Ocular Changes with Head-Down Tilt Bed Rest
Head-Down Tilt Bed Rest (HDTBR) is a spaceflight analog used to further investigate the pathophysiology of Spaceflight associated Neuro-Ocular Syndrome (SANS) – formally called visual impairment and intracranial pressure (VIIP) syndrome. During spaceflight, crewmembers experience cephalad fluid shifts that may contribute to optic disc edema, globe flattening, hyperopic shift, and choroidal engorgement – hallmark findings of SANS in approximately 70% of astronauts. Due to high costs of microgravity (e.g., International Space Station) research and limited sample size of humans embarking on spaceflight missions, HDTBR is a common terrestrial SANS analog utilized as a model for studying the physiological changes occurring in weightlessness during spaceflight as well as testing potential countermeasures and treatments.
Since 1990, 6-degree HDT has been effectively established as the internationally-preferred terrestrial analog for weightlessness, allowing for SANS research with larger sample sizes, greater data parameters, more extensive tests, and significantly reduced financial costs. HDTBR is a terrestrial analog that induces cephalad fluid shifts like that observed in microgravity, by altering the vector of gravitational force on the body. In addition to cephalad fluid shifts, translaminar pressure differences, choroidal engorgement, intracerebral volume shifts, collagen beam orientation, and hydrostatic fluid distribution are all hypotheses for contributing factors to the morphological changes observed in HDTBR. Parabolic flight and other techniques have been used to test devices in microgravity conditions before being sent to the International Space Station (ISS); however, the brief duration of exposure is not sufficient to induce SANS-like manifestations. Moreover, early HDTBR studies for 70 days did not present SANS findings, which were later suggested that use of standard pillows and forearm to eat meals were sufficient maneuvers to lower intracranial pressure and re-introduce hydrostatic gradients that may contribute to visual abnormalities. A “strict” 6-degree HDTBR protocol with preclusion of standard pillows and arm propping was implemented, subsequently. Strict HDTBR studies have been able to present SANS manifestations, such as choroidal folds and optic disc edema; however, the exact mechanism in which this pathophysiology manifests is still not well-characterized. Of course, no current analog perfectly mimics the effects of microgravity, but HDTBR is a strong analog allowing for the exploration of human physiological adaptations to the unloading of earth’s vertical gravitational force.
A primary risk factor for morphological changes in HDTBR may be the extent of duration. Increases in intraocular pressure (IOP) have been induced with +1.42mmHg and +1.79mmHg from baseline in 14-day and 70-day HDTBR, respectively. Moreover, peripapillary retinal thickness was nearly 2.5 times more prominent in the superior, nasal, and inferior locations for the 70-day vs.14-day HDTBR. Moderate myopes have also been shown to have a higher peak IOP values and significantly greater increases in IOP relative to emmetropes and low myopes during HDTBR, which may increase risks for ocular hypertension and potential glaucoma. Associated risk factors have also been linked to B-vitamin status and genetic predisposition. The magnitude of optic disc edema in subjects experiencing HDTBR in a mild hypercapnic environment has been found to be higher in individuals possessing more MTRR 66G and SHMT1 1420 C alleles. Anatomical variations, such as a crowded optic nerve head with a small optic cup, have been suggestive of increasing susceptibility to developing optic pathologies in idiopathic intracranial patients, which may be a similar predisposing risk factor in HDTBR subjects. One subject who participated in multiple HDTBR experiments presented with more than twice an increase in total retinal thickness (TRT) relative to the previous study, so there may be a possibility that prior exposure to sustained fluid shift during HDT may cause an increased susceptibility to morphological changes. However, future research is needed to determine if repeated exposure to headward fluid shift increases risks of developing optic disc edema.
Although HDTBR has been used as a spaceflight microgravity analog for several decades, the exact pathophysiology of SANS-like manifestations (e.g., hyperopic shift, choroidal and retinal folds, optic disc edema, optic nerve sheath distension, and globe flattening) remains ill-defined. Vast improvements in imaging technology and progressive research experiments have indicated competing mechanisms for SANS and HDTBR findings. In SANS, it is hypothesized that cerebral venous congestion, chronic choroidal vessel distension, and enhanced capillary filtration are possible candidates for choroidal engorgement. However, in HDTBR, choroidal expansion does not occur as does in spaceflight. Jugular venous flow patterns documented during spaceflight may be different from what is observed during bed rest, which could explain differences in findings between the two groups. Moreover, during the spaceflight analog, gravity in the vertical axis (Gz) is still present, which may generate tissue weight and subsequently impede increases in choroid thickness. Posture changes between the prone and supine positions have also been found to result in ocular changes, which demonstrates the transient and sustained effects of gravitational forces on the eye.
