NOTE: Extended to 1/31/2022 per NSSC information (Ed., 1/6/21)

NOTE: Extended to 1/31/2021 per NSSC information (Ed., 10/16/18)

We will use state-of-the-art, non-invasive technologies to quantify upper-body compartmental volumes and pressures in crewmembers before, during, and after prolonged space flight. Importantly, we will correlate these data with vision deficits that occur in order to establish pathophysiologic mechanisms that will serve as a basis for future countermeasure development. After successful completion of our investigation, we will deliver a comprehensive database of microgravity-induced, head-ward volume and pressure changes (type and magnitude), and a prioritization of these changes as to their deleterious effects on vision in crewmembers during and after prolonged space flight. We are proposing a well-documented and validated battery of non-invasive or minimally-invasive, image-based tests developed to identify and quantify microgravity-induced, head-ward volume and pressure changes. We hypothesize that prolonged microgravity-induced, head-ward volume and pressure shifts are responsible for elevating intracranial pressure (ICP) and producing deficits in crewmembers’ vision. Our project directly addresses Critical Path Roadmap Risks and Questions regarding "Risk of Spaceflight Associated Neuro-ocular Syndrome (SANS)" (previously called “Risk of Microgravity-Induced Visual Alterations and Intracranial Pressure”), specifically Integrated Research Plan (IRP) Gap Cardiovascular (CV) 7: How are fluids redistributed in-flight? and IRP Gap We do not know the etiological mechanisms and contributing risk factors for ocular structural and functional changes seen in-flight and postflight (SANS1) [previoulsy VIIP 1: What is the etiology of visual acuity and ocular structural and functional changes seen in-flight and post-flight?]. Our first specific aim is to study periocular fluid volumes, intraocular pressure (IOP), upper-body compartment volumes before, during, and after prolonged microgravity exposure. The second specific aim is to measure jugular vein dimensions and blood flow using ultrasound before, during, and after prolonged microgravity exposure. The third specific aim is to quantify ventricular and cerebrospinal volumes using ultrasound before, during, and after prolonged microgravity exposure. A fourth specific aim is to perform retinal imaging to observe retinal venous distension in space. Tests of ocular structure will include optic nerve head tomography, nerve fiber layer thickness, axial length, and orbital retrolaminar subarachnoidal space. Tests of ocular function will include visual acuity, total retinal blood flow, and capillary blood flow in the optic nerve head and macula. Finally, changes in ICP, IOP, and ocular structures and functions will be investigated while applying a purely-mechanical countermeasure of low-level lower body negative pressure or thigh cuffs to counteract the head-ward fluid shift in space.

To our knowledge, this study will be the first to provide detailed and non-invasive measures of compartmental volume and pressure changes in the upper body induced by prolonged microgravity and to correlate these specific changes with decrements in vision for crewmembers. The proposed techniques represent the best available, state-of-the-art tools to quantify and document features that are clinically suspected as vision deficit generators. By correlating volume and pressure changes with vision problems, we expect to identify factors that will later motivate targeted development of effective physiologic countermeasures such as low-level lower body negative pressure exposure or thigh cuffs in space. This project has the potential to prevent loss of vision in crewmembers exposed to prolonged space flight and upon return to Earth.

NOTE: This study was merged with investigations from Dr. Michael Stenger who was replaced by Steve Laurie (Distribution of Body Fluids during Long Duration Space Flight and Subsequent Effects on Intraocular Pressure and Vision Disturbance) and Dr. Scott Dulchavsky (Microgravity associated compartmental equilibration) resulting in a comprehensive study titled “Fluid Shifts Before, During and After Prolonged Space Flight and Their Association with Intracranial Pressure and Visual Impairment” (short title: Fluid Shifts).

This research has strong Earth benefits such as development and validation of a noninvasive ICP device and greater understanding of glaucoma using the latest technology for measuring intraocular and intracranial pressures.

We have made significant progress over the past 10 years on possible mechanisms of Spaceflight Associated Neuro-ocular Syndrome (SANS); all approvals were received and experimental schedules were optimized. We have completed our project NNX13AJ12G (entitled, “Fluid Distribution before, during and after Prolonged Space Flight”) by testing 13 astronauts. Moreover, we have updated and renewed our NASA and University of California San Diego (UCSD) Institutional Review Board (IRB) approvals. To date, all pre/in/post-flight data collection are completed on 13 subjects for this experiment.

Results from our spaceflight and other related investigation are available as part of three publications and three chapters. (Ed. Note: See Cumulative Bibliography).

NOTE: Extended to 1/31/2022 per NSSC information (Ed., 1/6/21)

NOTE: Extended to 1/31/2021 per NSSC information (Ed., 10/16/18)

We will use state-of-the-art, non-invasive technologies to quantify upper-body compartmental volumes and pressures in crewmembers before, during, and after prolonged space flight. Importantly, we will correlate these data with vision deficits that occur in order to establish pathophysiologic mechanisms that will serve as a basis for future countermeasure development. After successful completion of our investigation, we will deliver a comprehensive database of microgravity-induced, head-ward volume and pressure changes (type and magnitude), and a prioritization of these changes as to their deleterious effects on vision in crewmembers during and after prolonged space flight. We are proposing a well-documented and validated battery of non-invasive or minimally-invasive, image-based tests developed to identify and quantify microgravity-induced, head-ward volume and pressure changes. We hypothesize that prolonged microgravity-induced, head-ward volume and pressure shifts are responsible for elevating intracranial pressure (ICP) and producing deficits in crewmembers’ vision. Our project directly addresses Critical Path Roadmap Risks and Questions regarding "Risk of Spaceflight Associated Neuro-ocular Syndrome (SANS)" (previously called “Risk of Microgravity-Induced Visual Alterations and Intracranial Pressure”), specifically Integrated Research Plan (IRP) Gap Cardiovascular (CV) 7: How are fluids redistributed in-flight? and IRP Gap We do not know the etiological mechanisms and contributing risk factors for ocular structural and functional changes seen in-flight and postflight (SANS1) [previoulsy VIIP 1: What is the etiology of visual acuity and ocular structural and functional changes seen in-flight and post-flight?]. Our first specific aim is to study periocular fluid volumes, intraocular pressure (IOP), upper-body compartment volumes before, during, and after prolonged microgravity exposure. The second specific aim is to measure jugular vein dimensions and blood flow using ultrasound before, during, and after prolonged microgravity exposure. The third specific aim is to quantify ventricular and cerebrospinal volumes using ultrasound before, during, and after prolonged microgravity exposure. A fourth specific aim is to perform retinal imaging to observe retinal venous distension in space. Tests of ocular structure will include optic nerve head tomography, nerve fiber layer thickness, axial length, and orbital retrolaminar subarachnoidal space. Tests of ocular function will include visual acuity, total retinal blood flow, and capillary blood flow in the optic nerve head and macula. Finally, changes in ICP, IOP, and ocular structures and functions will be investigated while applying a purely-mechanical countermeasure of low-level lower body negative pressure or thigh cuffs to counteract the head-ward fluid shift in space.

To our knowledge, this study will be the first to provide detailed and non-invasive measures of compartmental volume and pressure changes in the upper body induced by prolonged microgravity and to correlate these specific changes with decrements in vision for crewmembers. The proposed techniques represent the best available, state-of-the-art tools to quantify and document features that are clinically suspected as vision deficit generators. By correlating volume and pressure changes with vision problems, we expect to identify factors that will later motivate targeted development of effective physiologic countermeasures such as low-level lower body negative pressure exposure or thigh cuffs in space. This project has the potential to prevent loss of vision in crewmembers exposed to prolonged space flight and upon return to Earth.

NOTE: This study was merged with investigations from Dr. Michael Stenger who was replaced by Steve Laurie (Distribution of Body Fluids during Long Duration Space Flight and Subsequent Effects on Intraocular Pressure and Vision Disturbance) and Dr. Scott Dulchavsky (Microgravity associated compartmental equilibration) resulting in a comprehensive study titled “Fluid Shifts Before, During and After Prolonged Space Flight and Their Association with Intracranial Pressure and Visual Impairment” (short title: Fluid Shifts).

This research has strong Earth benefits such as development and validation of a noninvasive ICP device and greater understanding of glaucoma using the latest technology for measuring intraocular and intracranial pressures.

