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

Fifty percent of American astronauts have developed ocular refraction change after long duration space flight on the International Space Station (ISS). Recent findings have also included structural changes of the eye (papilledema, globe flattening, choroidal folds) and the optic nerve (sheath dilatation, tortuosity, and kinking), as well as imaging signs and lumbar puncture data indicative of elevated intracranial pressure (ICP). While short duration space flight is also characterized by vision disturbances, these are generally transient and do not appear to have lasting impacts on the structure or function of the eye. Changes in vision, eye, and adnexa morphology are hypothesized to be the result of space flight-induced cephalad fluid shifts and transiently elevated intracranial pressure. This hypothesis, however, has not been systematically tested. In earlier anecdotal publications, ICP elevation in long-duration space flight has been inferred but without association with structural or functional changes of the eye. Furthermore, while fluid shifts and compartmentalization during short-duration space flight (Space Shuttle missions) have been studied, the fluid distribution patterns and their effects on intracranial pressure or the structure and function of the sensory organs in the course of long-duration space flight are not well known.

Several ISS crewmembers have reported consistent worsening of nasal congestion and associated symptoms in late afternoon hours, necessitating topical and systemic decongestant use. Although several explanations have been entertained, food (salt) and water intake are likely to have provoked these symptoms through postprandial modification of fluid balance or increase in the circulating volume that manifests in the most susceptible individuals.

The purpose of the proposed work is to objectively characterize the changes in fluid distribution, including intra/extracellular and intra/extravascular fluid shifts, by applying advanced non-invasive assessment technologies before, during, and after long duration space flight. Additionally, we will examine the relationship between the type and magnitude of the fluid shift with any effects on eye morphology and vision disturbances, intraocular pressure (IOP), and measures of intracranial pressure. Further, we seek to determine whether the magnitude of fluid shifts during space flight, as well as the above effects of those shifts can be predicted based upon crewmember baseline data and responses to acute head-down tilt tests performed before launch. Finally, we propose to evaluate the effect of lower body negative pressure (LBNP) on the above parameters.

To our knowledge, this is the first attempt to systematically determine the impact of the fluid distribution in microgravity on a comprehensive set of structural and functional measures including, but not limited to, those related to intracranial pressure, vision, morphology of the eye and its adnexa, and the vascular systems of the head and neck, during and after long duration space flight. The study design and methodology are based on the extensive relevant experience of the Investigators, including many successful ground-based, space flight analogue, and space flight projects and investigations.

Primary Hypothesis

Prolonged microgravity-induced, headward volume, and pressure shifts promote elevation of intracranial pressure and result in alterations in crewmembers’ vision.

Specific Aims

Specific Aim I: To characterize fluid distribution and compartmentalization before, during, and after long-duration space flight.

Hypothesis 1: Fluid distribution measured by dilution techniques will reflect a headward fluid shift and an intra- to extra-vascular fluid shift during space flight, returning to pre-flight condition after landing.

Hypothesis 2: Regional headward fluid shifts in-flight are documented by increased cephalad venous dimensions (jugular veins) and flow characteristics, skin and soft tissue thickness.

Hypothesis 3: Fluid re-distribution towards the eye (detected in choroid, retina, and optic nerve head using ultrasonography and optical coherence tomography), and in arteries supplying ocular vascular beds, contributes to vision alterations.

Hypothesis 4: Splanchnic venous congestion (detected by portal vein size) contributes to headward volume shift, but is not in communication with the veins of head and neck. Thus, there should be a different level of venous congestion in these two compartments.

Specific Aim II: To correlate in-flight alterations of eye structure, ocular vascular parameters, and vision with headward fluid shifts, vascular dimensions, and flow patterns.

Hypothesis 5: Space flight-induced fluid shifts will have an upregulating effect on ICP and will alter ocular refraction / visual acuity. These changes will vary in magnitude and respectively, in their resolution pattern after space flight.

Hypothesis 6: In-flight ICP-related measures, IOP (intraocular pressure), venous and arterial morphometric and flow characteristics, vascular resistance of ocular vascular beds, and optic nerve anatomy will trend towards normal-gravity levels temporarily during and residually after fluid sequestration (LBNP) interventions.

Specific Aim III: To determine systemic and ocular factors of individual susceptibility to the development of ICP elevation and/or vision alterations.

Hypothesis 7: Subjects with greater fluid shifts (as measured by the ultrasound method in Aim 1) during pre-flight testing will experience greater fluid shifts in-flight and will be more susceptible to flight-induced vision alterations.

Hypothesis 8: Subjects who are resistant to the reversal of in-flight symptoms and physiological status through the application of LBNP will be more susceptible to persistent flight-induced vision alterations.

Hypothesis 9: Propensity towards more severe changes in-flight and the more indolent postflight resolution pattern will correlate with a range of individual characteristics of the crewmembers, such as anatomical and microanatomical and physiological features and potentially, hitherto unsuspected factors.

NOTE: This study was merged with investigations from Dr. Alan Hargens (Fluid distribution before, during and after prolonged space flight) and Dr. Michael Stenger (Distribution of Body Fluids during Long Duration Space Flight and Subsequent Effects on Intraocular Pressure and Vision Disturbance) 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).

The primary goals of this study were 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.

The Fluid Shifts study has greatly enhanced our understanding of numerous aspects of spaceflight physiology and our understanding of SANS (spaceflight-associated neuro-ocular syndrome).

• The 12 crewmembers who participated in 52 sessions of lower body negative pressure (25 mmHg) for up to 60 minutes per session tolerated the sessions without needing to terminate a test. • During spaceflight, numerous key outcome measures were similar to values in the seated or supine posture on Earth, and use of LBNP during spaceflight partially reversed some values. Still, none reached values measured in the seated upright posture on Earth. • The effects of LBNP appear to be transmitted to the level of the eye, although the mechanism is unclear. • Noninvasive indicators of intracranial pressure during long-duration spaceflight appear most similar to the seated or supine posture on Earth. Acute use of LBNP during spaceflight did not lower nICP indicators other than OAE (otoacoustic emission) phase at FD 150. Measurements during spaceflight were overall mostly similar to the seated posture on Earth. • Our team identified altered cerebral venous blood flow draining the head and, for the first time, observed a venous thrombus in the left internal jugular vein. • We have advanced our understanding of the effects of spaceflight on ocular morphology based on enhanced analyses of optical coherence tomography (OCT) images. • We corroborated previous findings from brain MRI (magnetic resonance imaging) analyses and demonstrated that there is no association between the change in lateral ventricular volume and magnitude of optic disc edema that develops during spaceflight. • MRI data analysis confirmed the hypothesis of an increased response to HDT (head-down tilt) position in postflight compared to preflight, indicating a physiological change induced by extended microgravity.