In SANS, choroidal thickening may facilitate choroidal fold development due to anterior expansion of the choroid during spaceflight. However, choroidal folds have developed in HDTBR despite the lack of choroidal thickening. Moreover, choroidal folds have been hypothesized to be induced by globe flattening due to decreases in surface area of the posterior globe; however, globe flattening has neither been observed in HDTBR. In terrestrial diseases, decreases in IOP and increases in ICP have been linked to chorioretinal fold development; however, IOP does not decrease in HDTBR, which also does not explain its presence. In idiopathic intracranial hypertension (IIH) patients with papilledema, only 10% were observed to have choroidal folds in SD-OCT, which suggests that elevated ICP alone with papilledema is not sufficient to induce choroidal folds in all subjects. Previously direct measurements during 24-hour HDTBR and brief periods of parabolic flight have indicated non-pathologically elevated ICP. Mild elevation of ICP during HDTBR may be a potential factor contributing to retinal structural changes, but it has never been directly measured during spaceflight nor long duration HDTBR. Increases in ICP have also been hypothesized to induce strain distributions within the lamina cribrosa and retrolaminar neural tissue, which would result in deformations and ocular pathologies. Non-invasive methods for measuring ICP, such as Distortion-Product Oto-Acoustic Emissions, may be feasible for in-flight use and potentially provide more insight on changes in ICP for future missions.
Optic disc edema is one of the hallmark findings in both SANS and strict HDTBR, and mean increases in TRT are similar for astronauts and 30-day HDT subjects at similar time points. When comparing the two groups, strict HDTBR induced optic disc edema to a greater degree relative to actual spaceflight. It is speculated that HDTBR subjects may experience slightly greater magnitudes of ICP compared to their astronaut counterparts, which may contribute to differences in optic disc edema severity. A previous 70-day HDTBR study did not observe thickening of the TRT, which emphasizes the importance of implementing the strict HDTBR paradigm for inducing SANS manifestations in future studies.  It is hypothesized that headward fluid shifts during HDTBR may elevate venous pressure and subsequently increase capillary filtration in the prelaminar region of the optic nerve head. This mechanism may contribute to the development of optic disc edema; therefore, artificial gravity exposure would be expected to slightly reduce TRT. However, 30-min of artificial gravity exposure was not sufficient to offset these effects, potentially due to limited duration, inadequate G-forces at the level of the eye, or a different underlying mechanism. Previous studies have also hypothesized that choroidal thickening may be a contributing factor towards optic disc edema through strain at the optic nerve head. Short-term HDTBR studies (e.g., 3-days) have reported statistically significant increases in choroid thickness; however, recent 30-day strict HDTBR studies have demonstrated that increases in choroidal thickness and optic disc edema may be mutually exclusive.
The physical exam after HDTBR studies have shown no change in visual acuity, normal cycloplegic and manifest refractions, and on fundoscopy retinal nerve fiber layer (RNFL) thickening, optic disc edema, chorioretinal folds, and peripapillary wrinkles.
There are no changes in axial length, anterior chamber depth, or corneal curvature. Modified Amsler grid, red dot test, confrontational visual field, and color vision remain in normal limits. There may be cases of slight increases in IOP within normal range.
HDTBR subjects may present with RNFL thickening, optic disc edema, chorioretinal folds, and peripapillary wrinkles on optical coherence tomography (OCT). No cases thus far have presented with life-threatening potential.
Symptoms of HDTBR may present with pulsatile, pressing, and bilateral headaches during the initial duration of studies, likely due to cephalad fluid shifts. With regards to ophthalmic-specific symptoms, experimental conditions do not significantly affect participants’ visual function. There may be slight myopic shift throughout the study, potentially due to sustained near vision activities that may lead to transient myopia. In a HDTBR study with carbon dioxide intervention to simulate hypercapnic conditions on the ISS, subjects demonstrated elevated reliance on visual cues when tested on cognitive performance compared to non-SANS HDTBR individuals. Overall, no significant major visual occurrences otherwise have been reported during or after the spaceflight analog.