INTRODUCTION

The Fluid Shifts flight study was funded starting in 2012 and resulted from the combination of three selected grant proposals into a single study (Principal Investigators (PIs): Mike Stenger/Cardiovascular and Vision Laboratory-Johnson Space Center (JSC); Alan Hargens/University of California-San Diego; and Scott Dulchavsky/Henry Ford Health System)). In 2013, the Cardiovascular & Vision Laboratory (CVL) portion of the project budget was re-scoped at the request of Human Health Countermeasures (HHC) management to increase the grant from 3 years to 7 years. Data collection on 10 subjects began in 2014, and 3 additional subjects were added to the CVL scope of work in 2017. This international investigation included astronauts from NASA, European Space Agency (ESA), and the Japan Aerospace Exploration Agency (JAXA), as well as Russian Cosmonauts.

The primary goal of this study was to (1) characterize the fluid shift that occurs during spaceflight, (2) determine if measurements obtained preflight could be used to predict ocular changes during spaceflight, and (3) evaluate the effectiveness of lower body negative pressure (LBNP) during spaceflight to acutely reverse the headward fluid shift.

METHODS

Subjects were studied before (L-90), during (FD45, FD150), and after (R+10, R+30, R+180) spaceflight. Before and after spaceflight subjects were studied in the seated, supine, and 15° head-down tilt postures; before flight also included a posture of 15° head-down tilt plus 25 mmHg lower body negative pressure (LBNP). During spaceflight subjects were studied during nominal weightlessness, and again during use of 25 mmHg LBNP using the Russian Chibis device. Outcome measures included a variety of vascular, cardiac, and ocular ultrasound measures, noninvasive estimates of intracranial pressure, eye structural measures with optical coherence tomography, and intraocular pressure.

Fluid distribution measures included assessment of plasma volume (pre- and post-flight, supine), total body water, and intracellular and extracellular fluid volumes.

Magnetic resonance imaging (MRI) of the brain and eyes was obtained pre- and post-flight in the seated, supine, and 15° head-down tilt postures.

RESULTS

Data collected in the Fluid Shifts study have been published as part of two manuscripts, with multiple additional manuscripts being planned.

Early Signs of Optic Disc Edema. Optical coherence tomography (OCT) imaging provides quantitative measures of retinal thickness that can be used to identify the earliest signs of optic disc edema. We published a subset of the data collected in this study collected on ~flight day 30 and, combined with the same measures obtained in the Ocular Health study, compared to the same data collected in subjects exposed to 30 days of strict head-down tilt bed rest.

Venous Thrombosis in Spaceflight. During a test session with a Fluid Shifts subject on ISS our ultrasound team discovered a venous thrombosis in the left internal jugular vein (IJV) of an astronaut participating in the Fluid Shifts study. This unexpected finding resulted in the PI team reviewing images of prior subjects and determined that a second earlier Fluid Shift subject also had an unconfirmed IJV thrombosis. These findings, along with IJV cross-sectional area and pressure data, were published in the journal JAMA Network (Marshall-Goebel K, Laurie SS, Alferova IV, Arbeille P, Auñón-Chancellor SM, Ebert DJ, Lee SMC, Macias BR, Martin DS, Pattarini JM, Ploutz-Snyder R, Ribeiro LC, Tarver WJ, Dulchavsky SA, Hargens AR, Stenger MB. "Assessment of jugular venous blood flow stasis and thrombosis during spaceflight." JAMA Netw Open. 2019 Nov 1;2(11):e1915011). In addition to 2 of 11 subjects demonstrating thrombosis in the left IJV, this publication also revealed that IJV cross-sectional area during spaceflight is similar to that in the supine posture on Earth and that there are IJV flow pattern abnormalities during weightlessness that do not occur on Earth. These findings highlight that cerebral venous congestion occurs in weightlessness and underscore the need for additional characterization of all cerebral venous outflow pathways, including both left and right IJVs and left and right vertebral veins.

Cardiovascular Responses to LBNP during Spaceflight. While use of LBNP during spaceflight has been studied in astronauts during short-duration spaceflight missions, long-duration astronauts have not been systematically evaluated during exposure to a sustained mild level of LBNP during spaceflight. Russian Cosmonauts routinely use LBNP during various research studies, as well as during the final 21 days of spaceflight as a countermeasures to prepare for re-adaptation to gravity. A key question being investigated here was how the cardiovascular system would respond to up to 60 minutes of LBNP during weightlessness during long-duration spaceflight when there are known musculoskeletal and cardiovascular changes that could limit the physiological responses to the LBNP stressor. The preliminary data below will be included in an upcoming manuscript.

LBNP reduces venous return to the heart, thereby lowering cardiac output and ultimately arterial blood pressure. To compensate, heart rate increases in order to maintain appropriate blood pressure levels. If the negative pressure is increased far enough, or the physiological responses designed to prevent a fall in blood pressure are inadequate, syncope can occur. Here we report preliminary data on the change in mean arterial pressure (MAP) and heart rate (HR) during exposure to 25 mmHg LBNP in 12 subjects throughout long-duration spaceflight missions. These preliminary data reveal that all subjects tolerated the LBNP sessions without a substantial fall in MAP, yet HR was elevated in all subjects. During FY21 our team will continue analysis of these preliminary data and draft a manuscript with these and other data to highlight the similarities and differences in the LBNP response during spaceflight, compared to that with occurs in a gravitational environment on Earth.

LBNP Effect on Ocular Venous Drainage. We and others have hypothesized that the cerebral venous congestion that develops during spaceflight may contribute to the development of optic disc edema in astronauts. A key question is whether use of LBNP, which we have demonstrated reduces IJV cross-sectional area thereby reducing cerebral venous congestion, effectively reaches the eye. We are currently drafting a manuscript that explores the ability for LBNP during spaceflight to reduce venous pressure draining the eye, as quantified by a fall in intraocular pressure (IOP). However, if this same hypothesis holds for the veins draining the choroidal vasculature, then the observation that choroid thickness during application of LBNP does not change suggests choroid thickness measures may represent fluid both within and external to the choroidal vasculature.

Ocular Structural Changes During Spaceflight. Recent publications by members of the Cardiovascular and Vision Laboratory reveal early signs of edema develop in most crewmembers during long-duration spaceflight and this can take up to 1 year post-flight to fully resolve. Similarly, in the Fluid Shifts study astronauts and Cosmonauts developed increased retinal thickening. These data will serve as the backbone of a publication in FY21 that will explore if there are other outcome data collected within the Fluid Shifts study that can predict these changes in total retinal thickness.

Fluid Shift Characterization. A primary aim of the original grant proposal submitted by the Cardiovascular and Vision Laboratory centered on the shift of fluids both towards the head, as quantified through ultrasound measures of the cerebral venous system, as well as shifts of fluid between intracellular and extracellular, and intravascular and extravascular fluid compartments. To accomplish this collaborators from the Nutritional Biochemistry Laboratory have developed dilution measure techniques that will provide assessment of total body water and intracellular and extracellular fluid volume preflight, inflight, and postflight. Plasma volume measured during preflight and postflight testing will also allow for quantification of intravascular and extravascular fluid volumes as well. The data from the dilution measures will be batch processed and combined with other ocular outcome data to determine if variability in fluid distributions may provide insight into the variability of the ocular findings.

Noninvasive Measures of Intracranial Pressure. At the start of the Fluid Shifts study in 2012 there was a desire to use noninvasive approaches to measure intracranial pressure during spaceflight. Because any single approach has the potential for errors or pitfalls, we took the strategy of using multiple approaches with the goal of improving the likelihood of correctly interpreting the data if all the techniques demonstrated similar trends. Data collected with the Cerebral and Cochlear Fluid Pressure (CCFP) analyzer, shifts in otoacoustic emissions, and measures of optic nerve sheath diameter will all be incorporated into a single manuscript in FY21. Preliminary review of these data suggest that noninvasive estimates of ICP do not reveal pathologically elevated ICP during spaceflight.

Magnetic Resonance Imaging Reveals Brain Structural Changes. Multiple groups from around the world, including members of the Fluid Shifts team, have reported on brain ventricular enlargement on MRI following spaceflight. These data reveal ~10.7% to 14.6% increase in lateral ventricular volume, which is ~2-3 ml increase in volume. These measures have been obtained on Fluid Shifts subjects and reveal similar magnitude increase as previously reported. In FY21 we will combine these measures with other outcome measures obtained on these crewmembers to gain insight into possible etiology of the brain structural change. Preliminary data in the Fluid Shifts subjects reveal substantial variability between subjects, including a single subject demonstrating no change in lateral ventricular volume. There has been speculation that the brain and eye structural changes are related, although the limited data that have been published suggest that a lack of change in lateral ventricular volume is related to the development of SANS as determined based on presence of a subjective optic disc edema or choroidal folds. Quantitative data collected in this Fluid Shifts study cohort suggest there is not a relationship between the brain structural changes and total retinal thickness changes as quantified from OCT images. These data will be incorporated into a manuscript planned for FY21.