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

Fifty percent of American astronauts have developed ocular refraction change after long duration space flight on the International Space Station (ISS). Recent findings have also included structural changes of the eye (papilledema, globe flattening, choroidal folds) and the optic nerve (sheath dilatation, tortuosity, and kinking), as well as imaging signs and lumbar puncture data indicative of elevated intracranial pressure (ICP). While short duration space flight is also characterized by vision disturbances, these are generally transient and do not appear to have lasting impacts on the structure or function of the eye. Changes in vision, eye, and adnexa morphology are hypothesized to be the result of space flight-induced cephalad fluid shifts and transiently elevated intracranial pressure. This hypothesis, however, has not been systematically tested. In earlier anecdotal publications, ICP elevation in long-duration space flight has been inferred but without association with structural or functional changes of the eye. Furthermore, while fluid shifts and compartmentalization during short-duration space flight (Space Shuttle missions) have been studied, the fluid distribution patterns and their effects on intracranial pressure or the structure and function of the sensory organs in the course of long-duration space flight are not well known.

Several ISS crewmembers have reported consistent worsening of nasal congestion and associated symptoms in late afternoon hours, necessitating topical and systemic decongestant use. Although several explanations have been entertained, food (salt) and water intake are likely to have provoked these symptoms through postprandial modification of fluid balance or increase in the circulating volume that manifests in the most susceptible individuals.

The purpose of the proposed work is to objectively characterize the changes in fluid distribution, including intra/extracellular and intra/extravascular fluid shifts, by applying advanced non-invasive assessment technologies before, during, and after long duration space flight. Additionally, we will examine the relationship between the type and magnitude of the fluid shift with any effects on eye morphology and vision disturbances, intraocular pressure (IOP), and measures of intracranial pressure. Further, we seek to determine whether the magnitude of fluid shifts during space flight, as well as the above effects of those shifts can be predicted based upon crewmember baseline data and responses to acute head-down tilt tests performed before launch. Finally, we propose to evaluate the effect of lower body negative pressure (LBNP) on the above parameters.

To our knowledge, this is the first attempt to systematically determine the impact of the fluid distribution in microgravity on a comprehensive set of structural and functional measures including, but not limited to, those related to intracranial pressure, vision, morphology of the eye and its adnexa, and the vascular systems of the head and neck, during and after long duration space flight. The study design and methodology are based on the extensive relevant experience of the Investigators, including many successful ground-based, space flight analogue, and space flight projects and investigations.

Primary Hypothesis

Prolonged microgravity-induced, headward volume, and pressure shifts promote elevation of intracranial pressure and result in alterations in crewmembers’ vision.

Specific Aims

Specific Aim I: To characterize fluid distribution and compartmentalization before, during, and after long-duration space flight.

Hypothesis 1: Fluid distribution measured by dilution techniques will reflect a headward fluid shift and an intra- to extra-vascular fluid shift during space flight, returning to pre-flight condition after landing.

Hypothesis 2: Regional headward fluid shifts in-flight are documented by increased cephalad venous dimensions (jugular veins) and flow characteristics, skin and soft tissue thickness.

Hypothesis 3: Fluid re-distribution towards the eye (detected in choroid, retina, and optic nerve head using ultrasonography and optical coherence tomography), and in arteries supplying ocular vascular beds, contributes to vision alterations.

Hypothesis 4: Splanchnic venous congestion (detected by portal vein size) contributes to headward volume shift, but is not in communication with the veins of head and neck. Thus, there should be a different level of venous congestion in these two compartments.

Specific Aim II: To correlate in-flight alterations of eye structure, ocular vascular parameters, and vision with headward fluid shifts, vascular dimensions, and flow patterns.

Hypothesis 5: Space flight-induced fluid shifts will have an upregulating effect on ICP and will alter ocular refraction / visual acuity. These changes will vary in magnitude and respectively, in their resolution pattern after space flight.

Hypothesis 6: In-flight ICP-related measures, IOP (intraocular pressure), venous and arterial morphometric and flow characteristics, vascular resistance of ocular vascular beds, and optic nerve anatomy will trend towards normal-gravity levels temporarily during and residually after fluid sequestration (LBNP) interventions.

Specific Aim III: To determine systemic and ocular factors of individual susceptibility to the development of ICP elevation and/or vision alterations.

Hypothesis 7: Subjects with greater fluid shifts (as measured by the ultrasound method in Aim 1) during pre-flight testing will experience greater fluid shifts in-flight and will be more susceptible to flight-induced vision alterations.

Hypothesis 8: Subjects who are resistant to the reversal of in-flight symptoms and physiological status through the application of LBNP will be more susceptible to persistent flight-induced vision alterations.

Hypothesis 9: Propensity towards more severe changes in-flight and the more indolent postflight resolution pattern will correlate with a range of individual characteristics of the crewmembers, such as anatomical and microanatomical and physiological features and potentially, hitherto unsuspected factors.

NOTE: This study was merged with investigations from Dr. Alan Hargens (Fluid distribution before, during and after prolonged space flight) and Dr. Michael Stenger (Distribution of Body Fluids during Long Duration Space Flight and Subsequent Effects on Intraocular Pressure and Vision Disturbance) 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).

Dr. Mark Haacke’s group was added to the team in 2019 in order to enhance analytical capabilities for 3T magnetic resonance imaging (MRI) data. Dr. Haacke and his team has unique specialization in the analysis of susceptibility-weighted imaging (SWI) data from brain MRI protocols, as well as other vascular aspects of MRI protocols. Therefore, emphasis in the recent period was put on the analysis of SWI and Time-of-Flight (TOF) venography data collected as part of the 3T MRI protocol from the head and neck. Preliminary analysis of large neck vessels is complete; further analysis on this and other objectives is underway. The resultant data are verified and organized for statistical analysis, and reviewed periodically as more progress is made. This subset of data was reviewed in detail on 11/13/2020 at the Fluid Shifts Workshop (internal to Fluid Shifts/FS investigators) as a status presentation. The team at large acknowledged the scientific value of the data derived so far.

Dr. David Kemp continues to provide invaluable otoacoustic emission (OAE) expertise, streamlining and refining OAE analysis methods. We have focused our analysis on transient evoked OAE (TEOAE) phase shifts, which are highly systematic in response to posture change and lower body negative pressure during ground testing. OAE results indicate that overall, oval window tension (a surrogate for intracranial pressure) is not significantly elevated during spaceflight. Preliminary analysis has been completed on all data collected to date.

