Simulated microgravity","lastPublishedDoi":"10.21203/rs.3.rs-9064673/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-9064673/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e \u003cp\u003eCephalad fluid shift during microgravity may disrupt intracranial fluid homeostasis and contribute to spaceflight-associated neuro-ocular syndrome (SANS). However, longitudinal quantitative data characterizing intracranial dural venous sinus adaptation to these fluid shifts remain limited.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e \u003cp\u003eWe conducted a prospective cohort study of 38 healthy adult men undergoing 7-day\u0026thinsp;\u0026minus;\u0026thinsp;6\u0026deg; head-down tilt (HDT) followed by 5-day recovery. 4D Flow MRI was acquired at eight time points (Baseline, HDT 12 h, HDT 1 d, HDT 3 d, HDT 7 d, Recovery (R) 1 d, R 3 d, and R 5 d). Hemodynamic and morphometric metrics were quantified in the superior sagittal sinus and the transverse sinuses. Time effects were tested using repeated-measures ANOVA or Friedman tests with post-hoc comparisons corrected for multiple testing. Linear mixed-effects models evaluated associations between dural venous outflow rate (DVO) and baseline physiological and biochemical variables within HDT and recovery phases.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e \u003cp\u003eVenous sinuses hemodynamics and morphology changed significantly over time. Mean blood flow rate in both the superior sagittal sinus and representative transverse sinus decreased by HDT 3d and remained below baseline into recovery, while mean cross-sectional area of aforementioned sinuses showed significant reductions most clearly by HDT 7d. Indices reflecting pulsatility and resistance decreased later in HDT and persisted into recovery. DVO declined significantly by HDT 3d and remained reduced at R 1d. Arterial inflow rate (AI) progressively declined during HDT and rebounded rapidly at the onset of recovery. DVO/ AI was significantly reduced at R 1d and increased by R 5d. Inter-sinus relative pressure difference showed no significant time effect. Baseline renin (\u003cem\u003eβ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.013, 95% CI: 0.002 to 0.024; \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.022) and sodium (\u003cem\u003eβ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.240, 95% CI: 0.040 to 0.440; \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.019) were positively associated with DVO during HDT, whereas baseline cortisol was negatively associated with DVO during recovery (\u003cem\u003eβ\u003c/em\u003e=\u0026minus;0.084, 95% CI: \u0026minus;0.150 to \u0026minus;\u0026thinsp;0.017; \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.014).\u003c/p\u003e\u003ch2\u003eConclusions\u003c/h2\u003e \u003cp\u003eShort-term\u0026thinsp;\u0026minus;\u0026thinsp;6\u0026deg; HDT induces time-dependent remodeling of intracranial dural venous sinus flow and geometry, with early functional changes preceding later caliber changes and a transient impairment in venous-arterial coupling during early recovery. These findings support DVO and DVO/ AI as potential imaging markers relevant to SANS research.\u003c/p\u003e\u003ch2\u003eTrial registration\u003c/h2\u003e \u003cp\u003eChiCTR2500096128 Registration date January 17, 2025\u003c/p\u003e","manuscriptTitle":"Hemodynamic and morphologic adaptations of the Dural venous sinus to 7-day −6° head-down tilt and recovery: an eight-timepoint 4D flow MRI longitudinal study","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2026-04-19 08:06:30","doi":"10.21203/rs.3.rs-9064673/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2026-05-04T20:24:41+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-05-04T19:45:45+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-04-29T13:55:49+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-04-27T22:02:47+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-04-23T07:00:29+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"30130241068701932826510083244403668267","date":"2026-04-16T19:04:58+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"47998538266950495628624446699815300562","date":"2026-04-16T13:15:22+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"72503630862831656343578169118403363908","date":"2026-04-14T07:03:38+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"27612557891816349408558507427884600076","date":"2026-04-13T21:55:19+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2026-04-08T18:21:09+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2026-03-15T05:39:52+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2026-03-10T09:03:14+00:00","index":"","fulltext":""},{"type":"submitted","content":"Fluids and Barriers of the CNS","date":"2026-03-08T13:49:07+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"fluids-and-barriers-of-the-cns","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"fbcn","sideBox":"Learn more about [Fluids and Barriers of the CNS](http://fluidsbarrierscns.biomedcentral.com/)","snPcode":"12987","submissionUrl":"https://submission.nature.com/new-submission/12987/3","title":"Fluids and Barriers of the CNS","twitterHandle":"@BioMedCentral","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"4fbd1e6d-2ee5-41c7-a630-b32bfeb83d61","owner":[],"postedDate":"April 19th, 2026","published":true,"recentEditorialEvents":[{"type":"decision","content":"Revision requested","date":"2026-05-04T20:24:41+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-05-04T19:45:45+00:00","index":37,"fulltext":""}],"rejectedJournal":[],"revision":"","amendment":"","status":"in-revision","subjectAreas":[],"tags":[],"updatedAt":"2026-05-04T20:39:34+00:00","versionOfRecord":[],"versionCreatedAt":"2026-04-19 08:06:30","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-9064673","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-9064673","identity":"rs-9064673","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}