DISCUSSION

Data collection will be completed on the final Fluid Shifts subjects in early FY21, and the continued analysis and reporting of findings are anticipated to continue through FY21 and FY22. Due to the international collaborations that make up the Fluid Shifts team, we are planning to hold a data summits to discuss data products and identify how multiple data sets link together to develop a comprehensive picture about (1) the fluid shift that occurs during long-duration spaceflight, (2) the ability for LBNP to reverse the fluid shift, and (3) if there are anatomic, physiologic, or other factors that can provide insight into which subjects may be most at risk for developing SANS findings. These analyses and results will inform the OMB Milestone to characterize SANS by the end of FY21.

NOTE: Extended to 1/31/2021 per NSSC information (Ed., 10/16/18)

We will use state-of-the-art, non-invasive technologies to quantify upper-body compartmental volumes and pressures in crewmembers before, during, and after prolonged space flight. Importantly, we will correlate these data with vision deficits that occur in order to establish pathophysiologic mechanisms that will serve as a basis for future countermeasure development. After successful completion of our investigation, we will deliver a comprehensive database of microgravity-induced, head-ward volume and pressure changes (type and magnitude), and a prioritization of these changes as to their deleterious effects on vision in crewmembers during and after prolonged space flight. We are proposing a well-documented and validated battery of non-invasive or minimally-invasive, image-based tests developed to identify and quantify microgravity-induced, head-ward volume and pressure changes. We hypothesize that prolonged microgravity-induced, head-ward volume and pressure shifts are responsible for elevating intracranial pressure (ICP) and producing deficits in crewmembers’ vision. Our project directly addresses Critical Path Roadmap Risks and Questions regarding "Risk of Spaceflight Associated Neuro-ocular Syndrome (SANS)" (previously called “Risk of Microgravity-Induced Visual Alterations and Intracranial Pressure”), specifically Integrated Research Plan (IRP) Gap Cardiovascular (CV) 7: How are fluids redistributed in-flight? and IRP Gap We do not know the etiological mechanisms and contributing risk factors for ocular structural and functional changes seen in-flight and postflight (SANS1) [previoulsy VIIP 1: What is the etiology of visual acuity and ocular structural and functional changes seen in-flight and post-flight?]. Our first specific aim is to study periocular fluid volumes, intraocular pressure (IOP), upper-body compartment volumes before, during, and after prolonged microgravity exposure. The second specific aim is to measure jugular vein dimensions and blood flow using ultrasound before, during, and after prolonged microgravity exposure. The third specific aim is to quantify ventricular and cerebrospinal volumes using ultrasound before, during, and after prolonged microgravity exposure. A fourth specific aim is to perform retinal imaging to observe retinal venous distension in space. Tests of ocular structure will include optic nerve head tomography, nerve fiber layer thickness, axial length, and orbital retrolaminar subarachnoidal space. Tests of ocular function will include visual acuity, total retinal blood flow, and capillary blood flow in the optic nerve head and macula. Finally, changes in ICP, IOP, and ocular structures and functions will be investigated while applying a purely-mechanical countermeasure of low-level lower body negative pressure or thigh cuffs to counteract the head-ward fluid shift in space.

To our knowledge, this study will be the first to provide detailed and non-invasive measures of compartmental volume and pressure changes in the upper body induced by prolonged microgravity and to correlate these specific changes with decrements in vision for crewmembers. The proposed techniques represent the best available, state-of-the-art tools to quantify and document features that are clinically suspected as vision deficit generators. By correlating volume and pressure changes with vision problems, we expect to identify factors that will later motivate targeted development of effective physiologic countermeasures such as low-level lower body negative pressure exposure or thigh cuffs in space. This project has the potential to prevent loss of vision in crewmembers exposed to prolonged space flight and upon return to Earth.

NOTE: This study was merged with investigations from Dr. Michael Stenger (Distribution of Body Fluids during Long Duration Space Flight and Subsequent Effects on Intraocular Pressure and Vision Disturbance) and Dr. Scott Dulchavsky (Microgravity associated compartmental equilibration) resulting in a comprehensive study titled “Fluid Shifts Before, During and After Prolonged Space Flight and Their Association with Intracranial Pressure and Visual Impairment” (short title: Fluid Shifts).

This research has strong Earth benefits such as development and validation of a noninvasive ICP device and greater understanding of glaucoma using the latest technology for measuring intraocular and intracranial pressures.

To date, all pre/in/post-flight data collection has been completed on 12 subjects for this experiment. The final subject will require 1 more post-flight session, which will mark the completion of data collection for this study. This is expected to be completed by November 2020. Partial results from our space flight and other related investigation are available as part of three publications and one abstract.

INTRODUCTION

The Fluid Shifts flight study was funded starting in 2012 and resulted from the combination of three selected grant proposals into a single study (Principal Investigators: Mike Stenger/Cardiovascular and Vision Laboratory-JSC; Alan Hargens/University of California-San Diego; and Scott Dulchavsky/Henry Ford Health System). In 2013, the Cardiovascular & Vision Laboratory (CVL) portion of the project budget was re-scoped at the request of Human Health Countermeasures (HHC) management to increase the grant from 3 years to 7 years. Data collection on 10 subjects began in 2014, and 3 additional subjects were added to the CVL scope of work in 2017. This international investigation included astronauts from NASA, the European Space Agency (ESA), and the Japan Aerospace Exploration Agency (JAXA) , as well as Russian Cosmonauts.

The primary goal of this study was to (1) characterize the fluid shift that occurs during space flight, (2) determine if measurements obtained preflight could be used to predict ocular changes during space flight, and (3) evaluate the effectiveness of lower body negative pressure (LBNP) during space flight to acutely reverse the headward fluid shift.

METHODS

Subjects were studied before (L-90), during (FD45, FD150), and after (R+10, R+30, R+180) space flight. Before and after space flight subjects were studied in the seated, supine, and 15° head-down tilt postures; before flight also included a posture of 15° head-down tilt plus 25 mmHg lower body negative pressure (LBNP). During space flight subjects were studied during nominal weightlessness, and again during use of 25 mmHg LBNP using the Russian Chibis device. Outcome measures included a variety of vascular, cardiac, and ocular ultrasound measures, noninvasive estimates of intracranial pressure, eye structural measures with optical coherence tomography, and intraocular pressure.

Fluid distribution measures included assessment of plasma volume (pre- and post-flight, supine), total body water, and intracellular and extracellular fluid volumes.

Magnetic resonance imaging (MRI) of the brain and eyes was obtained pre- and post-flight in the seated, supine, and 15° head-down tilt postures.

RESULTS

Data collected in the Fluid Shifts study have been published as part of two manuscripts, with multiple additional manuscripts being planned.

Early Signs of Optic Disc Edema: Optical coherence tomography (OCT) imaging provides quantitative measures of retinal thickness that can be used to identify the earliest signs of optic disc edema. We published a subset of the data collected in this study collected on ~flight day 30 and, combined with the same measures obtained in the Ocular Health study, compared to the same data collected in subjects exposed to 30 days of strict head-down tilt bed rest. This publication in the journal JAMA Ophthalmology highlighted similarities and differences in ocular changes between astronauts exposed to space flight and subjects exposed to a space flight analog.

Venous Thrombosis in Spaceflight. During a test session with a Fluid Shifts subject on ISS our ultrasound team discovered a venous thrombosis in the left internal jugular vein (IJV) of an astronaut participating in the Fluid Shifts study. This unexpected finding resulted in the PI team reviewing images of prior subjects and determined that a second earlier Fluid Shift subject also had an unconfirmed IJV thrombosis. These findings, along with IJV cross-sectional area and pressure data, were published in the journal JAMA Network. In addition to 2 of 11 subjects demonstrating thrombosis in the left IJV, this publication also revealed that IJV cross-sectional area during space flight is similar to that in the supine posture on Earth and that there are IJV flow pattern abnormalities during weightlessness that do not occur on Earth. These findings highlight that cerebral venous congestion occurs in weightlessness and underscore the need for additional characterization of all cerebral venous outflow pathways, including both left and right IJVs and left and right vertebral veins.

Cardiovascular Responses to LBNP during Space Flight

While use of LBNP during space flight has been studied in astronauts during short-duration space flight missions, long-duration astronauts have not been systematically evaluated during exposure to a sustained mild level of LBNP during space flight. Russian Cosmonauts routinely use LBNP during various research studies, as well as during the final 21 days of space flight as a countermeasures to prepare for re-adaptation to gravity. A key question being investigated here was how the cardiovascular system would respond to up to 60 minutes of LBNP during weightlessness during long-duration space flight when there are known musculoskeletal and cardiovascular changes that could limit the physiological responses to the LBNP stressor. The preliminary data will be included in an upcoming manuscript.