Data collected as a part of this project were included in two presentations at the 2020 Human Research Program Investigators' Workshop in Galveston, TX. In addition, a crew report was completed to highlight individual results from that crewmembers’ participation in this study. Partial results from this investigation were made available as part of a publication in JAMA Network which described a venous thrombosis in a crewmember during spaceflight, resulting in a number of news requests and media coverage.

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

Fifty percent of American astronauts have developed ocular refraction change after long duration space flight on the International Space Station (ISS). Recent findings have also included structural changes of the eye (papilledema, globe flattening, choroidal folds) and the optic nerve (sheath dilatation, tortuosity, and kinking), as well as imaging signs and lumbar puncture data indicative of elevated intracranial pressure (ICP). While short duration space flight is also characterized by vision disturbances, these are generally transient and do not appear to have lasting impacts on the structure or function of the eye. Changes in vision, eye, and adnexa morphology are hypothesized to be the result of space flight-induced cephalad fluid shifts and transiently elevated intracranial pressure. This hypothesis, however, has not been systematically tested. In earlier anecdotal publications, ICP elevation in long-duration space flight has been inferred but without association with structural or functional changes of the eye. Furthermore, while fluid shifts and compartmentalization during short-duration space flight (Space Shuttle missions) have been studied, the fluid distribution patterns and their effects on intracranial pressure or the structure and function of the sensory organs in the course of long-duration space flight are not well known.

Several ISS crewmembers have reported consistent worsening of nasal congestion and associated symptoms in late afternoon hours, necessitating topical and systemic decongestant use. Although several explanations have been entertained, food (salt) and water intake are likely to have provoked these symptoms through postprandial modification of fluid balance or increase in the circulating volume that manifests in the most susceptible individuals.

The purpose of the proposed work is to objectively characterize the changes in fluid distribution, including intra/extracellular and intra/extravascular fluid shifts, by applying advanced non-invasive assessment technologies before, during, and after long duration space flight. Additionally, we will examine the relationship between the type and magnitude of the fluid shift with any effects on eye morphology and vision disturbances, intraocular pressure (IOP), and measures of intracranial pressure. Further, we seek to determine whether the magnitude of fluid shifts during space flight, as well as the above effects of those shifts can be predicted based upon crewmember baseline data and responses to acute head-down tilt tests performed before launch. Finally, we propose to evaluate the effect of lower body negative pressure (LBNP) on the above parameters.

To our knowledge, this is the first attempt to systematically determine the impact of the fluid distribution in microgravity on a comprehensive set of structural and functional measures including, but not limited to, those related to intracranial pressure, vision, morphology of the eye and its adnexa, and the vascular systems of the head and neck, during and after long duration space flight. The study design and methodology are based on the extensive relevant experience of the Investigators, including many successful ground-based, space flight analogue, and space flight projects and investigations.

Primary Hypothesis

Prolonged microgravity-induced, headward volume, and pressure shifts promote elevation of intracranial pressure and result in alterations in crewmembers’ vision.

Specific Aims

Specific Aim I: To characterize fluid distribution and compartmentalization before, during, and after long-duration space flight.

Hypothesis 1: Fluid distribution measured by dilution techniques will reflect a headward fluid shift and an intra- to extra-vascular fluid shift during space flight, returning to pre-flight condition after landing.

Hypothesis 2: Regional headward fluid shifts in-flight are documented by increased cephalad venous dimensions (jugular veins) and flow characteristics, skin and soft tissue thickness.

Hypothesis 3: Fluid re-distribution towards the eye (detected in choroid, retina, and optic nerve head using ultrasonography and optical coherence tomography), and in arteries supplying ocular vascular beds, contributes to vision alterations.

Hypothesis 4: Splanchnic venous congestion (detected by portal vein size) contributes to headward volume shift, but is not in communication with the veins of head and neck. Thus, there should be a different level of venous congestion in these two compartments.

Specific Aim II: To correlate in-flight alterations of eye structure, ocular vascular parameters, and vision with headward fluid shifts, vascular dimensions, and flow patterns.

Hypothesis 5: Space flight-induced fluid shifts will have an upregulating effect on ICP and will alter ocular refraction / visual acuity. These changes will vary in magnitude and respectively, in their resolution pattern after space flight.

Hypothesis 6: In-flight ICP-related measures, IOP (intraocular pressure), venous and arterial morphometric and flow characteristics, vascular resistance of ocular vascular beds, and optic nerve anatomy will trend towards normal-gravity levels temporarily during and residually after fluid sequestration (LBNP) interventions.

Specific Aim III: To determine systemic and ocular factors of individual susceptibility to the development of ICP elevation and/or vision alterations.

Hypothesis 7: Subjects with greater fluid shifts (as measured by the ultrasound method in Aim 1) during pre-flight testing will experience greater fluid shifts in-flight and will be more susceptible to flight-induced vision alterations.

Hypothesis 8: Subjects who are resistant to the reversal of in-flight symptoms and physiological status through the application of LBNP will be more susceptible to persistent flight-induced vision alterations.

Hypothesis 9: Propensity towards more severe changes in-flight and the more indolent postflight resolution pattern will correlate with a range of individual characteristics of the crewmembers, such as anatomical and microanatomical and physiological features and potentially, hitherto unsuspected factors.

NOTE: This study was merged with investigations from Dr. Alan Hargens (Fluid distribution before, during and after prolonged space flight) and Dr. Michael Stenger (Distribution of Body Fluids during Long Duration Space Flight and Subsequent Effects on Intraocular Pressure and Vision Disturbance) 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).

Dr. Mark Haacke’s group was added to the team in 2019 in order to enhance analytical capabilities for 3T MRI data. Dr. Haacke and his team have unique specialization in the analysis of susceptibility-weighted imaging (SWI) data from brain MRI protocols, as well as other vascular aspects of MRI protocols. Therefore, emphasis in the recent period was put on the analysis of SWI and Time-of-Flight (TOF) venography data collected as part of the 3T MRI protocol from the head and neck. Preliminary analysis of large neck vessels is complete; further analysis on this and other objectives is underway. The resultant data are verified and organized for statistical analysis, and reviewed periodically as more progress is made. This subset of data was reviewed in detail on 11/13/2020 at the Fluid Shifts Workshop (internal to FS investigators) as a status presentation. The team at large acknowledged the scientific value of the data derived so far.

Dr. David Kemp continues to provide invaluable otoacoustic emission (OAE) expertise, streamlining and refining OAE analysis methods. We have focused our analysis on transient evoked OAE (TEOAE) phase shifts, which are highly systematic in response to posture change and lower body negative pressure during ground testing. OAE results indicate that overall, oval window tension (a surrogate for intracranial pressure) is not significantly elevated during space flight. Preliminary analysis has been completed on all data collected to date.

