Association of Exercise and Swimming Goggles With Modulation of Cerebro-ocular Hemodynamics and Pressures in a Model of Spaceflight-Associated Neuro-ocular Syndrome

This study examines whether different types of exercise or artificially increasing intraocular pressure are associated with modulation of cerebro-ocular hemodynamic and pressure changes during head-down tilt, an analog of spaceflight, in healthy male adults.

Key Points

Question

Can exercise and swimming goggles modulate cerebro-ocular pressures and dynamics in a model of spaceflight-associated neuro-ocular syndrome?

Findings

In this study of 20 healthy men, exercise was associated with decreases in intraocular pressure and estimated translaminar pressure gradient in a spaceflight analogue of head-down tilt. Adding swimming goggles was associated with increases in intraocular pressure and translaminar pressure gradient during head-down tilt.

Meaning

These findings suggest that modestly increasing intraocular pressure with swimming goggles could be used to mitigate spaceflight-associated neuro-ocular syndrome.

Abstract

Importance

Astronauts on International Space Station missions demonstrate adverse neuro-ocular changes. Reversing a negative translaminar pressure gradient (TLPG) by modulating cerebral blood flow, decreasing intracranial pressure, or increasing intraocular pressure (IOP) has been proposed as potential intervention for spaceflight-associated neuro-ocular syndrome (SANS).

Objective

To examine whether exercise (resistance, moderate-intensity aerobic, and high-intensity aerobic) or artificially increasing IOP is associated with modulated cerebro-ocular hemodynamic and pressure changes during head-down tilt (HDT), an analogue of spaceflight, in healthy adults.

Design, Setting, and Participants

A single-center investigation was conducted at Johnson Space Center, Houston, Texas, from January 1, 2014, to December 31, 2016, in 20 healthy men.

Exposure

On 3 separate days, participants rested supine, were tilted to −15° HDT, and then completed 1 of 3 experimental exercise conditions (moderate-intensity aerobic, resistance, or high-intensity interval aerobic). A subset of 10 participants wore swimming goggles on all days.

Main Outcomes and Measures

Applanation rebound tonometry was used to noninvasively assess IOP, and compression sonography was used to assess internal jugular venous pressure (IJVP). Estimated TLPG was calculated as the difference between IOP and IJVP. Cerebral inflow and outflow were measured in extracranial arteries using color-coded duplex ultrasonography.

Results

Twenty men participated in the study (mean [SD] age, 36 [9] years). Compared with supine IOP (mean [SD], 19.3 [3.7] mm Hg), IJVP (mean [SD], 21.4 [6.0] mm Hg), and estimated TLPG (mean [SD], −2.1 [7.0] mm Hg), −15° HDT was associated with increased IOP (mean difference, 2.3 mm Hg; 95% CI, 1.4-3.3 mm Hg; P < .001) and IJVP (mean difference, 10.5 mm Hg; 95% CI, 8.9-12.2 mm Hg; P < .001) and with decreased TLPG (mean difference, −8.2 mm Hg; 95% CI, −10.1 to −6.3 mm Hg; P < .001). Exercise (regardless of modality) at −15° HDT was associated with decreased IOP (mean difference, −1.6 mm Hg; 95% CI, −2.6 to −0.6 mm Hg; P = .002) and TLPG (mean difference, −3.5 mm Hg; 95% CI, −6.2 to −0.7 mm Hg; P = .01) compared with rest. Both IOP (mean difference, 2.9 mm Hg; 95% CI, 0.7-5.1 mm Hg; P = .01) and TLPG (mean difference, 5.1 mm Hg; 95% CI, 0.8-9.4 mm Hg; P = .02) were higher in participants who wore swimming goggles compared with those not wearing goggles.

Conclusions and Relevance

In this study, exercise was associated with decreased IOP and estimated translaminar pressure gradient in a spaceflight analogue of HDT. The addition of swimming goggles was associated with increased IOP and TLPG in HDT. Further evaluation in spaceflight may be warranted to determine whether modestly increasing IOP is an effective SANS countermeasure.