LBNP reduces venous return to the heart, thereby lowering cardiac output and ultimately arterial blood pressure. To compensate, heart rate increases in order to maintain appropriate blood pressure levels. If the negative pressure is increased far enough, or the physiological responses designed to prevent a fall in blood pressure are inadequate, syncope can occur. Here we report preliminary data on the change in mean arterial pressure (MAP) and heart rate (HR) during exposure to 25 mmHg LBNP in 12 subjects throughout long-duration space flight missions. These preliminary data reveal that all subjects tolerated the LBNP sessions without a substantial fall in MAP, yet HR was elevated in all subjects. During FY21 our team will continue analysis of these preliminary data and draft a manuscript with these and other data to highlight the similarities and differences in the LBNP response during space flight, compared to that with occurs in a gravitational environment on Earth.

DISCUSSION

Data collection will be completed on the final Fluid Shifts subjects in early FY21, and the continued analysis and reporting of findings are anticipated to continue through FY21 and FY22. Due to the international collaborations that make up the Fluid Shifts team, we are planning to hold a data summit to discuss data products and identify how multiple data sets link together to develop a comprehensive picture about (1) the fluid shift that occurs during long-duration space flight, (2) the ability for LBNP to reverse the fluid shift, and (3) if there are anatomic, physiologic, or other factors that can provide insight into which subjects may be most at risk for developing SANS findings.

OTHER RECENT RESULTS

FLUID DISTRIBUTION AND COMPARTMENTALIZATION DURING LONG-DURATION SPACE FLIGHT

INTRODUCTION. Visual acuity changes observed after short-duration missions are largely transient, but now up to 70% of ISS astronauts returning from long-duration missions demonstrate ocular structural changes such as optic disc edema, globe flattening, and/or choroidal folds. These structural and functional changes are referred to as the Spaceflight Associated Neuro-ocular Syndrome (SANS). The purpose of this study is to characterize the fluid distribution and compartmentalization associated with long-duration space flight and to determine whether a relationship exists between these fluid distribution measures and the ocular structural and functional changes associated with SANS. We also seek to determine whether headward fluid shifts during space flight, as well as any SANS-related effects of those shifts, can be predicted by preflight responses to acute hemodynamic manipulations, including posture changes with and without lower body negative pressure (LBNP).

METHODS. A variety of physiologic were investigated in 13 long-duration ISS crewmembers. Measures include (1) fluid compartmentalization (total body water by D2O, extracellular fluid by NaBr, intracellular fluid by calculation, plasma volume by carbon monoxide rebreathe, interstitial fluid by calculation); (2) upper and lower body skin tissue thickness by ultrasound; (3) vascular dimensions by ultrasound (jugular veins, cerebral and carotid arteries, vertebral arteries and veins, portal vein); (4) vascular dynamics by MRI (head/neck blood flow, cerebrospinal fluid pulsatility); (5) ocular measures (optical coherence tomography; intraocular pressure; 2-dimensional ultrasound including optic nerve sheath diameter, globe anterior-posterior diameter, and retina-choroid thickness; Doppler ultrasound of ophthalmic and retinal arteries and veins); (6) cardiac variables by ultrasound (inferior vena cava, stroke volume, right heart dimensions and function, four-chamber views); and (7) noninvasive ICP measures (tympanic membrane displacement, otoacoustic emissions). Before and after space flight, tests during acute posture changes included supine and head-down tilt (HDT) to induce headward fluid shifts, whereas LBNP (only preflight) will oppose these shifts. Through interventions applied before, during, and after flight, we intend to evaluate the relationship between headward fluid shifts, SANS, and possible SANS countermeasures.

DISCUSSION. Twelve subjects have completed all testing and all subjects have completed the flight phase of this experiment. Preliminary results suggest that relative to the seated posture, jugular vein cross-sectional area and pressure, intraocular pressure, and noninvasive indices of ICP increase in the supine and HDT conditions, yet choroid thickness does not change. Measures obtained during space flight generally are similar to supine values on Earth, but the choroid is thicker in weightlessness. Use of 25 mmHg LBNP appears to be partially effective in reducing the cephalad fluid shift both on Earth and in space, but does not affect choroid thickness measured within the first 15 min of LBNP. Analyses of the following outcomes are expected this year: blood pressure and heart rate responses to LBNP during space flight; total body water and extracellular fluid volume; optic nerve head morphology changes and their relationship to other variables; magnetic resonance imaging (MRI) of cerebral venous compartment; and MRI metrics of globe flattening.

JUGULAR, MIDDLE CEREBRAL AND PORTAL VEIN RESPONSES TO SIX MONTHS ISS SPACEFLIGHT AT REST AND WITH LBNP

BACKGROUND. Cephalad fluid shifts are suspected to cause ocular edema and increase ocular and intracranial pressures, likely resulting in the development of the SANS. Lower body negative pressure (LBNP) can be used as a method to shift fluid towards the legs in the absence of gravity. Our hypothesis was that inflight jugular and portal vein volumes would increase due to the fluid shift and that intracranial vein velocity would increase due a narrowing of the vessel lumen from increased intracranial pressure. LBNP was tested to restore these variables to preflight levels.

METHODS. During 6-month ISS spaceflights 13 astronauts performed echographic investigations with verbal remote guidance assistance from the ground. Jugular vein volume (JV vol, cm3), portal vein cross-sectional area (PV cm²), and intracranial vein velocity (MCV; cm/s) were measured pre-flight, in-flight (FD45, FD150), and post-flight (R+40, R+180), at rest and during 25 mmHg LBNP with the Russian Chibis device.

RESULTS. With space flight, JV vol increased from pre-flight supine and seated values (46±48% from supine at FR45 & FD150) and 520±291%, from seated at FD45 & FD150. P<0.05), MCV increased (43±19% from supine and 109±110% from seated on FD45 and FD150, P<0.05). PV tended to increase but was not significant. Inflight LBNP of 25 mmHg restored JV vol, and MCV to pre-flight supine levels (P<0.05).

CONCLUSION. The increase in JV vol confirms the sustained headward fluid shift during the 6-month ISS flight. MCV increased, probably by compression of the vein (lumen reduction) or reduction in backpressure/interstitial resistance as neither cerebral nor carotid flows changed in space flight. The application of LBNP during the flight restored JV and MCV to pre-flight supine levels.

We will use state-of-the-art, non-invasive technologies to quantify upper-body compartmental volumes and pressures in crewmembers before, during, and after prolonged space flight. Importantly, we will correlate these data with vision deficits that occur in order to establish pathophysiologic mechanisms that will serve as a basis for future countermeasure development. After successful completion of our investigation, we will deliver a comprehensive database of microgravity-induced, head-ward volume and pressure changes (type and magnitude) and a prioritization of these changes as to their deleterious effects on vision in crewmembers during and after prolonged space flight. We are proposing a well-documented and validated battery of non-invasive or minimally-invasive, image-based tests developed to identify and quantify microgravity-induced, head-ward volume and pressure changes. We hypothesize that prolonged microgravity-induced, head-ward volume and pressure shifts are responsible for elevating intracranial pressure (ICP) and producing deficits in crewmembers’ vision. Our project directly addresses Critical Path Roadmap Risks and Questions regarding "Risk of Spaceflight Associated Neuro-ocular Syndrome (SANS)" (previously called “Risk of Microgravity-Induced Visual Alterations and Intracranial Pressure”), specifically Integrated Research Plan (IRP) Gap Cardiovascular (CV) 7: How are fluids redistributed in-flight? and IRP Gap We do not know the etiological mechanisms and contributing risk factors for ocular structural and functional changes seen in-flight and postflight (SANS1) [previoulsy VIIP 1: What is the etiology of visual acuity and ocular structural and functional changes seen in-flight and post-flight?]. Our first specific aim is to study periocular fluid volumes, intraocular pressure (IOP), upper-body compartment volumes before, during, and after prolonged microgravity exposure. The second specific aim is to measure jugular vein dimensions and blood flow using ultrasound before, during, and after prolonged microgravity exposure. The third specific aim is to quantify ventricular and cerebrospinal volumes using ultrasound before, during, and after prolonged microgravity exposure. A fourth specific aim is to perform retinal imaging to observe retinal venous distension in space. Tests of ocular structure will include optic nerve head tomography, nerve fiber layer thickness, axial length, and orbital retrolaminar subarachnoidal space. Tests of ocular function will include visual acuity, total retinal blood flow, and capillary blood flow in the optic nerve head and macula. Finally, changes in ICP, IOP, and ocular structures and functions will be investigated while applying a purely-mechanical countermeasure of low-level lower body negative pressure or thigh cuffs to counteract the head-ward fluid shift in space.

