Head-down tilt bed rest (HDTBR) is a ground-based analog model for studying the pathophysiology of Spaceflight Associated Neuro-Ocular Syndrome (SANS).
SANS is a syndrome caused by a cephalad fluid shift during spaceflight. Main findings include optic disc edema, globe flattening, hyperopic shift, and choroidal congestion, with some findings observed in approximately 70% of astronauts. It was previously called Visual Impairment and Intracranial Pressure (VIIP) syndrome 1).
Since 1990, HDTBR has been an internationally established ground-based analog involving sustained bed rest with a 6-degree head-down tilt. Parabolic flights have short exposure times and are insufficient to induce SANS-like symptoms, so HDTBR, which can reproduce sustained fluid shifts, is emphasized 1).
Early 70-day HDTBR studies did not induce SANS findings. It was thought that the use of pillows or forearm support might have lowered intracranial pressure (ICP). Subsequently, by adopting a strict protocol prohibiting pillows and arm support, they succeeded in inducing choroidal folds and optic disc edema 1).
In short-term missions (less than 6 months), 29% of astronauts, and in long-term missions (6 months or more), 60% report decreased visual acuity due to hyperopia1).
QWhy is HDTBR set at a 6-degree angle?
A
Since 1990, a 6-degree head-down tilt has been established as the international standard analog for microgravity. This angle continuously induces a headward fluid shift similar to that in spaceflight.
Headache: In the early stages of research, pulsating, pressing, bilateral headaches appear. This is thought to be due to headward fluid shift.
Minimal impact on visual function: The experimental conditions do not significantly affect participants’ visual function. No subjects experienced severe visual abnormalities.
Slight myopic shift: Transient myopia may occur due to sustained near-work activities.
Cognitive changes (in SANS-affected individuals): In the hypercapnic HDTBR study, SANS-affected individuals showed increased reliance on visual cues in cognitive tests1).
QCan vision decrease in HDTBR?
A
Both visual acuity and refraction tests remain within normal limits. No significant changes have been observed in Amsler chart, red dot test, confrontation visual field, or color vision tests. No subjects have reported severe visual abnormalities.
The main findings of ocular changes observed in HDTBR are shown below.
RNFL thickening: After 14 days of HDTBR, the average peripapillary retinal thickness increases by +4.69 μm, and after 70 days of HDTBR, it increases by an average of +11.50 μm1).
Optic disc edema: After strict 30-day HDTBR, Frisén grade 1–2 disc edema was observed in 45% of subjects1). Subjects undergoing 30-day HDTBR tend to exhibit more severe optic disc edema than astronauts.
Peripapillary TRT increase: Strict HDTBR subjects show a greater peripapillary TRT increase than astronauts (mean difference 37 μm)1).
Choroidal folds: May occur despite no increase in choroidal thickness.
Choroidal thickness changes: A statistically significant increase is observed in short-term 3-day studies. An increase in subfoveal choroidal thickness has been confirmed after 60 minutes of HDT1). On the other hand, astronauts show a greater increase in choroidal thickness than HDTBR subjects (mean difference 27 μm)1).
Optic nerve sheath dilation: Confirmed by orbital ultrasound at 60 minutes HDT, similar to findings in astronauts after one month of flight 1).
Increased intraocular pressure: Increases by +1.42 mmHg over 14 days and +1.79 mmHg over 70 days, but both remain within normal range.
Findings not observed in HDTBR include globe flattening, hyperopic shift, and cotton wool spots1). Visual acuity, refraction, axial length, anterior chamber depth, and corneal curvature also show no significant changes.
The following table compares the main findings of HDTBR and SANS (spaceflight).
The basic mechanism of HDTBR is a cephalad fluid shift due to the change in the direction of the gravity vector acting on the body. This induces fluid distribution changes similar to those in microgravity.
Contributing factors include pressure differences across the lamina cribrosa, choroidal congestion, intracranial volume shift, orientation of collagen fiber bundles, and hydrostatic fluid distribution.
The main risk factors are as follows.
HDTBR duration: This is the greatest risk factor. A 70-day HDTBR shows approximately 2.5 times more pronounced peripapillary retinal thickness increase compared to 14 days.
Myopia: Moderately myopic individuals show higher peak intraocular pressure (19.8 mmHg vs. 18.6–18.7 mmHg) and significantly greater intraocular pressure elevation compared to emmetropic or mildly myopic individuals1).