Introduction

Up to 75% of astronauts develop neuro-ocular changes, including increased intracranial pressure (ICP), decreased visual acuity, optic disc edema, globe flattening, choroidal folds, optic nerve sheath distention, and cotton wool spots during or after long-duration (>3 months) International Space Station missions.^1,2,3 Given that these neuro-ocular changes may persist for years after a mission, the spaceflight associated neuro-ocular syndrome (SANS) is a significant clinical concern. Elucidating the mechanistic underpinnings of SANS is important to protect the health of astronauts and continued human space exploration.²

Loss of the hydrostatic pressure gradient in spaceflight results in a cephalad fluid shift of approximately 2000 mL from the lower body, which together with loss of gravitationally induced cranial venous outflow, may increase both ICP and intraocular pressure (IOP).^4,5,6,7 Healthy adults in the supine position on Earth have a normal mean IOP of approximately 15 mm Hg and a normal mean ICP of approximately 10 mm Hg,⁸ causing a positive translaminar pressure gradient (TLPG) directed posteriorly across the lamina cribrosa in the eye.⁹ However, spaceflight provokes larger increases in ICP than IOP,¹⁰ resulting in a negative and anteriorly directed TLPG. Given that a negative TLPG is associated with adverse changes to the optic nerve head, lamina cribrosa, and optic nerve subarachnoid space,¹⁰ spaceflight-induced TLPG change is likely a key mechanism in the clinical manifestation of SANS. Accordingly, countermeasures that prevent or reverse a negative TLPG through modulating cerebral blood flow, decreasing ICP, or elevating IOP could be used to prevent or treat SANS.

Exercise has been used as a mandatory countermeasure against microgravity-induced skeletal muscle atrophy,^11,12 cardiac atrophy,^13,14 reduction in cardiorespiratory fitness,^15,16 and bone loss^17,18 since 1965.¹⁹ Despite the multisystem benefits of exercise, moderate-intensity aerobic exercise increases cerebral blood inflow,^20,21 and resistance exercise increases ICP,²² which together with exercise-related decreases in IOP^23,24 could further reduce TLPG and thus exacerbate SANS.¹⁰ In contrast, high-intensity aerobic exercise (>70% of maximal oxygen uptake) decreases cerebral blood inflow and might therefore modulate SANS.²⁵ Artificially increasing IOP has also been proposed as a potential SANS countermeasure.⁹ Previous findings suggest that donning swimming goggles modestly increases IOP (approximately 3 mm Hg)²⁶ and could therefore increase the TLPG. However, whether exercise or artificially increasing IOP modulates cerebro-ocular hemodynamic and pressure changes is not known.

The aims of this study were to characterize the cerebro-ocular hemodynamic and pressure responses to head-down tilt (HDT), an analogue of spaceflight,²⁷ and to examine whether exercise (resistance, moderate-intensity aerobic, or high-intensity aerobic) or artificially increasing IOP during HDT is associated with modulated hemodynamic and pressure changes in healthy adults. If modulating cerebral blood flow, decreasing ICP, or increasing IOP prevents or reverses a negative TLPG in HDT, as well as in long-duration spaceflight, exercise and/or swimming goggles could potentially be used to mitigate SANS. We hypothesized that (1) the HDT would alter cerebral blood inflow and outflow, jugular venous pressure (JVP, an estimate of ICP), and IOP; (2) cerebro-ocular hemodynamics and pressures would increase more during resistance and moderate-intensity aerobic exercise than during high-intensity aerobic exercise; and (3) swimming goggles would increase the IOP and TLPG.

Methods

Participants

All participants underwent a brief medical examination, including a detailed health history, and did not have cardiovascular, pulmonary, or kidney disease. Participants were asked to refrain from caffeine, alcohol, and strenuous physical activity for 24 hours before each experimental visit. Detailed methods are provided in the eMethods in the Supplement. Each participant gave written informed consent before participation. All data were deidentified. This study was approved by the National Aeronautics and Space Administration (NASA) Institutional Review Board and conformed to the ethical standards set by the Declaration of Helsinki.²⁸

Study Design

All exercise trials and data collection were conducted in a thermoneutral laboratory environment (22 °C-23 °C) at NASA Johnson Space Center in Houston, Texas, from January 1, 2014, to December 31, 2016. During the initial study visit, all participants were familiarized with different postural allocations (supine and HDT) and exercise equipment (cycle ergometer [eFigure 1 in the Supplement] and leg press machine [eFigure 2 in the Supplement]) that they would use during subsequent study visits. This familiarization visit concluded with the assessment of maximal oxygen consumption (V̇o₂max) and 1-repetition maximum (1-RM) to quantify maximal aerobic and strength capacity. Both V̇o₂max and 1-RM were also used to prescribe exercise intensity for each of the subsequent exercise visits.