To our knowledge, this study will be the first to provide detailed and non-invasive measures of compartmental volume and pressure changes in the upper body induced by prolonged microgravity and to correlate these specific changes with decrements in vision for crewmembers. The proposed techniques represent the best available, state-of-the-art tools to quantify and document features that are clinically suspected as vision deficit generators. By correlating volume and pressure changes with vision problems, we expect to identify factors that will later motivate targeted development of effective physiologic countermeasures such as low-level lower body negative pressure exposure or thigh cuffs in space. This project has the potential to prevent loss of vision in crewmembers exposed to prolonged space flight and upon return to Earth.

NOTE: This study was merged with investigations from Dr. Michael Stenger (Distribution of Body Fluids during Long Duration Space Flight and Subsequent Effects on Intraocular Pressure and Vision Disturbance) and Dr. Scott Dulchavsky (Microgravity associated compartmental equilibration) resulting in a comprehensive study titled “Fluid Shifts Before, During and After Prolonged Space Flight and Their Association with Intracranial Pressure and Visual Impairment” (short title: Fluid Shifts).

This research has strong Earth benefits such as development and validation of a noninvasive ICP device and greater understanding of glaucoma using the latest technology for measuring intraocular and intracranial pressures.

Data collection is progressing; a total of 13 ISS crewmembers have been enrolled including the One-Year mission crewmembers. Preflight data from 10 crewmembers have been completed and are now being analyzed. Inflight data from 10 of the 13 crewmembers have been collected along with post-flight data from most crewmembers. We expect that all inflight data collection will be completed and analysis well underway by the end of 2019. Current regulations preclude us from publishing any specific data at this point, but initial analysis demonstrates reliable and reproducible data. Preliminary results indicate individual differences in acute responses to head-ward fluid shifts during transition from upright to supine and head down tilt (HDT) postures, such as jugular venous engorgement, choroidal swelling, and increases in noninvasive estimates of ICP. Reversal of these changes with LBNP is also subject dependent. These data are useful in identifying pathophysiological mechanisms behind the Spaceflight Associated Neuro-ocular Syndrome (SANS).

Our team continues the bi-weekly Fluid Shifts (FS) team telecons, coordinated and led by our new flight project coordinator, Alonso Fuentes.

Our team attended and presented data in numerous scientific sessions during the Human Research Program (HRP) meeting in Galveston in January 2019. Please see Bibliograpy section below for additional publications.

At UCSD we have conducted IRB-approved, whole body tilt to further investigate short-term changes to choroidal layer of the eye (OCT) along with measurements of IOP and systemic cardiovascular responses to both augmented and attenuated gravitational stress (by head-up tilt and HDT). These tests were valuable in order to verify data from tests on actual crew members. The data demonstrate that short duration exposures to HDT increase choroidal thickness and IOP.

We will use state-of-the-art, non-invasive technologies to quantify upper-body compartmental volumes and pressures in crewmembers before, during, and after prolonged space flight. Importantly, we will correlate these data with vision deficits that occur in order to establish pathophysiologic mechanisms that will serve as a basis for future countermeasure development. After successful completion of our investigation, we will deliver a comprehensive database of microgravity-induced, head-ward volume and pressure changes (type and magnitude) and a prioritization of these changes as to their deleterious effects on vision in crewmembers during and after prolonged space flight. We are proposing a well-documented and validated battery of non-invasive or minimally-invasive, image-based tests developed to identify and quantify microgravity-induced, head-ward volume and pressure changes. We hypothesize that prolonged microgravity-induced, head-ward volume and pressure shifts are responsible for elevating intracranial pressure (ICP) and producing deficits in crewmembers’ vision. Our project directly addresses Critical Path Roadmap Risks and Questions regarding “Risk of Microgravity-Induced Visual Alterations and Intracranial Pressure,” specifically Integrated Research Plan (IRP) Gap Cardiovascular (CV) 7: How are fluids redistributed in-flight? and IRP Gap Vision Impairment and Intracranial Pressure (VIIP) 1: What is the etiology of visual acuity and ocular structural and functional changes seen in-flight and post-flight? Our first specific aim is to study periocular fluid volumes, intraocular pressure (IOP), upper-body compartment volumes before, during, and after prolonged microgravity exposure. The second specific aim is to measure jugular vein dimensions and blood flow using ultrasound before, during, and after prolonged microgravity exposure. The third specific aim is to quantify ventricular and cerebrospinal volumes using ultrasound before, during, and after prolonged microgravity exposure. A fourth specific aim is to perform retinal imaging to observe retinal venous distension in space. Tests of ocular structure will include optic nerve head tomography, nerve fiber layer thickness, axial length, and orbital retrolaminar subarachnoidal space. Tests of ocular function will include visual acuity, total retinal blood flow, and capillary blood flow in the optic nerve head and macula. Finally, changes in ICP, IOP, and ocular structures and functions will be investigated while applying a purely-mechanical countermeasure of low-level lower body negative pressure or thigh cuffs to counteract the head-ward fluid shift in space.

To our knowledge, this study will be the first to provide detailed and non-invasive measures of compartmental volume and pressure changes in the upper body induced by prolonged microgravity and to correlate these specific changes with decrements in vision for crewmembers. The proposed techniques represent the best available, state-of-the-art tools to quantify and document features that are clinically suspected as vision deficit generators. By correlating volume and pressure changes with vision problems, we expect to identify factors that will later motivate targeted development of effective physiologic countermeasures such as low-level lower body negative pressure exposure or thigh cuffs in space. This project has the potential to prevent loss of vision in crewmembers exposed to prolonged space flight and upon return to Earth.

NOTE: This study was merged with investigations from Dr. Michael Stenger (Distribution of Body Fluids during Long Duration Space Flight and Subsequent Effects on Intraocular Pressure and Vision Disturbance) and Dr. Scott Dulchavsky (Microgravity associated compartmental equilibration) resulting in a comprehensive study titled “Fluid Shifts Before, During and After Prolonged Space Flight and Their Association with Intracranial Pressure and Visual Impairment” (short title: Fluid Shifts).

This research has immense Earth benefits such as development and validation of a noninvasive ICP device and greater understanding of glaucoma using the latest technology for measuring intraocular and intracranial pressures.

Data collection has been performed on a total of 10 ISS crewmembers preflight, including the One-Year mission crewmembers. Preflight data from all 10 crewmembers have been completed and were analyzed. Inflight data from 7 of the 10 crewmembers have been collected along with post-flight data from 6 crewmembers. We expect that all inflight data collection will be completed and analysis well underway by 2018. Current regulations preclude us from publishing any specific data at this point, but initial analysis demonstrates reliable and reproducible data. Preliminary results indicate individual differences in acute responses to head-ward fluid shifts during transition from upright to supine and head down tilt (HDT) postures such as jugular venous engorgement, choroidal swelling, and increases in noninvasive estimates of ICP. Reversal of these changes with LBNP is also subject dependent. These data are useful in identifying pathophysiological mechanisms behind the VIIP syndrome.

Because we are missing jugular vein pressure data on three early ISS crew members, we were approved to study three more ISS crew members, giving us a total of 13 ISS crew members. Our preliminary results to date are: 1) increased jugular vein dimensions and pressure, 2) increased total retinal thickness and choroidal engorgement by optical coherence tomography (OCT), and 3) no evidence of pathologically high ICP. These preliminary results were recently reported by Dr Mike Stenger at the 2018 Human Research Program (HRP) Workshop.

At UCSD we have conducted IRB-approved, whole body tilt studies to further investigate short-term changes to choroidal layer of the eye (OCT) along with measurements of IOP and systemic cardiovascular responses to both augmented and attenuated gravitational stress (by head-up tilt and head-down tilt, HDT). These tests provided unique insights and helped verify data from tests on actual crewmembers. The data demonstrate that short duration exposures to HDT increase choroidal thickness and IOP.

We have involved UCSD graduate and undergraduate student in projects using ground-based, Lower Body Negative Pressure (LBNP) chambers and Leg Negative Pressure chambers related to fluid-shift countermeasure studies. These projects involve various LBNP chambers, LBNP pants, limb and foot blood flow and sensation with various pressures and development of better waist seals for LBNP.