Data collected as a part of this project were included in two presentations at the 2020 Human Research Program Investigators' Workshop in Galveston, TX. In addition, a crew report was completed to highlight individual results from that crewmembers’ participation in this study.

Partial results from this investigation were made available as part of a publication in JAMA Network which described a venous thrombosis in a crewmember during space flight, resulting in a number of news requests and media coverage.

Bibliography:

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. doi: 10.1001/jamanetworkopen.2019.15011. PMID: 31722025

Abstracts:

M. B. Stenger, A. R. Hargens, S. A. Dulchavsky, P. Arbeille, R. W. Danielson, D. J. Ebert, S. S. Laurie, S. Johnston, S. M. C. Lee, J. Liu, B. Macias, D. S. Martin, L. Minkoff, R. Ploutz-Snyder, L. C. Ribeiro, A. Sargsyan, and S. M. Smith. Fluid Shifts. Human Research Program Investigators Workshop. Galveston, TX, January 2020.

Related abstracts:

D. Kemp, D. Ebert, R. Danielson, K. Marshall-Goebel, B. Macias, and M. Stenger. Use of Otoacoustic Phase Change to Evaluate Countermeasures for Spaceflight-associated Neuro-ocular Syndrome. Human Research Program Investigators Workshop. Galveston, TX, January 2020.

Fifty percent of American astronauts have developed ocular refraction change after long duration space flight on the International Space Station (ISS). Recent findings have also included structural changes of the eye (papilledema, globe flattening, choroidal folds) and the optic nerve (sheath dilatation, tortuosity, and kinking), as well as imaging signs and lumbar puncture data indicative of elevated intracranial pressure (ICP). While short duration space flight is also characterized by vision disturbances, these are generally transient and do not appear to have lasting impacts on the structure or function of the eye. Changes in vision, eye, and adnexa morphology are hypothesized to be the result of space flight-induced cephalad fluid shifts and transiently elevated intracranial pressure. This hypothesis, however, has not been systematically tested. In earlier anecdotal publications, ICP elevation in long-duration space flight has been inferred but without association with structural or functional changes of the eye. Furthermore, while fluid shifts and compartmentalization during short-duration space flight (Space Shuttle missions) have been studied, the fluid distribution patterns and their effects on intracranial pressure or the structure and function of the sensory organs in the course of long-duration space flight are not well known.

Several ISS crewmembers have reported consistent worsening of nasal congestion and associated symptoms in late afternoon hours, necessitating topical and systemic decongestant use. Although several explanations have been entertained, food (salt) and water intake are likely to have provoked these symptoms through postprandial modification of fluid balance or increase in the circulating volume that manifests in the most susceptible individuals.

The purpose of the proposed work is to objectively characterize the changes in fluid distribution, including intra/extracellular and intra/extravascular fluid shifts, by applying advanced non-invasive assessment technologies before, during, and after long duration space flight. Additionally, we will examine the relationship between the type and magnitude of the fluid shift with any effects on eye morphology and vision disturbances, intraocular pressure (IOP), and measures of intracranial pressure. Further, we seek to determine whether the magnitude of fluid shifts during space flight, as well as the above effects of those shifts can be predicted based upon crewmember baseline data and responses to acute head-down tilt tests performed before launch. Finally, we propose to evaluate the effect of lower body negative pressure (LBNP) on the above parameters.

To our knowledge, this is the first attempt to systematically determine the impact of the fluid distribution in microgravity on a comprehensive set of structural and functional measures including, but not limited to, those related to intracranial pressure, vision, morphology of the eye and its adnexa, and the vascular systems of the head and neck, during and after long duration space flight. The study design and methodology are based on the extensive relevant experience of the Investigators, including many successful ground-based, space flight analogue, and space flight projects and investigations.

Primary Hypothesis

Prolonged microgravity-induced, headward volume, and pressure shifts promote elevation of intracranial pressure and result in alterations in crewmembers’ vision.

Specific Aims

Specific Aim I: To characterize fluid distribution and compartmentalization before, during, and after long-duration space flight.

Hypothesis 1: Fluid distribution measured by dilution techniques will reflect a headward fluid shift and an intra- to extra-vascular fluid shift during space flight, returning to pre-flight condition after landing.

Hypothesis 2: Regional headward fluid shifts in-flight are documented by increased cephalad venous dimensions (jugular veins) and flow characteristics, skin and soft tissue thickness.

Hypothesis 3: Fluid re-distribution towards the eye (detected in choroid, retina, and optic nerve head using ultrasonography and optical coherence tomography), and in arteries supplying ocular vascular beds, contributes to vision alterations.

Hypothesis 4: Splanchnic venous congestion (detected by portal vein size) contributes to headward volume shift, but is not in communication with the veins of head and neck. Thus, there should be a different level of venous congestion in these two compartments.

Specific Aim II: To correlate in-flight alterations of eye structure, ocular vascular parameters, and vision with headward fluid shifts, vascular dimensions, and flow patterns.

Hypothesis 5: Space flight-induced fluid shifts will have an upregulating effect on ICP and will alter ocular refraction / visual acuity. These changes will vary in magnitude and respectively, in their resolution pattern after space flight.

Hypothesis 6: In-flight ICP-related measures, IOP (intraocular pressure), venous and arterial morphometric and flow characteristics, vascular resistance of ocular vascular beds, and optic nerve anatomy will trend towards normal-gravity levels temporarily during and residually after fluid sequestration (LBNP) interventions.

Specific Aim III: To determine systemic and ocular factors of individual susceptibility to the development of ICP elevation and/or vision alterations.

Hypothesis 7: Subjects with greater fluid shifts (as measured by the ultrasound method in Aim 1) during pre-flight testing will experience greater fluid shifts in-flight and will be more susceptible to flight-induced vision alterations.

Hypothesis 8: Subjects who are resistant to the reversal of in-flight symptoms and physiological status through the application of LBNP will be more susceptible to persistent flight-induced vision alterations.

Hypothesis 9: Propensity towards more severe changes in-flight and the more indolent postflight resolution pattern will correlate with a range of individual characteristics of the crewmembers, such as anatomical and microanatomical and physiological features and potentially, hitherto unsuspected factors.

NOTE: This study was merged with investigations from Dr. Alan Hargens (Fluid distribution before, during and after prolonged space flight) and Dr. Michael Stenger (Distribution of Body Fluids during Long Duration Space Flight and Subsequent Effects on Intraocular Pressure and Vision Disturbance ) 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).

Hardware and procedures have run smoothly this past year, with no major failures. However, the FS team has continued to collectively respond to changes in circumstances, most notably the ascent abort of Soyuz MS-10 which was to carry the Expedition 57 crew to the ISS. This event necessitated adjustment of inflight and postflight data collection schedules.