Experimental Protocol

On the day of experimental testing, participants arrived at the laboratory at least 4 hours fasted. After instrumentation, participants rested quietly for 15 minutes in the supine position and then were tilted down to rest quietly in a −15° HDT position for 15 minutes. Thereafter, all participants underwent 1 of 3 experimental exercise conditions in the −15° HDT position in a randomized order on separate days: (1) 30 minutes of continuous moderate-intensity aerobic exercise at 60% of V̇o₂max on a cycle ergometer; (2) 4 sets of 12 repetitions of leg press exercise at 100% of 1-RM; and (3) 4 intervals of 4-minute high-intensity aerobic exercise at 85% of V̇o₂max interspersed with 3-minute periods of rest on a cycle ergometer (eFigure 1 in the Supplement). All exercise protocols were based on prescriptions currently performed by astronauts during long-duration spaceflight. Data on respiratory metabolism (ie, oxygen consumption [V̇o₂] and end-tidal partial pressure of carbon dioxide), cardiovascular function (ie, heart rate, beat-by-beat arterial blood pressure, left ventricular end-diastolic and end-systolic volumes, stroke volume, and cardiac output), cerebrovascular blood flow (ie, common carotid artery [CCA], external carotid artery [ECA], internal carotid artery [ICA], vertebral artery [VA], internal jugular vein [IJV], and vertebral vein [VV]) (eFigure 3 in the Supplement), and estimated pressure (ie, IJV pressure [IJVP] and external jugular vein pressure [EJVP]) were acquired throughout each study day. Ocular pressure was noninvasively measured using an applanation rebound tonometer (Icare PRO) in the left eye. Corneoscleral circumference was acquired with a contact lens sensor (Triggerfish, Sensimed) placed in the right eye as previously described.^29,30 A subset of 10 participants donned a pair of commercially available swimming goggles (Vanquisher, Speedo) and adjusted them as they would when entering a swimming pool (eFigure 4 in the Supplement).²⁶ The posterior rubber portion of the goggles pushes into the orbital fat and slightly increases the IOP (approximately 3 mm Hg).²⁶ A large hole was cut into the lens for the IOP measurements, leaving the posterior rubber portion of the goggles to fit into the orbital soft tissue.

Statistical Analysis

All statistical analyses were conducted with SPSS software (IBM Corp), using a 2-tailed α of .05 to reject the null hypotheses. Statistical assumptions for the statistical analyses used were tested and met before hypothesis testing. First, a 2-way repeated-measures analysis of variance was used to assess the association of a postural change (from supine to −15° HDT; within-visit association) with cerebral and cardiorespiratory variables across the 3 different exercise conditions (between-visit association). A 2-way repeated-measures analysis of variance was then used to assess changes in these same variables with exercise in the −15° HDT position (from resting −15° HDT to exercise −15° HDT; within-visit association) and whether these variables differed across the 3 different exercise conditions (between-visit association). Bonferroni adjustments were used on post hoc tests. A 2-sided P < .05 after Bonferroni adjustments was considered to be statistically significant. To assess whether IOP (measured by applanation rebound tonometer during each postural allocation and directly after exercise) and estimated TLPG (calculated as IOP minus IVJP) were different between those who wore goggles (n = 10) and those who did not (n = 10), unpaired t tests were assessed with men in the supine position, at −15° HDT at rest, and at −15° HDT with exercise. Values are expressed as mean (SD), with differences within or between visits presented as mean (95% CI).

Results

Twenty healthy men (age, 36 [9] years; height, 180.2 [5.2] cm; weight, 81.5 [10.5] kg; body mass index [calculated as weight in kilograms divided by the square of height in meters], 24.7 [2.9]; and V̇o₂max, 38.2 [7.8] mL/kg/min) were recruited and completed testing.