We will use state-of-the-art, non-invasive technologies to quantify upper-body compartmental volumes and pressures in crewmembers before, during, and after prolonged space flight. Importantly, we will correlate these data with vision deficits that occur in order to establish pathophysiologic mechanisms that will serve as a basis for future countermeasure development. After successful completion of our investigation, we will deliver a comprehensive database of microgravity-induced, head-ward volume and pressure changes (type and magnitude) and a prioritization of these changes as to their deleterious effects on vision in crewmembers during and after prolonged space flight. We are proposing a well-documented and validated battery of non-invasive or minimally-invasive, image-based tests developed to identify and quantify microgravity-induced, head-ward volume and pressure changes. We hypothesize that prolonged microgravity-induced, head-ward volume and pressure shifts are responsible for elevating intracranial pressure (ICP) and producing deficits in crewmembers’ vision. Our project directly addresses Critical Path Roadmap Risks and Questions regarding “Risk of Microgravity-Induced Visual Alterations and Intracranial Pressure,” specifically Integrated Research Plan (IRP) Gap Cardiovascular (CV) 7: How are fluids redistributed in-flight? and IRP Gap Vision Impairment and Intracranial Pressure (VIIP) 1: What is the etiology of visual acuity and ocular structural and functional changes seen in-flight and post-flight? Our first specific aim is to study periocular fluid volumes, intraocular pressure (IOP), upper-body compartment volumes before, during, and after prolonged microgravity exposure. The second specific aim is to measure jugular vein dimensions and blood flow using ultrasound before, during, and after prolonged microgravity exposure. The third specific aim is to quantify ventricular and cerebrospinal volumes using ultrasound before, during, and after prolonged microgravity exposure. A fourth specific aim is to perform retinal imaging to observe retinal venous distension in space. Tests of ocular structure will include optic nerve head tomography, nerve fiber layer thickness, axial length, and orbital retrolaminar subarachnoidal space. Tests of ocular function will include visual acuity, total retinal blood flow, and capillary blood flow in the optic nerve head and macula. Finally, changes in ICP, IOP, and ocular structures and functions will be investigated while applying a purely-mechanical countermeasure of low-level lower body negative pressure or thigh cuffs to counteract the head-ward fluid shift in space.

To our knowledge, this study will be the first to provide detailed and non-invasive measures of compartmental volume and pressure changes in the upper body induced by prolonged microgravity and to correlate these specific changes with decrements in vision for crewmembers. The proposed techniques represent the best available, state-of-the-art tools to quantify and document features that are clinically suspected as vision deficit generators. By correlating volume and pressure changes with vision problems, we expect to identify factors that will later motivate targeted development of effective physiologic countermeasures such as low-level lower body negative pressure exposure or thigh cuffs in space. This project has the potential to prevent loss of vision in crewmembers exposed to prolonged space flight and upon return to Earth.

NOTE: This study was merged with investigations from Dr. Michael Stenger (Distribution of Body Fluids during Long Duration Space Flight and Subsequent Effects on Intraocular Pressure and Vision Disturbance) and Dr. Scott Dulchavsky (Microgravity associated compartmental equilibration) resulting in a comprehensive study titled “Fluid Shifts Before, During and After Prolonged Space Flight and Their Association with Intracranial Pressure and Visual Impairment” (short title: Fluid Shifts).

This research has immense Earth benefits such as development and validation of a noninvasive ICP device and greater understanding of glaucoma using the latest technology for measuring intraocular and intracranial pressures.

Our team continues the bi-weekly Fluid Shifts (FS) team telecons, coordinated and led by our flight project manager Erik Hougland.

We have updated our “Fluid Shifts” NASA Experimental Document and its revision. We have completed all ten upright MRI sessions pre-flight data collections on International Space Station (ISS) crewmembers. We have also been directly involved with inflight and postflight data acquisition and quality control.

Our team attended and presented ground based preliminary and supportive ICP and cardiovascular data at the National Space Biomedical Research Institute (NSBRI) Numerical Modeling to Understand VIIP symposium Nov 17th – 18th 2016 at NSBRI HQ, Houston, TX. In addition, we will attend and present in numerous scientific sessions during the Human Research Program (HRP) meeting in Galveston in January 2017.

In 2016 Postdoctoral Fellow Dr. Lonnie G Petersen M.D., Ph.D. joined our team. She brings both clinical and experimental experience in diagnostics and treatment of intracranial hypertension as well as application of LBNP (lower body negative pressure) as means to non-invasively reduce ICP.

We will use state-of-the-art, non-invasive technologies to quantify upper-body compartmental volumes and pressures in crew members before, during, and after prolonged space flight. Importantly, we will correlate these data with vision deficits that occur in order to establish pathophysiologic mechanisms that will serve as a basis for future countermeasure development. After successful completion of our investigation, we will deliver a comprehensive database of microgravity-induced, head-ward volume and pressure changes (type and magnitude) and a prioritization of these changes as to their deleterious effects on vision in crewmembers during and after prolonged space flight. We are proposing a well-documented and validated battery of non-invasive or minimally-invasive, image-based tests developed to identify and quantify microgravity-induced, head-ward volume and pressure changes. We hypothesize that prolonged microgravity-induced, head-ward volume and pressure shifts are responsible for elevating intracranial pressure (ICP) and producing deficits in crewmembers’ vision. Our project directly addresses Critical Path Roadmap Risks and Questions regarding “Risk of Microgravity-Induced Visual Alterations and Intracranial Pressure,” specifically Integrated Research Plan (IRP) Gap Cardiovascular (CV) 7: How are fluids redistributed in-flight? and IRP Gap Vision Impairment and Intracranial Pressure (VIIP) 1: What is the etiology of visual acuity and ocular structural and functional changes seen in-flight and post-flight? Our first specific aim is to study periocular fluid volumes, intraocular pressure (IOP), upper-body compartment volumes before, during, and after prolonged microgravity exposure. The second specific aim is to measure jugular vein dimensions and blood flow using ultrasound before, during, and after prolonged microgravity exposure. The third specific aim is to quantify ventricular and cerebrospinal volumes using ultrasound before, during, and after prolonged microgravity exposure. A fourth specific aim is to perform retinal imaging to observe retinal venous distension in space. Tests of ocular structure will include optic nerve head tomography, nerve fiber layer thickness, axial length, and orbital retrolaminar subarachnoidal space. Tests of ocular function will include visual acuity, total retinal blood flow, and capillary blood flow in the optic nerve head and macula. Finally, changes in ICP, IOP, and ocular structures and functions will be investigated while applying a purely-mechanical countermeasure of low-level lower body negative pressure or thigh cuffs to counteract the head-ward fluid shift in space.

To our knowledge, this study will be the first to provide detailed and non-invasive measures of compartmental volume and pressure changes in the upper body induced by prolonged microgravity and to correlate these specific changes with decrements in vision for crewmembers. The proposed techniques represent the best available, state-of-the-art tools to quantify and document features that are clinically suspected as vision deficit generators. By correlating volume and pressure changes with vision problems, we expect to identify factors that will later motivate targeted development of effective physiologic countermeasures such as low-level lower body negative pressure exposure or thigh cuffs in space. This project has the potential to prevent loss of vision in crewmembers exposed to prolonged space flight and upon return to Earth.

NOTE: This study was merged with investigations from Dr. Michael Stenger (Distribution of Body Fluids during Long Duration Space Flight and Subsequent Effects on Intraocular Pressure and Vision Disturbance) and Dr. Scott Dulchavsky (Microgravity associated compartmental equilibration) resulting in a comprehensive study titled “Fluid Shifts Before, During and After Prolonged Space Flight and Their Association with Intracranial Pressure and Visual Impairment” (short title: Fluid Shifts).

This research has immense Earth benefits such as development and validation of a noninvasive ICP device and greater understanding of glaucoma using the latest technology for measuring intraocular and intracranial pressures.

To date our team has met with one another with the coordination of Erik Hougland, our flight project manager, who has led our bi-weekly Fluid Shifts (FS) team telecons.

We have updated our “Fluid Shifts” NASA Experimental Document and its revision.

We have completed five upright MRI sessions pre-flight data collections on ISS crew members. We have also been involved with inflight data acquisition and quality control. Our first post-flight data collections on ISS crew members are expected in March 2016.

Our team attended the National Space Biomedical Research Institute (NSBRI) VIIP Working Group Jan. 13th, 2015, during the NASA Human Research Program (HRP) Investigators’ Workshop in Galveston, TX.

Our team attended the NSBRI Ultrasound working group to present on ultrasound based ICP data collection.

In addition to these FS operational activities, we were successful in leveraging our NASA funded research to host an undergraduate Howard University student last summer, Amarachi Uzosike, funded by the American Physiological Society Undergraduate Summer Research Fellowship.

Brandon Macias attended the 2015 Heidelberg Engineering Academy: Spectralis Hands-On Operation Course.