Supine and tilted 3T MRI data collections continued at the Victory Lakes facility (University of Texas Medical Branch-UTMB) facility, taking advantage of the existing MRID (MED B) pulse sequences. Subjects continued to tolerate the procedure well and all early assessments of data quality gave satisfactory results. Since 2016, the team includes Dr. Larry Kramer (University of Texas Health Science Center-Houston (UTHSC-H)) for general MRI advising and assistance with data analysis. Specifically, work is underway for CSF (cerebrospinal fluid) flow quantification in the Sylvian aqueduct and determination of pre- and postflight CSF production rates. Other MRI analysis methods continue to be refined to optimize data analysis in terms of quality and resources. Notwithstanding the decision by Medical Operations to use IV contrast during MED B MRI scans as the preferred version for venography, none of the Fluid Shifts subjects has received contrast injections and data collections are likely to continue with non-contrast techniques. Dr. Mark Haacke has recently been added to the team, who is a specialist in the collection and analysis of MRI venography data. He will complete the MRI analysis team, adding expertise in the analysis of susceptibility weighted imaging (SWI), and time of flight (TOF venography) in the head and neck. The subcontract has been established for this work and analysis will begin in the near future.

The remaining three subjects are US crewmembers; therefore, challenges that the team experienced with remote (Moscow and Cologne) postflight MRI and physiological testing are not a concern.

The “free-floating” use of the optical coherence tomography (OCT) device for inflight Chibis sessions continues to work well for crewmembers, resulting in similar exam times and data quality when compared to the traditional chinrest method. The Johnson Space Center (JSC) Cardiovascular and Vision Laboratory upgraded to the Heidelberg Engineering OCT2 in 2017, and the ISS unit was upgraded in 2018. OCT2 provides faster scanning time, and better image depth and resolution.

Similar to other measures, ultrasound data are collected in the inflight baseline state (Columbus module) and again during Chibis (Russian Service Module), which allows us to contrast space normal to the lower negative pressure state induced by the Chibis device. Transcranial Doppler, optic nerve sheath diameter (ONSD), central retinal and ophthalmic artery Doppler, among other parameters, are being analyzed to compare conditions and individual subject variation.

Our team has continued to make advances in the analysis of otoacoustic emission (OAE) data over the past year. Dr. David Kemp continues to provide invaluable OAE expertise, streamlining and refining the OAE analysis methods. We have focused our analysis on transient evoked OAE (TEOAE) phase shifts, which have been highly systematic in response to posture change and lower body negative pressure during preflight testing. TEOAE phase shifts are consistent with expected intracranial pressure changes due to HDT (head down tilt), and appear to be consistent across multiple subjects. OAE results indicate that overall, oval window tension (a surrogate for intracranial pressure) is not systematically elevated during space flight. Our team attended the NASA Human Research Program (HRP) Investigators’ Workshop in Galveston, TX in January 2019, presenting an overall project poster for Fluid Shifts and participating in many Spaceflight Associated Neuro-ocular Syndrome (SANS)-related sessions and discussions. Our team also presented a poster highlighting our otoacoustic emissions findings in FS subjects. These findings were combined with prior data collected in collaboration with our 2016 summer intern (T. Caldwell), as well as with data from the impedance threshold device (ITD) project, to present the mechanistic relationships between TEOAE stimulation and response phases, middle ear pressure, and intracranial pressure. Tympanometry data from the Fluid Shifts study indicates a trend toward negative middle ear pressure in flight, and therefore there has been increased interest in the effects of middle ear pressure on OAE and cerebral and cochlear fluid pressure (CCFP) measures.

Presentations (past year):

1) Kemp D, Ebert D, Melgoza R, Danielson R, Stenger M, Hargens A, Dulchavsky S. Otoacoustic Emissions Phase as an Indicator of Intracranial Pressure Change: Basis and Optimization for Fluid Shifts Studies. Presented at the Human Research Program Investigators’ Workshop, Galveston, TX, January 22-25, 2019.

2) Stenger MB, Hargens AR, Dulchavsky SA, Arbielle P, Danielson RW, Ebert DJ, Johnston SL, Laurie SS, Lee SMC, Liu J, Macias B, Martin DS, Minkoff L, Ploutz-Snyder R, Ribeiro LC, Sargsyan A, Smith SM. Fluid Shifts. Presented at the Human Research Program Investigators’ Workshop, Galveston, TX, January 22-25, 2019.

3) Macias BR, Laurie SS, Lee SMC, Martin DS, Ploutz-Snyder R, Sargsyan A, Marshall-Goebel K, Ebert DJ, Dulchavsky SA, Hargens AR, Stenger MB. Elevated Intracranial Pressure Does Not Explain Spaceflight-Induced Optic Disc Edema. Presented at the Association for Research in Vision and Ophthalmology Annual Meeting, Vancouver, B.C., April 28-May 2, 2019.

Related Publication:

1) Garrett-Bakelman F.E., et al. (including D. Ebert). The NASA Twins Study: A multi-dimensional analysis of a year-long human spaceflight. Science. 2019 Apr 12;364 (6436).

Fifty percent of American astronauts have developed ocular refraction change after long duration space flight on the International Space Station (ISS). Recent findings have also included structural changes of the eye (papilledema, globe flattening, choroidal folds) and the optic nerve (sheath dilatation, tortuosity, and kinking), as well as imaging signs and lumbar puncture data indicative of elevated intracranial pressure (ICP). While short duration space flight is also characterized by vision disturbances, these are generally transient and do not appear to have lasting impacts on the structure or function of the eye. Changes in vision, eye, and adnexa morphology are hypothesized to be the result of space flight-induced cephalad fluid shifts and transiently elevated intracranial pressure. This hypothesis, however, has not been systematically tested. In earlier anecdotal publications, ICP elevation in long-duration space flight has been inferred but without association with structural or functional changes of the eye. Furthermore, while fluid shifts and compartmentalization during short-duration space flight (Space Shuttle missions) have been studied, the fluid distribution patterns and their effects on intracranial pressure or the structure and function of the sensory organs in the course of long-duration space flight are not well known.

Several ISS crewmembers have reported consistent worsening of nasal congestion and associated symptoms in late afternoon hours, necessitating topical and systemic decongestant use. Although several explanations have been entertained, food (salt) and water intake are likely to have provoked these symptoms through postprandial modification of fluid balance or increase in the circulating volume that manifests in the most susceptible individuals.