Association of HDT With Cerebro-ocular Hemodynamics and Pressures

Moving from the supine position to −15° HDT was not associated with a change in heart rate, stroke volume, or cardiac output (eTable 1 in the Supplement). Compared with the supine readings, global cerebral inflow was unchanged, with a 4.4% increase in ICA blood flow (mean difference, 13 mL/min; 95% CI, −14 to 41 mL/min; P = .32) and a 4.7% reduction in VA blood flow (mean difference, −8 mL/min; 95% CI, −20 to −3 mL/min; P = .13) (eTable 2 in the Supplement). Total blood inflow (mean difference, −172 mL/min; 95% CI, −237 to −106 mL/min; P < .001) decreased by 8.5%, with a 9.0% decrease in CCA blood flow (mean difference, −76 mL/min; 95% CI, −103 to −49 mL/min; P < .001) and a 4.7% decrease in VA blood flow (mean difference, −8 mL/min; 95% CI, −20 to −3 mL/min; P = .13) associated with −15° HDT (eTable 2 in the Supplement). Compared with middle cerebral artery (MCA) blood flow velocity (mean difference, 49.1 [10.9] cm/s) in the supine position, blood velocity in the MCA increased a mean of 2.5 cm/s (95% CI, 0.7-4.3 cm/s; P = .01) with −15° HDT. The VV blood flow decreased (mean difference, −16 mL/min; 95% CI, −29 to −2 mL/min; P = .02) by 20.5%, whereas the IJV blood flow was unchanged. The HDT was associated with increased IOP (Figure 1A), IJVP (Figure 1B), and EJVP (Figure 1C) and an almost 5-fold reduction in estimated TLPG (Figure 1D).

Figure 1. Change in Pressure Measurements With −15° Head-Down Tilt (HDT) to Simulate Microgravity.

Data are presented as estimated marginal mean (SD) for each postural allocation. EJVP indicates external jugular venous pressure; IJVP, internal jugular venous pressure; IOP, intraocular pressure; and TLPG, translaminar pressure gradient.

^aP < .001 supine vs −15° HDT.

Association of HDT Exercise With Cerebro-ocular Hemodynamics and Pressures

The HDT exercise was associated with increased heart rate, stroke volume, cardiac output, V̇o₂, ventilation, and systolic and diastolic blood pressure (Table 1) compared with HDT rest. A greater increase in heart rate, cardiac output, V̇o₂, ventilation, and mean arterial pressure was observed during high-intensity aerobic exercise compared with the other exercise modalities (Table 1).

Table 1. Cardiovascular and Cerebrovascular Responses to Different Exercises Performed in −15° HDT Position.

Response	Estimated Marginal Means			Exercise Conditions
	Mean (SD)		Change With Exercise (95% CI)a	Mean (SD)			P Valueb
	−15° HDT	−15° HDT With Exercise		Moderate	Resistance	High
Cardiovascular responses
Heart rate, /min	59 (9)	107 (21)	48 (45 to 52)c	98 (15)	100 (18)	123 (18)d,e	<.001
Stroke volume, mL	91 (15)	101 (22)	10 (6 to 13)c	96 (22)	101 (21)	106 (22)	.47
Cardiac output, L/min	5.4 (1.0)	10.8 (3.0)	5.4 (4.8 to 6.0)c	9.4 (2.3)	10.0 (2.2)	13.0 (3.1)d,e	.003
V̇o2, L/min	0.3 (0.1)	1.7 (0.5)	1.4 (1.3 to 1.6)c	1.7 (0.4)	1.4 (0.5)	2.2 (0.4)d,e	.003
V̇o2, mL/kg/min	3.7 (0.9)	21.9 (6.4)	18.2 (16.1 to 20.3)c	21.2 (5.3)	17.2 (5.4)	27.2 (4.6)d,e	.001
V̇e, L/min	11.2 (3.0)	59.1 (19.4)	47.9 (41.9 to 53.8)c	54.3 (16.4)	45.0 (11.3)	78.0 (14.7)d,e	<.001
MAP, mm Hg	95 (8)	119 (12)	24 (22 to 27)c	117 (8)	112 (9)	128 (11)d,e	.002
SBP, mm Hg	127 (12)	188 (29)	61 (55 to 67)c	188 (22)	167 (20)	208 (29)e	.001
DBP, mm Hg	78 (7)	84 (8)	6 (4 to 8)c	82 (7)	84 (7)	88 (8)d	.04
Cerebrovascular responses
Intraocular pressure, mm Hg	21.6 (4.1)	20.0 (3.9)	−1.6 (−2.6 to −0.6)f	20.0 (4.5)	19.2 (3.7)	20.9 (3.3)	.51
Venous pressure, mm Hg
Internal jugular pressure, mm Hg	31.8 (6.9)	33.9 (10.5)	2.1 (−0.4 to 4.4)	33.7 (8.6)	33.1 (8.8)	34.7 (13.9)	.98
External jugular pressure, mm Hg	17.6 (5.7)	18.0 (7.2)	0.4 (−1.5 to 2.2)	16.8 (4.6)	19.5 (8.7)	17.5 (7.5)	.50
Estimated translaminar pressure gradient, mm Hg	−10.6 (8.4)	−14.1 (11.3)	−3.5 (−6.2 to −0.7)f	−14.0 (9.7)	−14.5 (9.9)	−13.9 (14.2)	.87
Estimated cerebral transmural pressure, mm Hg	62.8 (8.1)	85.6 (14.8)	22.8 (19.7 to 25.9)c	85.3 (11.4)	78.4 (11.0)	93.1 (18.0)e	.04
OPP, mm Hg	73.6 (10.3)	99.5 (11.6)	25.9 (23.2 to 28.7)c	98.2 (10.0)	93.2 (9.2)	107.0 (11.6)	.09
Global CBF, mL/min	1247 (236)	1337 (325)	90 (2 to 179)f	1396 (287)	1250 (365)	1364 (325)	.54
Total head blood flow, mL/min	1844 (284)	2350 (521)	506 (360 to 651)c	2456 (580)	2134 (422)	2462 (503)	.40
CO to head, %	35.0 (7.1)	22.0 (7.3)	−13.0 (−15.4 to −10.3)c	26.2 (8.6)	21.3 (5.5)	18.6 (5.1)	.45