We will use state-of-the-art, non-invasive technologies to quantify upper-body compartmental volumes and pressures in crew members before, during, and after prolonged space flight. Importantly, we will correlate these data with vision deficits that occur in order to establish pathophysiologic mechanisms that will serve as a basis for future countermeasure development. After successful completion of our investigation, we will deliver a comprehensive database of microgravity-induced, head-ward volume and pressure changes (type and magnitude) and a prioritization of these changes as to their deleterious effects on vision in crewmembers during and after prolonged space flight. We are proposing a well-documented and validated battery of non-invasive or minimally-invasive, image-based tests developed to identify and quantify microgravity-induced, head-ward volume and pressure changes. We hypothesize that prolonged microgravity-induced, head-ward volume and pressure shifts are responsible for elevating intracranial pressure (ICP) and producing deficits in crewmembers’ vision. Our project directly addresses Critical Path Roadmap Risks and Questions regarding “Risk of Microgravity-Induced Visual Alterations and Intracranial Pressure”, specifically Integrated Research Plan (IRP) Gap Cardiovascular (CV)7: How are fluids redistributed in-flight? and IRP Gap Vision Impairment and Intracranial Pressure (VIIP)1: What is the etiology of visual acuity and ocular structural and functional changes seen in-flight and post-flight? Our first specific aim is to study periocular fluid volumes, intraocular pressure (IOP), upper-body compartment volumes before, during, and after prolonged microgravity exposure. The second specific aim is to measure jugular vein dimensions and blood flow using ultrasound before, during, and after prolonged microgravity exposure. The third specific aim is to quantify ventricular and cerebrospinal volumes using ultrasound before, during, and after prolonged microgravity exposure. A fourth specific aim is to perform retinal imaging to observe retinal venous distension in space. Tests of ocular structure will include optic nerve head tomography, nerve fiber layer thickness, axial length, and orbital retrolaminar subarachnoidal space. Tests of ocular function will include visual acuity, total retinal blood flow, and capillary blood flow in the optic nerve head and macula. Finally, changes in ICP, IOP, and ocular structures and functions will be investigated while applying a purely-mechanical countermeasure of low-level lower body negative pressure or thigh cuffs to counteract the head-ward fluid shift in space.

To our knowledge, this study will be the first to provide detailed and non-invasive measures of compartmental volume and pressure changes in the upper body induced by prolonged microgravity and to correlate these specific changes with decrements in vision for crewmembers. The proposed techniques represent the best available, state-of-the-art tools to quantify and document features that are clinically suspected as vision deficit generators. By correlating volume and pressure changes with vision problems, we expect to identify factors that will later motivate targeted development of effective physiologic countermeasures such as low-level lower body negative pressure exposure or thigh cuffs in space. This project has the potential to prevent loss of vision in crewmembers exposed to prolonged space flight and upon return to Earth.

NOTE: This study was merged with investigations from Dr. Michael Stenger (Distribution of Body Fluids during Long Duration Space Flight and Subsequent Effects on Intraocular Pressure and Vision Disturbance) and Dr. Scott Dulchavsky (Microgravity associated compartmental equilibration) resulting in a comprehensive study titled “Fluid Shifts Before, During and After Prolonged Space Flight and Their Association with Intracranial Pressure and Visual Impairment” (short title: Fluid Shifts).

This research has immense Earth benefits such as development and validation of a noninvasive ICP device and greater understanding of glaucoma using the latest technology for measuring intraocular and intracranial pressures.

Erik Hougland, our flight project manager, has been coordinating our bi-weekly FS (Fluid Shifts) team telecons. At the request of the NASA Element office we have merged three flight projects. We have successfully worked to integrate our proposed ground and flight measures among the research team (Hargens et al., Stenger et al., and Dulchavsky et al.). We have now finalized our research testing protocols for ISS crewmembers. We are currently working to update our “Fluid Shifts” NASA Experimental Document. We visited the upright magnetic resonance imaging (MRI) facility to brief the Fonar and MRI personnel on our proposed MRI measures and develop MRI protocols for our cerebral spinal fluid flow tests. We have completed feasibility studies and determined that our proposed tests can be successfully completed within the allotted crew time. We have successfully captured pre-flight upright MRI data from two ISS crewmembers, and one back-up crewmember. The Cerebral and Cochlear Fluid Pressure (CCFP)- Marchbanks device received a CE mark and the NASA unit was shipped 1/30/2014. In addition, two of the CCFP flight units have arrived NASA-JSC on 12/29/2014. These flight units are currently being configured for flight and transported to ISS on SpaceX6. We are in frequent contact with our collaborators, to coordinate their travel and participation in ground-based tests. Our collaborators visited NASA-JSC during our ground feasibility tests to help successfully integrate vascular ultrasound and ocular measurements. A major milestone completed this year was acquisition and modification of an optical coherence tomography (OCT) arm for OCT measurements in the upright, supine, and head-down-tilt position. A Wyle team member did an excellent job retrofitting the OCT device for use in our experiment. We have worked with our flight project manager to set up remote ultrasound guidance capabilities. Our study will utilize the Russian Chibis device; we have been in close contact with our Russian collaborators to coordinate ISS Chibis operations and study implementation. We continue to have productive meetings to coordinate our planned physiological measures in the Russian ISS segment during Chibis operations at NASA-JSC this year. We are currently working with the OCT manufacture to finalize automated, quantitative, and objective measures of ocular structures. Testing and training have been initiated to enable “free-floating” of the OCT device for in-flight measurements.

Over the past year other important milestones were met. We helped finalize the NASA informed consent briefing for the first one-year astronaut. We provided Professor Arbeille’s in-flight and ground ultrasound procedures to the NASA JSC in preparation for flight studies. We provided feedback on the acquisition of the research Spectralis OCT device with anterior segment module. We provided feedback on the acquisition of an iCARE intraocular pressure measurement devices. Also, we provided feedback on acquisition of the Marchbanks CCFP unit. We have held conferences with Drs. Mike Williams and Bob Marchbanks to learn lessons from their experiments and building of our CCFP units to facilitate implementation of the CCFP hardware into our ISS flight project. In addition, we have developed a CCFP data analysis protocol. Our team attended the National Space Biomedical Research Institute (NSBRI) VIIP Working Group Jan. 13th, 2015 during the NASA Human Research Program (HRP) Investigators’ Workshop in Galveston, TX.

At UCSD we have conducted IRB-approved, whole body tilt and lower body negative pressure (LBNP) studies to determine optimal head-down tilt angles for our ground-based ISS flight project. Twenty-five normal healthy, non-smoking volunteers participated in this study (mean age: 36 years). Right and left intraocular pressure (IOP), intracranial pressure (ICP) by non-invasive ultrasound pulse phase lock loop, arm blood pressure, and heart rate were measured during the last minute of each testing condition. Subjects were positioned supine (5 mins), sitting (5 mins), 15-degrees head-down tilt (HDT) (5 mins), and ten minutes of HDT with LBNP (25 mmHg). The order of HDT and HDT+LBNP tests were balanced. IOP significantly decreased from supine to sitting posture by 3.2 ± 1.4 mmHg (mean ± standard deviation), and increased by 0.9 ± 1.3 mmHg from supine to the HDT position. LBNP during HDT significantly lowered IOP to supine levels. In addition, LBNP significantly reduced transcranial ultrasound pulse amplitudes (noninvasive ICP) by 38% as compared to the HDT condition (n=9). Mean blood pressure and heart rate did not change significantly across all conditions. The times for each test were within the limits which we cited in our NASA and UCSD IRB applications; and the tests were valuable in order to optimize tests on actual crew members planned for next year. These data were published as the lead article in the Jan. 2015 issue of Aerospace Medicine and Human Performance. These data demonstrate that short duration exposures to HDT increase IOP and ICP significantly and further, that LBNP counteracts these elevations of IOP and ICP. Therefore, space flight countermeasures that simulate hydrostatic pressure gradients may mitigate vision problems. These data are now published (Macias BR, Grande-Gutierrez N, JHK Liu, and AR Hargens. Intraocular and Intracranial Pressures during Head-Down-Tilt with Lower Body Negative Pressure. Aerospace Medicine and Human Performance, 86(1):3-7, 2015).

More recently, seventeen normal healthy non-smoking volunteers participated in a Cerebral and Cochlear Fluid Pressure (CCFP, a noninvasive ICP surrogate) study. This CCFP study is currently in progress.