The purpose of the proposed work is to objectively characterize the changes in fluid distribution, including intra/extracellular and intra/extravascular fluid shifts, by applying advanced non-invasive assessment technologies before, during, and after long duration space flight. Additionally, we will examine the relationship between the type and magnitude of the fluid shift with any effects on eye morphology and vision disturbances, intraocular pressure (IOP), and measures of intracranial pressure. Further, we seek to determine whether the magnitude of fluid shifts during space flight, as well as the above effects of those shifts can be predicted based upon crewmember baseline data and responses to acute head-down tilt tests performed before launch. Finally, we propose to evaluate the effect of lower body negative pressure (LBNP) on the above parameters.

To our knowledge, this is the first attempt to systematically determine the impact of the fluid distribution in microgravity on a comprehensive set of structural and functional measures including, but not limited to, those related to intracranial pressure, vision, morphology of the eye and its adnexa, and the vascular systems of the head and neck, during and after long duration space flight. The study design and methodology are based on the extensive relevant experience of the Investigators, including many successful ground-based, space flight analogue, and space flight projects and investigations.

Primary Hypothesis

Prolonged microgravity-induced, headward volume, and pressure shifts promote elevation of intracranial pressure and result in alterations in crewmembers’ vision.

Specific Aims

Specific Aim I: To characterize fluid distribution and compartmentalization before, during, and after long-duration space flight.

Hypothesis 1: Fluid distribution measured by dilution techniques will reflect a headward fluid shift and an intra- to extra-vascular fluid shift during space flight, returning to pre-flight condition after landing.

Hypothesis 2: Regional headward fluid shifts in-flight are documented by increased cephalad venous dimensions (jugular veins) and flow characteristics, skin and soft tissue thickness.

Hypothesis 3: Fluid re-distribution towards the eye (detected in choroid, retina, and optic nerve head using ultrasonography and optical coherence tomography), and in arteries supplying ocular vascular beds, contributes to vision alterations.

Hypothesis 4: Splanchnic venous congestion (detected by portal vein size) contributes to headward volume shift, but is not in communication with the veins of head and neck. Thus, there should be a different level of venous congestion in these two compartments.

Specific Aim II: To correlate in-flight alterations of eye structure, ocular vascular parameters, and vision with headward fluid shifts, vascular dimensions, and flow patterns.

Hypothesis 5: Space flight-induced fluid shifts will have an upregulating effect on ICP and will alter ocular refraction / visual acuity. These changes will vary in magnitude and respectively, in their resolution pattern after space flight.

Hypothesis 6: In-flight ICP-related measures, IOP (intraocular pressure), venous and arterial morphometric and flow characteristics, vascular resistance of ocular vascular beds, and optic nerve anatomy will trend towards normal-gravity levels temporarily during and residually after fluid sequestration (LBNP) interventions.

Specific Aim III: To determine systemic and ocular factors of individual susceptibility to the development of ICP elevation and/or vision alterations.

Hypothesis 7: Subjects with greater fluid shifts (as measured by the ultrasound method in Aim 1) during pre-flight testing will experience greater fluid shifts in-flight and will be more susceptible to flight-induced vision alterations.

Hypothesis 8: Subjects who are resistant to the reversal of in-flight symptoms and physiological status through the application of LBNP will be more susceptible to persistent flight-induced vision alterations.

Hypothesis 9: Propensity towards more severe changes in-flight and the more indolent postflight resolution pattern will correlate with a range of individual characteristics of the crewmembers, such as anatomical and microanatomical and physiological features and potentially, hitherto unsuspected factors.

NOTE: This study was merged with investigations from Dr. Alan Hargens (Fluid distribution before, during and after prolonged space flight) and Dr. Michael Stenger (Distribution of Body Fluids during Long Duration Space Flight and Subsequent Effects on Intraocular Pressure and Vision Disturbance ) 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).

Since last year, three additional subjects have been approved for the FS experiment, bringing the total subject count to 13. As noted above, data collection is complete for the first 10 subjects and preflight data collection is complete for the eleventh subject. Training is underway for the last three subjects. The currently planned flight manifest will have one Fluid Shifts subject on each of the next three ISS missions.

Hardware and procedures have run smoothly this past year, with no major failures. However, the FS team has continued to collectively respond to changes in circumstances, most notably the extension of the mission length for the Expedition 51 Commander. This mission was previously planned as a standard 6 month mission but was extended to over 9 months, necessitating adjustment of inflight and postflight data collection schedules.

Supine and tilted 3T MRI data collections continued at the Victory Lakes facility (University of Texas Medical Branch-UTMB), taking advantage of the existing MRID (MED B) pulse sequences. Subjects continued to tolerate the procedure well and all early assessments of data quality gave satisfactory results. Since 2016, the team includes Dr. Larry Kramer (University of Texas Health Science Center-Houston (UTHSC-H)) for general MRI advising and assistance with data analysis. Specifically, work is underway for CSF (cerebrospinal fluid) flow quantification in the Sylvian aqueduct and determination of pre- and postflight CSF production rates. Other MRI analysis methods continue to be refined to optimize data analysis in terms of quality and resources. Notwithstanding the decision by Medical Operations to use IV contrast during MED B MRI scans as the preferred version for venography, none of the Fluid Shifts subjects has received contrast injections and data collections are likely to continue with non-contrast techniques. We are in the process of adding Dr. Mark Haacke to the team, who is a specialist in the collection and analysis of MRI venography data. He will complete the MRI analysis team with the analysis of susceptibility weighted imaging (SWI), and time of flight (TOF venography) in the head and neck.

Since Russian and European Space Agency (ESA) subjects “direct return” to their respective countries, immediate postflight testing in Houston is not possible. The imaging procedure was standardized among UTMB, Research Center of Neurology in Moscow, Russia, and DLR/:envihab in Cologne, Germany. Both Partner facilities were equipped with -15 degree foam wedges and have prior experience with tilted MRI. Postflight MRI sessions for Russian and ESA crewmembers this past year were successful.

Fifty percent of American astronauts have developed ocular refraction change after long duration space flight on the International Space Station (ISS). Recent findings have also included structural changes of the eye (papilledema, globe flattening, choroidal folds) and the optic nerve (sheath dilatation, tortuosity, and kinking), as well as imaging signs and lumbar puncture data indicative of elevated intracranial pressure (ICP). While short duration space flight is also characterized by vision disturbances, these are generally transient and do not appear to have lasting impacts on the structure or function of the eye. Changes in vision, eye, and adnexa morphology, are hypothesized to be the result of space flight-induced cephalad fluid shifts and transiently elevated intracranial pressure. This hypothesis, however, has not been systematically tested. In earlier anecdotal publications, ICP elevation in long-duration space flight has been inferred but without association with structural or functional changes of the eye. Furthermore, while fluid shifts and compartmentalization during short-duration space flight (Space Shuttle missions) have been studied, the fluid distribution patterns and their effects on intracranial pressure or the structure and function of the sensory organs in the course of long-duration space flight are not well known.