Abbreviations: CBF, cerebral blood flow; CO, cardiac output; DBP, diastolic blood pressure; EMM, estimated marginal means; HDT, head-down tilt; MAP, mean arterial pressure; OPP, ocular perfusion pressure; SBP, systolic blood pressure; V̇e, expired volume per unit time; V̇o₂, oxygen consumption.

^aChange with exercise was calculated as EMM for −15° HDT with exercise minus EMM for −15° HDT during rest.

^bP values reflect between-condition main effects.

^cP < .001 for −15° HDT with exercise vs −15° HDT during rest.

^dP < .05 for high-intensity aerobic exercise vs moderate-intensity aerobic exercise.

^eP < .05 for high-intensity aerobic exercise vs resistance exercise. All statistical tests are Bonferroni adjusted.

^fP < .05 for −15° HDT with exercise vs −15° HDT during rest.

Compared with global cerebral inflow (1247 [236] mL/min) and total head inflow (1844 [284] mL/min) at HDT rest, exercise was associated with increased global cerebral inflow (mean difference, 90 mL/min; 95% CI, 2-179 mL/min; P = .04) by 7.2% and total head inflow (mean difference, 506 mL/min; 95% CI, 360-651 mL/min; P < .001) by 24.7%, which did not differ among the exercise modalities (Table 1). Increased global cerebral inflow and total head inflow during HDT exercise were associated with a 9.1% increase in ICA blood flow (mean difference, 42 mL/min; 95% CI, 6-78 mL/min; P = .001) and a 30% increase in CCA blood flow (mean difference, 227 mL/min; 95% CI, 169-285 mL/min; P < .001), with VA blood flow remaining unchanged (Table 2). The MCA blood flow velocity or conductance did not change with exercise. The VV blood flow increased (mean difference, 18 mL/min; 95% CI, 6-30 mL/min; P = .004), whereas the IJV blood flow was unchanged (mean difference, −29 mL/min; 95% CI, −195 to 136 mL/min; P = .72) with HDT exercise compared with HDT rest; no differences were found among the exercise modalities (Table 2).

Table 2. Cerebral Arterial and Venous Blood Flow Responses to Different Exercises Performed in −15° HDT Position.