Genetic predisposition: Carriers of the MTRR 66G and SHMT1 1420 C alleles have been reported to have a greater degree of optic disc edema1). These are genetic polymorphisms involved in vitamin B metabolism.
Anatomical features of the optic disc: A crowded optic disc with a small optic cup may be a risk factor.
Previous HDTBR exposure history: Subjects who participated multiple times have been reported to have a TRT increase of more than twice the previous value, suggesting that repeated exposure may increase risk.
QOnce you have experienced HDTBR, does the risk increase for the next time?
A
In subjects who participated in multiple HDTBR experiments, a TRT increase of more than twice the previous value has been reported. Repeated exposure may increase the risk, and this should be considered when selecting study participants.
The main examination methods used to evaluate and monitor ocular changes observed in HDTBR are shown below.
OCT (Optical Coherence Tomography): Can quantitatively evaluate RNFL thickening, optic disc edema, and choroidal thickness changes. Changes in Bruch’s membrane can also be observed. Heidelberg Spectralis (OCT2) provides higher digital resolution.
OCTA (OCT Angiography): A non-invasive three-dimensional angiography method introduced to the ISS in December 2018. It can evaluate retinal and choroidal vascular changes1).
MRI: Can quantify optic nerve sheath dilation, optic nerve tortuosity, and changes in vitreous chamber depth. Phase-contrast MRI enables measurement of blood flow, cross-sectional area, and flow velocity in the internal jugular vein, vertebral artery, and internal carotid artery.
Orbital ultrasound: A simple method to detect dilation of the optic nerve sheath diameter1).
Noninvasive ICP measurement (research stage): Lumbar puncture for direct ICP measurement is invasive and impossible during flight. Phase changes in distortion product otoacoustic emissions (DPOAE) are being studied as a candidate for noninvasive ICP monitoring1). Ocular vestibular evoked myogenic potentials (oVEMP) are also under investigation as a noninvasive ICP monitoring tool because they correlate with head-down tilt angle1).
Genetic and blood tests: Measurement of vitamin B levels and SNPs (MTRR 66G, SHMT1 1420C) are used for risk factor assessment.
Basic ophthalmic examinations (visual acuity, cycloplegic refraction, fundus, Amsler chart, color vision, etc.) all remain within normal limits.
HDTBR is an experimental model and is not a “treatment” in the usual sense. The following shows research results on countermeasures against SANS.
LBNP
Lower Body Negative Pressure (LBNP): A non-invasive device that applies negative pressure to the lower body to draw fluid back to the periphery.
Evidence: -20 mmHg LBNP suppressed optic nerve sheath diameter increase and attenuated choroidal expansion by 40% during 3-day HDTBR1). Suppression of CSF volume increase during 5-hour HDTBR was also demonstrated1).
Assessment: Currently considered the most promising countermeasure.
Thigh Cuff
Venous constrictive thigh cuffs (VTC): Reduced cardiac preload and jugular vein distension have been reported in ISS crew members. They decrease stroke volume, internal jugular vein cross-sectional area, and intraocular pressure.
Limitations: No direct effect on CSF distribution or ICP. In 15-degree HDT with 60 mmHg thigh cuffs for 10 minutes, no significant differences were found in peripapillary choroidal thickness or optic nerve sheath diameter 1).
Artificial Gravity
Artificial gravity via centrifuge: Daily 30-minute centrifuge exposure.
Limitations: 30-minute exposure was insufficient to suppress choroidal folds and optic disc edema. Possible causes include limited exposure duration, insufficient G-force at eye level, and involvement of different underlying mechanisms 1).
In a study that performed NASA’s iRAT protocol (Integrated Resistance and Aerobic Training) during 70 days of non-hypercapnic HDTBR, no significant differences in retinal thickness changes or optic disc edema were found between the exercise group and the control group 1). However, a slightly higher intraocular pressure (less than 1 mmHg) was observed in the exercise group. Short-duration moderate aerobic, resistance, and high-intensity interval exercise have been shown to be associated with reduced intraocular pressure1).
QWhy is lower body negative pressure (LBNP) considered a promising countermeasure?
A
LBNP at -20 mmHg has been reported to suppress optic nerve sheath diameter increase, attenuate choroidal expansion by 40% during 3-day HDTBR, and suppress CSF volume increase 1). The mechanism of directly inhibiting headward fluid shifts by pulling fluid back to the periphery is considered superior to other countermeasures.