Several ISS crewmembers have reported consistent worsening of nasal congestion and associated symptoms in late afternoon hours, necessitating topical and systemic decongestant use. Although several explanations have been entertained, food (salt) and water intake are likely to have provoked these symptoms through postprandial modification of fluid balance or increase in the circulating volume that manifests in the most susceptible individuals.

The purpose of the proposed work is to objectively characterize the changes in fluid distribution, including intra/extracellular and intra/extravascular fluid shifts, by applying advanced non-invasive assessment technologies before, during, and after long duration space flight. Additionally, we will examine the relationship between the type and magnitude of the fluid shift with any effects on eye morphology and vision disturbances, intraocular pressure (IOP), and measures of intracranial pressure. Further, we seek to determine whether the magnitude of fluid shifts during space flight, as well as the above effects of those shifts can be predicted based upon crewmember baseline data and responses to acute head-down tilt tests performed before launch. Finally, we propose to evaluate the effect of lower body negative pressure (LBNP) on the above parameters.

To our knowledge, this is the first attempt to systematically determine the impact of the fluid distribution in microgravity on a comprehensive set of structural and functional measures including, but not limited to, those related to intracranial pressure, vision, morphology of the eye and its adnexa, and the vascular systems of the head and neck, during and after long duration space flight. The study design and methodology are based on the extensive relevant experience of the Investigators, including many successful ground-based, space flight analogue, and space flight projects and investigations.

Primary Hypothesis

Prolonged microgravity-induced, headward volume, and pressure shifts promote elevation of intracranial pressure and result in alterations in crewmembers’ vision.

Specific Aims

Specific Aim I: To characterize fluid distribution and compartmentalization before, during, and after long-duration space flight.

Hypothesis 1: Fluid distribution measured by dilution techniques will reflect a headward fluid shift and an intra- to extra-vascular fluid shift during space flight, returning to pre-flight condition after landing.

Hypothesis 2: Regional headward fluid shifts in-flight are documented by increased cephalad venous dimensions (jugular veins) and flow characteristics, skin and soft tissue thickness.

Hypothesis 3: Fluid re-distribution towards the eye (detected in choroid, retina, and optic nerve head using ultrasonography and optical coherence tomography), and in arteries supplying ocular vascular beds, contributes to vision alterations.

Hypothesis 4: Splanchnic venous congestion (detected by portal vein size) contributes to headward volume shift, but is not in communication with the veins of head and neck. Thus, there should be a different level of venous congestion in these two compartments.

Specific Aim II: To correlate in-flight alterations of eye structure, ocular vascular parameters, and vision with headward fluid shifts, vascular dimensions, and flow patterns.

Hypothesis 5: Space flight-induced fluid shifts will have an upregulating effect on ICP and will alter ocular refraction / visual acuity. These changes will vary in magnitude and respectively, in their resolution pattern after space flight.

Hypothesis 6: In-flight ICP-related measures, IOP (intraocular pressure), venous and arterial morphometric and flow characteristics, vascular resistance of ocular vascular beds, and optic nerve anatomy will trend towards normal-gravity levels temporarily during and residually after fluid sequestration (LBNP) interventions.

Specific Aim III: To determine systemic and ocular factors of individual susceptibility to the development of ICP elevation and/or vision alterations.

Hypothesis 7: Subjects with greater fluid shifts (as measured by the ultrasound method in Aim 1) during pre-flight testing will experience greater fluid shifts in-flight and will be more susceptible to flight-induced vision alterations.

Hypothesis 8: Subjects who are resistant to the reversal of in-flight symptoms and physiological status through the application of LBNP will be more susceptible to persistent flight-induced vision alterations.

Hypothesis 9: Propensity towards more severe changes in-flight and the more indolent postflight resolution pattern will correlate with a range of individual characteristics of the crewmembers, such as anatomical and microanatomical and physiological features and potentially, hitherto unsuspected factors.

NOTE: This study was merged with investigations from Dr. Alan Hargens (Fluid distribution before, during and after prolonged space flight) and Dr. Michael Stenger (Distribution of Body Fluids during Long Duration Space Flight and Subsequent Effects on Intraocular Pressure and Vision Disturbance ) 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).

The FS team has continued to collectively respond to changes in circumstances (inflight schedules, Russian travel limitations, hardware failures, etc.). The Cochlear and Cerebral Fluid Pressure (CCFP) Analyzer’s hard drive failed in August 2016 which resulted in the loss of inflight CCFP and tympanometry data until a replacement unit was delivered on orbit in November 2016. In January 2017 one of the otoacoustic emission analyzer’s probes became clogged with earwax so the backup probe is being used for continued data collection. Procedures were developed and successfully implemented in February 2017 to clean the primary probe. The Fluid Shifts team has also developed several alternate data collection plans based on changing crew schedules, most recently including the potential for an extended mission for the Expedition 51 Commander.

Supine and tilted 3T MRI data collections continued at the Victory Lakes facility (UTMB--University of Texas Medical Branch), taking advantage of the existing MRID (MED B) pulse sequences. Subjects continued to tolerate the procedure well and all early assessments of data quality gave satisfactory results. Since 2016, the team includes Dr. Larry Kramer (UTHSC-H) for general MRI advising and assistance with data analysis. Specifically, work is underway for CSF (cerebrospinal fluid) flow quantification in the Sylvian aqueduct and determination of pre- and postflight CSF production rates. Other MRI analysis methods continue to be refined to optimize data analysis in terms of quality and resources. Despite the decision by Medical Operations to use IV contrast during MED B MRI scans as the preferred version for venography, none of the Fluid Shifts subjects has received contrast injections and data collections are likely to continue with non-contrast techniques.

Since Russian and European Space Agency (ESA) subjects will “direct return” to their respective countries, immediate postflight testing in Houston will not be possible. We have been working to standardize the imaging procedure and protocol elements among UTMB, Research Center of Neurology in Moscow, Russia, and DLR/:envihab in Cologne, Germany. Both Partner facilities are equipped with -15 degree foam wedges and have prior experience with tilted MRI. A test run of all sequences was performed at DLR in a healthy volunteer (February 2017), and subsequent evaluation of data was performed. Additional testing may be conducted in March to complete standardization. A similar effort is underway with the Russian facility, which has demonstrated the ability to perform the protocol with satisfactory results. Additional efforts will be made to optimize the data in the 2 remaining postflight sessions.

The “free-floating” use of the OCT device for inflight Chibis sessions continues to work well for crewmembers, resulting in similar exam times and data quality when compared to the traditional chinrest method.