Response	Estimated Marginal Means			Exercise Conditions
	Mean (SD)		Change With Exercise (95% CIs)a	Mean (SD)			P Valueb
	−15° HDT	−15° HDT With Exercise		Moderate	Resistance	High
Common carotid artery
Blood flow, mL/min	759 (128)	986 (243)	227 (169 to 285)c	1049 (268)	863 (184)	1046 (183)	.11
Diameter, cm	0.69 (0.03)	0.67 (0.04)	−0.02 (−0.03 to −0.01)c	0.67 (0.04)	0.68 (0.04)	0.67 (0.05)	.95
Mean blood flow velocity, cm/s	33.7 (5.7)	46.2 (10.1)	12.5 (10.1 to 14.8)c	49.0 (10.0)	40.7 (8.1)	48.8 (10.0)	.14
Internal carotid artery
Blood flow, mL/min	462 (110)	504 (143)	42 (6 to 78)d	526 (140)	479 (162)	508 (130)	.58
Diameter, cm	0.55 (0.06)	0.54 (0.06)	−0.01 (−0.03 to 0)d	0.54 (0.05)	0.54 (0.07)	0.54 (0.06)	.93
Mean blood flow velocity, cm/s	32.8 (8.6)	37.5 (10.7)	4.7 (2.1 to 7.1)d	39.0 (11.2)	36.1 (12.9)	37.2 (7.9)	.59
External carotid artery
Blood flow, mL/min	300 (60)	525 (215)	225 (169 to 281)c	502 (153)	452 (227)	619 (235)	.10
Diameter, cm	0.50 (0.03)	0.52 (0.06)	0.02 (−0.01 to 0.03)	0.50 (0.04)	0.54 (0.08)	0.51 (0.06)	.47
Mean blood flow velocity, cm/s	25.2 (4.8)	40.9 (12.6)	15.7 (12.7 to 18.6)c	41.6 (9.3)	32.1 (9.4)	48.9 (13.1)e	.004
Vertebral artery
Blood flow, mL/min	159 (61)	171 (70)	12 (−7 to 32)	179 (79)	165 (68)	169 (66)	.91
Diameter, cm	0.40 (0.04)	0.38 (0.04)	−0.02 (−0.03 to −0.01)c	0.38 (0.04)	0.39 (0.04)	0.38 (0.04)	.92
Mean blood flow velocity, cm/s	20.6 (4.8)	24.7 (8.0)	4.1 (2.2 to 5.9)c	26.9 (9.8)	22.6 (7.1)	24.3 (6.2)	.44
Middle cerebral artery
Mean blood flow velocity, cm/s	52.4 (11.1)	53.7 (13.7)	1.3 (−1.1 to 3.8)	54.3 (15.3)	52.3 (13.9)	54.6 (12.3)	.97
Conductance	0.56 (0.13)	0.46 (0.13)	−0.10 (−0.13 to −0.08)c	0.47 (0.14)	0.47 (0.13)	0.43 (0.10)	.51
Vertebral vein blood flow, mL/min	64 (55)	82 (69)	18 (6 to 30)d	82 (64)	78 (72)	85 (73)	.97
Internal jugular vein blood flow, mL/min	890 (394)	861 (466)	−29 (−195 to 136)	843 (290)	960 (685)	779 (379)	.87

Abbreviations: EMM, estimated marginal means; HDT, head-down tilt.

^aChange with exercise (95% CI) was calculated as EMM for −15° HDT with exercise minus EMM −15° for HDT during rest.

^bP values reflect between condition main effects.

^cP < .001 for −15° HDT with exercise vs −15° HDT during rest.

^dP < .05 for −15° HDT with exercise vs −15° HDT during rest.

^eP < .05 for high-intensity aerobic exercise vs resistance exercise. All statistical tests are Bonferroni-adjusted.

No condition (between-visit) or interaction associations were observed for IOP, IJVP, EJVP, and estimated TLPG (Table 1). Compared with HDT rest, there was a 7.4% decrease in IOP (mean difference, −1.6 mm Hg; 95% CI, −2.6 to −0.6 mm Hg; P = .002) during HDT exercise, whereas IJVP and EJVP were unchanged, with a reduction of estimated TLPG (mean difference, −3.5 mm Hg; 95% CI, −6.2 to −0.7 mm Hg; P = .01) (Table 1).

Association of Swimming Goggles With IOP and TLPG

The addition of goggles was associated with increased IOP during supine (mean difference, 2.8 mm Hg; 95% CI, 1.0-4.7 mm Hg; P = .003) and HDT (mean difference, 2.9 mm Hg; 95% CI, 0.7-5.1; P = .01) testing and with increased estimated TLPG during supine (mean difference, 7.2 mm Hg; 95% CI, 4.0-10.5 mm Hg; P < .001) and HDT (mean difference, 5.1 mm Hg; 95% CI, 0.8-9.4 mm Hg; P = .02) testing compared with no use of goggles (Table 3). During the HDT exercise with goggles, the IOP was higher compared with that with no goggles (mean difference, 1.9 mm Hg; 95% CI, −0.1 to 3.9 mm Hg; P = .06); estimated TLPG was not increased (mean difference, −0.2 mm Hg; 95% CI, −6.4 to 5.9 mm Hg; P = .93).