Limitations: Post-flight lumbar puncture shows only normal to mildly elevated pressure (21–28.5 cm H₂O). Typical IIH symptoms (headache, pulsatile tinnitus) are absent. Papilledema persists for 6 months after flight, whereas in IIH it resolves quickly with pressure reduction. Increased ICP alone cannot explain the findings.
CSF Compartmentalization Hypothesis
Mechanism: Under microgravity, CSF pressure within the optic nerve sheath rises locally due to a one-way valve mechanism. Pressure equilibration with the cranial subarachnoid space is incomplete.
Significance: Explains why papilledema persists despite normal to mildly elevated ICP.
Brain Upward Shift Hypothesis
Mechanism: In microgravity, the brain rotates slightly and shifts upward, pulling the optic chiasm upward and causing compression of the optic nerve sheath.
Evidence: MRI has confirmed an increase in optic nerve length (0.80 ± 0.74 mm) after spaceflight1).
There are several important differences between HDTBR and spaceflight.
Degree of choroidal expansion: In HDTBR, choroidal expansion does not occur to the same extent as during spaceflight, because vertical gravitational force (Gz) still exists, generating tissue weight.
Mechanism of choroidal folds: In HDTBR, choroidal folds can occur without an increase in choroidal thickness, suggesting that choroidal thickening may not be a necessary condition for folds.
Intraocular pressure changes: In HDTBR, there is no decrease in intraocular pressure, so the mechanism of choroidal retinal fold formation due to the combination of decreased intraocular pressure and increased ICP does not apply.
Degree of ICP elevation: HDTBR subjects may experience slightly greater ICP than astronauts, which may contribute to differences in the severity of optic disc edema.
According to a review by Ong et al. (2021), cerebral perfusion decreases in all subjects during HDTBR. However, those who developed SANS symptoms maintained higher perfusion than those who did not 1).
No significant changes in cerebrovascular reactivity or hypercapnic ventilatory response were observed under hypercapnic conditions (approximately 4 mmHg PCO₂) 1).
Introduction of OCTA on the ISS (December 2018): By comparing retinal vascular data during spaceflight with HDTBR results, it is expected to deepen understanding of the effects of fluid shifts on retinal and choroidal circulation1).
Development of non-invasive ICP measurement methods: Phase changes in otoacoustic emissions (OAE) are being studied as candidates for ICP monitoring on the ISS, with testing underway in HDTBR1). oVEMP is also considered promising as a non-invasive ICP monitoring tool due to its association with head-down tilt angle1).
Response to the era of commercial space travel: With the rise of private space companies such as SpaceX and Blue Origin, short-term HDTBR may be applicable for screening the general public’s susceptibility to cephalad fluid shifts1).
Genetic screening: MTRR and SHMT1 polymorphisms have been identified as risk factors, and research is ongoing into whether HDTBR can be used for genetic screening of astronaut candidates1).
Unverified countermeasures: Many countermeasures, such as dietary therapy, vitamin supplementation, topical medications, and oral medications, remain unverified1).
Challenges for manned Mars missions: For Mars missions lasting 1 to 3 years, there is an urgent need to elucidate the pathophysiology of SANS, identify risk factors, and develop countermeasures1).
HDTBR as a ground analog has the following limitations1): small sample size, difficulty in recruiting subjects, differences in physical fitness compared to astronauts, lack of protocol standardization, and conditions that do not match spaceflight, such as back contact.
Ong J, Lee AG, Moss HE. Head-Down Tilt Bed Rest Studies as a Terrestrial Analog for Spaceflight Associated Neuro-Ocular Syndrome. Front Neurol. 2021;12:648958.
Taibbi G, Cromwell RL, Zanello SB, Yarbough PO, Ploutz-Snyder RJ, Godley BF, et al. Ocular Outcomes Comparison Between 14- and 70-Day Head-Down-Tilt Bed Rest. Invest Ophthalmol Vis Sci. 2016;57(2):495-501. PMID: 26868753.
He Y, Karanjia R, Zhang X, Wanderer D, Walker E, Lee SH, et al. Optic Nerve Vasculature and Countermeasure Assessment in a Bedrest Analogue of Spaceflight-Associated Neuro-Ocular Syndrome. Am J Ophthalmol. 2025;278:317-327. PMID: 40545016.
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