We will use state-of-the-art, non-invasive technologies to quantify upper-body compartmental volumes and pressures in crew members before, during, and after prolonged space flight. Importantly, we will correlate these data with vision deficits that occur in order to establish pathophysiologic mechanisms that will serve as basis for future countermeasure development. After successful completion of our investigation, we will deliver a comprehensive database of microgravity-induced, head-ward volume and pressure changes (type and magnitude) and a prioritization of these changes as to their deleterious effects on vision in crewmembers during and after prolonged space flight. We are proposing a well-documented and validated battery of non-invasive or minimally-invasive, image-based tests developed to identify and quantify microgravity-induced, head-ward volume and pressure changes. We hypothesize that prolonged microgravity-induced, head-ward volume and pressure shifts are responsible for elevating intracranial pressure (ICP) and producing deficits in crewmembers’ vision. Our project directly addresses Critical Path Roadmap Risks and Questions regarding “Risk of Microgravity-Induced Visual Alterations and Intracranial Pressure”, specifically Integrated Research Plan (IRP) Gap Cardiovascular (CV)7: How are fluids redistributed in-flight? and IRP Gap VIIP1: What is the etiology of visual acuity and ocular structural and functional changes seen in-flight and post-flight? Our first specific aim is to study periocular fluid volumes, intraocular pressure (IOP), upper-body compartment volumes before, during, and after prolonged microgravity exposure. The second specific aim is to measure jugular vein dimensions and blood flow using ultrasound before, during, and after prolonged microgravity exposure. The third specific aim is to quantify ventricular and cerebrospinal volumes using ultrasound before, during, and after prolonged microgravity exposure. A fourth specific aim is to perform retinal imaging to observe retinal venous distension in space. Tests of ocular structure will include optic nerve head tomography, nerve fiber layer thickness, axial length, and orbital retrolaminar subarachnoidal space. Tests of ocular function will include visual acuity, total retinal blood flow, and capillary blood flow in the optic nerve head and macula. Finally, changes in ICP, intraocular pressure (IOP), and ocular structures and functions will be investigated while applying a purely-mechanical countermeasure of low-level lower body negative pressure or thigh cuffs to counteract the head-ward fluid shift in space.

To our knowledge, this study will be the first to provide detailed and non-invasive measures of compartmental volume and pressure changes in the upper body induced by prolonged microgravity and to correlate these specific changes with decrements in vision for crewmembers. The proposed techniques represent the best available, state-of-the-art tools to quantify and document features that are clinically suspected as vision deficit generators. By correlating volume and pressure changes with vision problems, we expect to identify factors that will later motivate targeted development of effective physiologic countermeasures such low-level lower body negative pressure exposure or thigh cuffs in space. This project has the potential to prevent loss of vision in crewmembers exposed to prolonged space flight and upon return to Earth.

NOTE: This study was merged with investigations from Dr. Michael Stenger (Distribution of Body Fluids during Long Duration Space Flight and Subsequent Effects on Intraocular Pressure and Vision Disturbance) and Dr. Scott Dulchavsky (Microgravity associated compartmental equilibration) resulting in a comprehensive study titled “Fluid Shifts Before, During and After Prolonged Space Flight and Their Association with Intracranial Pressure and Visual Impairment” (short title: Fluid Shifts).

This research has immense Earth benefits such as development and validation of a noninvasive ICP device and greater understanding of glaucoma using the latest technology for measuring intraocular and intracranial pressures.

Over the past year other important milestones were met. We helped finalize the NASA informed consent briefing for the first one-year astronaut. We provided Professor Arbeille’s in-flight and ground ultrasound procedures to the NASA JSC in preparation for our feasibility and flight studies. We provided feedback on the acquisition of the research Spectralis OCT device with anterior segment module. We provided feedback on the acquisition of a iCARE intraocular pressure measurement devices. Also, we provided feedback on acquisition of the Marchbanks CCFP unit. We have held conferences with Drs. Mike Williams and Bob Marchbanks to gain lessons learned from their experiments and building of our CCFP units to facilitate implementation of the CCFP hardware into our ISS flight project.

At UCSD we have conducted IRB-approved, whole body tilt and lower body negative pressure (LBNP) studies to determine optimal head-down tilt angles for our ground-based ISS flight project. Seven normal healthy, non-smoking volunteers participated in this study (mean age: 36 years). Right and left intraocular pressure (IOP), intracranial pressure (ICP) by non-invasive ultrasound pulse phase lock loop, arm blood pressure, and heart rate were measured during the last minute of each testing condition. Subjects were positioned supine (5 mins), sitting (5 mins), 15-degrees head-down tilt (HDT) (5 mins), and ten minutes of HDT with LBNP (25 mmHg). The order of HDT and HDT+LBNP tests were balanced. Right and left IOP values were averaged and used for statistical analysis (significance accepted at p<0.05). The change from supine was calculated for IOP values. IOP significantly decreased from supine to sitting posture by 2.4 ± 0.7 mmHg, and increased by 1.3 ± 2.4 mmHg from supine to the HDT position. LBNP during head-down-tilt significantly lowered IOP to supine levels (difference from supine, 0.1 ± 0.8 mmHg). In addition, added LBNP during HDT significantly decreased ICP pulse amplitudes by 2.8±4.3 microns. Mean blood pressure and heart rate did not change significantly across all conditions. The times for each test were within the limits which we cited in our NASA and UCSD IRB applications; and the tests were valuable in order to optimize tests on actual crew members planned for next year.

These data demonstrate that short duration exposures to HDT increase IOP and ICP significantly and further, that LBNP counteracts these elevations of IOP and ICP. Therefore, space flight countermeasures that simulate hydrostatic pressure gradients may mitigate vision problems.

We will use state-of-the-art, non-invasive technologies to quantify upper-body compartmental volumes and pressures in crew members before, during and after prolonged space flight. Importantly, we will correlate these data with vision deficits that occur in order to establish pathophysiologic mechanisms that will serve as basis for future countermeasure development. After successful completion of our investigation, we will deliver a comprehensive database of microgravity-induced, head-ward volume and pressure changes (type and magnitude) and a prioritization of these changes as to their deleterious effects on vision in crewmembers during and after prolonged space flight. We are proposing a well-documented and validated battery of non-invasive or minimally-invasive, image-based tests developed to identify and quantify microgravity-induced, head-ward volume and pressure changes. We hypothesize that prolonged microgravity-induced, head-ward volume and pressure shifts are responsible for elevating intracranial pressure (ICP) and producing deficits in crewmembers’ vision. Our project directly addresses Critical Path Roadmap Risks and Questions regarding “Risk of Microgravity-Induced Visual Alterations and Intracranial Pressure”, specifically IRP Gap CV7: How are fluids redistributed in-flight? and IRP Gap VIIP1: What is the etiology of visual acuity and ocular structural and functional changes seen in-flight and post-flight? Our first specific aim is to study periocular fluid volumes, intraocular pressure (IOP), upper-body compartment volumes before, during and after prolonged microgravity exposure. The second specific aim is to measure jugular vein dimensions and blood flow using ultrasound before, during and after prolonged microgravity exposure. The third specific aim is to quantify ventricular and cerebrospinal volumes using ultrasound before, during and after prolonged microgravity exposure. A fourth specific aim is to perform retinal imaging to observe retinal venous distension in space. Tests of ocular structure will include optic nerve head tomography, nerve fiber layer thickness, axial length, and orbital retrolaminar subarachnoidal space. Tests of ocular function will include visual acuity, total retinal blood flow, and capillary blood flow in the optic nerve head and macula. Finally, changes in ICP, IOP, and ocular structures and functions will be investigated while applying a purely-mechanical countermeasure of low-level lower body negative pressure or thigh cuffs to counteract the head-ward fluid shift in space.

To our knowledge, this study will be the first to provide detailed and non-invasive measures of compartmental volume and pressure changes in the upper body induced by prolonged microgravity and to correlate these specific changes with decrements in vision for crewmembers. The proposed techniques represent the best available, state-of-the-art tools to quantify and document features that are clinically suspected as vision deficit generators. By correlating volume and pressure changes with vision problems, we expect to identify factors that will later motivate targeted development of effective physiologic countermeasures such low-level lower body negative pressure exposure or thigh cuffs in space. This project has the potential to prevent loss of vision in crewmembers exposed to prolonged space flight and upon return to Earth.

NOTE: This study was merged with investigations from Dr. Michael Stenger (Distribution of Body Fluids during Long Duration Space Flight and Subsequent Effects on Intraocular Pressure and Vision Disturbance) and Dr. Scott Dulchavsky (Microgravity associated compartmental equilibration) resulting in a comprehensive study titled “Fluid Shifts Before, During and After Prolonged Space Flight and Their Association with Intracranial Pressure and Visual Impairment” (short title: Fluid Shifts).

NOTE THIS IS A CONTINUATION OF FUNDING FOR NNX12AL66G WITH THE SAME TITLE AND PRINCIPAL INVESTIGATOR.