Diagnostic procedures in HDTBR subjects have included MRI and OCT before, during, and after experimental testing. These imaging procedures provide insight on the pathophysiology of morphological changes, such as RNFL thickening, optic disc edema, and choroidal folds. Phase-contrast MRI in the internal jugular veins, vertebral arteries, and internal carotid arteries allows for measurement of blood flow, cross-sectional area, and blood flow velocity to evaluate microgravity-induced cerebral hemodynamic changes. Changes in cerebral flow may be an underlying factor contributing to the structural and functional ophthalmic changes in HDTBR, and subsequently SANS. MRI has also been utilized in acute HDTBR studies to quantify changes in ophthalmic structures, such as optic nerve head sheath, optic nerve tortuosity, and change in vitreous chamber depth. Since HDT studies take place in much more controlled terrestrial environments relative to microgravity conditions in the International Space Station, use of MRI may be an effective method for exploring SANS through HDTBR experiments.
OCT angiography (OCTA) has been present on the ISS since December 2018, which has contributed to improvements in the understanding SANS manifestations. OCTA is a non-invasive imaging technique that generates volumetric angiography high-fidelity images. Enhanced images of the retinal vasculature at reduced scanning times in spaceflight will provide critical data for when comparing ocular changes with HDTBR studies. Furthermore, Heidelberg Spectralis “OCT2” is providing enhanced digital resolutions of retinal, vitreous, and choroidal structures. The OCT cross-sectional images may then be segmented either manually through an automated system to view changes in RNFL choroid, and Bruch’s membrane. Closer examination of specific ocular structures through OCT may narrow hypotheses for SANS and HDTBR pathophysiology.
Blood samples have been collected before HDTBR to assess vitamin levels and single-nucleotide polymorphism (MTRR 66G and SHMT1 1420 C alleles) to research genetic susceptibility to ocular manifestations. Previous studies have also examined blood samples to determine immunological responses to microgravity simulation.
HDTBR is a spaceflight analog used to study the physiological changes occurring in weightlessness during spaceflight as well as testing potential countermeasures and treatments. These manifestations are not “treated”; rather, countermeasures are investigated to mitigate pathological findings, which are described in the “Prevention” section.
HDTBR requires commitment of subjects to maintain a strict position for extended periods of time, even while eating, sleeping, and defecating. Maneuvers that disrupt the unloading of earth’s vertical gravitational force may lower intracranial pressure and re-introduce hydrostatic gradients that are critical for developing SANS manifestations. Astronauts are oftentimes in peak physical condition due to preflight strength and aerobic conditioning in preparation for missions. Subjects for current HDTBR studies must complete a modified Air Force Class III physical exam and be cleared by the NASA Test Subject Screening facility, which screens for astronaut-like subjects, but matching subjects with similar intensive training protocols is difficult.
Several countermeasures have been proposed as possible test conditions for HDTBR to reduce SANS manifestations, such as artificial gravity, lower body negative pressure (LBNP), and venoconstrictive thigh cuffs (VTC). Cephalad fluid shifts are a significant characteristic experienced in spaceflight and may be linked to the development of SANS. Therefore, several countermeasures target the reversal of these fluid shifts, which may be implemented on the ISS and future long-duration missions to the Moon and beyond. Daily exposure of 30-minutes of either continuous or intermittent artificial gravity via centrifugation during HDTBR has been tested to produce a footward fluid shift. Despite artificial gravity, chorioretinal folds and optic disc edema persisted to develop. Daily exposure to artificial gravity did not lessen ocular structural changes generated by HDTBR, which may potentially be due to limited duration, insufficient G-forces at the level of the eye, or a different underlying mechanism.
LBNP is a non-invasive device that creates a variable partial vacuum on the lower half of the body. The Russians first used the Chibis LBNP suit in 1971, and it has been implemented in several HDTBR studies. LBNP can generate a footward fluid shift, which was reported to attenuate choroid expansion after 3 days of strict HDTBR as well as reduce elevated jugular volume and blood accumulation at the head. Another study demonstrated that LBNP can reduce CSF pressure and subsequently reduce increases in optic nerve sheath distension and intracranial CSF during HDT. Significant attenuation of ocular manifestations suggests that LBNP may be an effective countermeasure for SANS.
Like LBNP devices, vasoconstrictive thigh cuffs (VTC) can create a more Earth-like fluid distribution when tightened to the upper thighs of individuals. Crewmembers on the ISS have been reported to reduce cardiac preload and distention of the jugular venous system when using VTC, which demonstrates a potentially effective countermeasure for SANS. In contrast to LBNP, VTC likely does not directly influence CSF distribution and will not lower ICP; however, it still has provided similar effects in reducing stroke volume, internal jugular veins cross-sectional area, and IOP.
Although some ocular structural changes from HDTBR may persist several days after the study, including chorioretinal folds and RNFL thickening, no subject has experienced severe visual abnormalities. However, there have been previous reports of the lumbar and other muscle atrophy taking several months to return to normal after the conclusion of bed rest.
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