Table 3. Association of Wearing Swimming Goggles With IOP and Estimated TLPG During Different Postural Allocations and/or Exercise.

Variable	Mean (SD)
	No Goggles (n = 10)	Goggles (n = 10)
IOP, mm Hg
Supine	18.0 (2.7)	20.8 (4.2)a
−15° HDT	20.3 (2.2)	23.2 (5.2)a
−15° HDT with exercise	19.1 (3.1)	21.0 (4.4)
Estimated TLPG, mm Hg
Supine	−5.5 (6.6)	1.7 (5.5)b
−15° HDT	−12.7 (6.7)	−7.6 (9.3)a
−15° HDT with exercise	−14.1 (8.7)	−14.2 (13.9)

Abbreviations: HDT, head-down tilt; IOP, intraocular pressure; TLPG, translaminar pressure gradient.

^aP < .05 for goggles vs no goggles.

^bP < .001 for goggles vs no goggles.

Association of HDT and Exercise With Corneoscleral Circumference

Compared with supine testing (mean [SD], 22 [57.2] mVEq), corneoscleral circumference increased during the HDT exercise (mean difference, 10.6 mVEq; 95% CI, −9.8 to 31.0 mVEq; P = .58). During the HDT exercise, corneoscleral circumference increased (mean increase across all exercise conditions, 15.4 mVEq; 95% CI, −8.5 to 39.3 mVEq; P = .33) compared with resting HDT (mean difference, 31.3 [78.5] mVEq); values were similar for all exercise modalities (Figure 2).

Figure 2. Changes in Corneoscleral Circumference Using Triggerfish Contact Lens.

Data were acquired continuously and averaged during supine rest, head-down tilt (HDT) rest, each high-intensity aerobic exercise interval, resistance set, and every 8 minutes during moderate-intensity aerobic exercise. Data are presented as estimated marginal mean (SD).

Discussion

The findings of this study suggest that HDT is associated with increased IOP and JVP but reduced TLPG. Furthermore, in testing countermeasures that could augment the TLPG, our results revealed that exercise during HDT was associated with increased cerebral venous outflow regardless of mode or intensity. However, the exercise-associated decrease in IOP was associated with further reduced estimated TLPG, whereas increasing IOP with swimming goggles was associated with increased TLPG. Such findings may be of clinical importance if replicated in long-duration spaceflight given that up to 75% of astronauts on International Space Station missions have SANS.

The magnitude of HDT-associated changes in cerebral blood inflow observed in the present study is consistent with a previous report.³¹ We extended this earlier investigation by comprehensively evaluating cerebral outflow and inflow. Our findings suggest a mismatch between arterial inflow and venous outflow with a phenotype consistent with venous congestion. We previously reported that IJV distention is coupled with an incrementally increasing IJV pressure as the HDT angle increases.³² In the present study, we observed a similar 49% increase in IJVP and a 71% increase in EJVP. Collectively, these findings suggest that venous engorgement is associated with increased JVP, which in turn is associated with increased ICP.³³ The magnitude of the HDT-associated change in the IOP is also consistent with previous reports.^34,35 This investigation evaluated the IOP and JVP simultaneously, thus providing an estimate of TLPG during a cephalad fluid shift and during exercise of varying modes and intensity. Our findings are consistent with the hypothesis that ICP may increase to a greater degree than IOP during spaceflight, resulting in a negative and anteriorly directed TLPG.³⁶

Prior studies^37,38,39,40 evaluating the association of exercise with cerebro-ocular hemodynamics and pressures have been conducted with patients in the upright position. In contrast to the previously reported finding^37,38 that blood flow increases proportionally with workflow, we found that cerebrovascular hemodynamics did not differ by exercise type (aerobic or resistance) or intensity (moderate or high-intensity) despite an acute bout of high-intensity exercise eliciting a greater cardiovascular response (heart rate, cardiac output, V̇o₂, and mean arterial pressure). Furthermore, the increase in total head inflow observed during exercise was associated in part with large increases in extracranial blood flow (ECA), with smaller increases in intracranial blood flow (ICA and VA). This finding is consistent with the findings of prior studies^37,38 that demonstrated that increased CCA blood flow during exercise (particularly higher-intensity aerobic exercise) was associated with large increases in ECA blood flow for thermoregulatory purposes. We found a significant decrease in the IOP during the HDT exercise, similar to findings from prior upright exercise IOP studies.^39,40 However, given that jugular pressures were unchanged, the HDT was associated with a reduction in the estimated TLPG. These findings highlight the importance of assessing multiple systems concurrently and suggest that alternate countermeasures are required to mitigate SANS.

Our findings corroborate a previous report²⁶ that found a simple intervention (wearing swimming goggles) may be associated with increased IOP and suggest that artificially increasing IOP is associated with decreased HDT-associated reduction of estimated TLPG. Although this is a straightforward and promising countermeasure, confirmatory studies are required to determine the appropriate dose (ie, duration and intensity) of artificial increase in IOP in spaceflight to modulate SANS. In addition, evaluation of the safety of prolonged or daily goggle use is needed. Swimming goggles firmly compress the orbital skin, and although the elevation in IOP with goggles is small (approximately 3 mm Hg), compression of the lamina cribrosa is possible, which in turn could ultimately increase the susceptibility of the retinal ganglion cell axons to damage, as observed in individuals with glaucoma.⁴¹ Accordingly, future studies should assess lamina cribrosa thickness with tools such as swept-source optical coherence tomography⁴² and evaluate the type and prevalence of serious (eg, neuroma)⁴³ and nonserious (eg, headache)⁴⁴ adverse events.

Limitations

Important limitations of the present study deserve consideration. First, our data were acquired in an acute care setting, whereas persistent engorgement of the IJV and elevated IOP have been reported during long-duration missions. For example, IJV was full and distended as measured using infrared photography during the 84-day Skylab mission,⁴⁵ and distention of the IJV and elevated IOP have persisted for the duration of the 6-month International Space Station missions (D.M., oral communication, October 2016). Second, −15° HDT does not fully simulate a microgravity environment because there are still hydrostatic pressures in the 1g environment; however, HDT is the best available model for evaluating the effects of exercise in space.²⁷ Third, we used JVP as a surrogate measure of ICP to estimate the TLPG. Only directly measured cranial and ocular pressures can accurately determine the TLPG.⁸ Nevertheless, invasive ICP assessments, such as an Ommaya catheter tap or lumbar puncture, are not practical for testing healthy humans during simulations; accordingly, noninvasively assessing ICP using JVP or other tools (eg, transcranial Doppler ultrasonography,⁴⁶ electroencephalography⁴⁷) is a feasible alternative. Fourth, no direct measures of vascular flow or anatomy of the optic nerve were obtained in this study. Assessment of ocular blood flow and optic nerve anatomy (eg, with optical coherence tomography angiography^42,48) could provide further insight into the cause and pathogenesis of SANS. Finally, SANS is a multifactorial condition, and other mechanisms potentially contributing to SANS, such as genetic risk and impaired lymphatic drainage, were not assessed.⁹ To this end, alternative countermeasures, such as intermittent artificial gravity⁴⁹ or pharmacologic and/or nutritional interventions,⁵⁰ could also be used to prevent and/or treat SANS.

Conclusions

Our findings suggest that HDT and HDT plus exercise are associated with altered cerebro-ocular hemodynamics and pressures in healthy men but changes can be partially mitigated by wearing swimming goggles. Further evaluation in spaceflight may be warranted to determine whether modestly increasing the IOP is a safe and effective SANS countermeasure during long-duration missions and future exploration missions.

Supplement.

eMethods. Supplemental Methods

eTable 1. Cardiovascular and Cerebrovascular Responses to Changes in Posture

eTable 2. Cerebral Arterial and Venous Blood Flow Responses to Changes in Posture

eFigure 1. Cycle ergometer modifications to achieve -15° head-down tilt to induce a cephalad-fluid shift that is analogous to microgravity conditions during spaceflight.

eFigure 2. Leg press modifications to achieve -15° head-down tilt to induce a cephalad-fluid shift that is analogous to microgravity conditions during spaceflight.

eFigure 3. Example of experimental setup for aerobic exercise and cerebral inflow/outflow vascular imaging.

eFigure 4. Example of participant wearing swimming googles with Triggerfish contact lens for continuous measurement of corneoscleral circumference (an estimate of IOP).

eReferences