Similar to other measures, ultrasound data is collected in the inflight baseline state (Columbus module) and again during Chibis (Russian Service Module), which allows us to contrast space normal to the lower negative pressure state induced by the Chibis device. Transcranial Doppler, optic nerve sheath diameter, central retinal and ophthalmic artery Doppler, among other parameters, are being analyzed to compare conditions and individual subject variation.

Our team has continued to make advances in the analysis of otoacoustic emission (OAE) data over the past year. Dr. David Kemp continues to provide invaluable OAE expertise and has further automated his OAE processing software. Rozela Melgoza returned for a second summer audiology internship in 2016 and continued to be a major contributor for data processing and exploration of data nuances under Dr. Kemp’s guidance. We have focused our analysis on transient evoked OAE (TEOAE) phase shifts, which have been highly systematic in response to posture change and lower body negative pressure during preflight testing. TEOAE phase shifts are consistent with expected intracranial pressure changes due to HDT, and appear to be consistent across multiple subjects. The team was fortunate to host a second audiology summer intern in 2016 (Tyler Caldwell). Tyler preformed ground studies to define the effect of probe positioning, middle ear pressure, and head-down tilt on OAE stimulus and response signals, which resulted in two posters related to Fluid Shifts, one at the NASA Human Research Program (HRP) Investigators’ Workshop 2017 and one at the Texas Academy of Audiology. A third abstract related to this summer internship work has been submitted to the American Academy of Audiology meeting which will be held in April 2017.

Our team attended the NASA HRP Investigators’ Workshop in Galveston, TX in January 2017, presenting an overall project lecture for Fluid Shifts and participating in many Vision Impairment and Intracranial Pressure (VIIP)-related sessions and discussions. Our team also presented two otoacoustic emissions posters based on methods developed and data collected for the Fluid Shifts project.

Presentations (past year):

1) Caldwell T, Ebert DJ, Danielson R, Kemp D, Le Prell C. Assessing the Utility of Otoacoustic Emissions for Monitoring Intracranial Pressure in Microgravity through Analog Observations. Presented at the 17th Annual Texas Academy of Audiology Conference, Dallas, TX, October 20-22, 2016.

2) Caldwell T, Ebert D, Kemp D, Danielson R, Stenger M. Effects of Middle Ear Pressure and Intracranial Pressure on Transient-Evoked Otoacoustic Emissions. Human Research Program Investigators’ Workshop, Galveston, TX, January 23-26, 2017.

3) Kemp D, Melgoza R, Ebert D, Danielson R, Stenger M, Hargens A, Dulchavsky S. Otoacoustic Emissions in Fluid Shift Studies: Methodology and Confounding Factors. Human Research Program Investigators’ Workshop, Galveston, TX, January 23-26, 2017.

4) Melgoza R, Kemp D, Ebert D, Danielson R, Stenger M, Hargens A, Dulchavsky S. A Longitudinal Study of Transient Evoked Otoacoustic Emissions in Relation to Spaceflight (Fluid Shifts). Human Research Program Investigators’ Workshop, Galveston, TX, January 23-26, 2017.

5) Stenger MB, Hargens AR, Dulchavsky SA, Arbielle P, Danielson RW, Ebert DJ, Garcia KM, Johnston SL, Laurie SS, Lee SMC, Liu J, Macias B, Martin DS, Minkoff L, Ploutz-Snyder R, Ribeiro LC, Sargsyan A, Smith SM. Fluid Shifts. Human Research Program Investigators’ Workshop, Galveston, TX, January 23-26, 2017.

Fifty percent of American astronauts have developed ocular refraction change after long duration space flight on the International Space Station (ISS). Recent findings have also included structural changes of the eye (papilledema, globe flattening, choroidal folds) and the optic nerve (sheath dilatation, tortuosity, and kinking), as well as imaging signs and lumbar puncture data indicative of elevated intracranial pressure (ICP). While short duration space flight is also characterized by vision disturbances, these are generally transient and do not appear to have lasting impacts on the structure or function of the eye. Changes in vision, eye, and adnexa morphology, are hypothesized to be the result of space flight-induced cephalad fluid shifts and transiently elevated intracranial pressure. This hypothesis, however, has not been systematically tested. In earlier anecdotal publications, ICP elevation in long-duration space flight has been inferred but without association with structural or functional changes of the eye. Furthermore, while fluid shifts and compartmentalization during short-duration space flight (Space Shuttle missions) have been studied, the fluid distribution patterns and their effects on intracranial pressure or the structure and function of the sensory organs in the course of long-duration space flight are not well known.

Several ISS crewmembers have reported consistent worsening of nasal congestion and associated symptoms in late afternoon hours, necessitating topical and systemic decongestant use. Although several explanations have been entertained, food (salt) and water intake are likely to have provoked these symptoms through postprandial modification of fluid balance or increase in the circulating volume that manifests in the most susceptible individuals.

The purpose of the proposed work is to objectively characterize the changes in fluid distribution, including intra/extracellular and intra/extravascular fluid shifts, by applying advanced non-invasive assessment technologies before, during, and after long duration space flight. Additionally, we will examine the relationship between the type and magnitude of the fluid shift with any effects on eye morphology and vision disturbances, intraocular pressure (IOP), and measures of intracranial pressure. Further, we seek to determine whether the magnitude of fluid shifts during space flight, as well as the above effects of those shifts can be predicted based upon crewmember baseline data and responses to acute head-down tilt tests performed before launch. Finally, we propose to evaluate the effect of lower body negative pressure (LBNP) on the above parameters.

To our knowledge, this is the first attempt to systematically determine the impact of the fluid distribution in microgravity on a comprehensive set of structural and functional measures including, but not limited to, those related to intracranial pressure, vision, morphology of the eye and its adnexa, and the vascular systems of the head and neck, during and after long duration space flight. The study design and methodology are based on the extensive relevant experience of the Investigators, including many successful ground-based, space flight analogue, and space flight projects and investigations.

Primary Hypothesis

Prolonged microgravity-induced, headward volume, and pressure shifts promote elevation of intracranial pressure and result in alterations in crewmembers’ vision.

Specific Aims

Specific Aim I: To characterize fluid distribution and compartmentalization before, during, and after long-duration space flight.

Hypothesis 1: Fluid distribution measured by dilution techniques will reflect a headward fluid shift and an intra- to extra-vascular fluid shift during space flight, returning to pre-flight condition after landing.

Hypothesis 2: Regional headward fluid shifts in-flight are documented by increased cephalad venous dimensions (jugular veins) and flow characteristics, skin and soft tissue thickness.

Hypothesis 3: Fluid re-distribution towards the eye (detected in choroid, retina, and optic nerve head using ultrasonography and optical coherence tomography), and in arteries supplying ocular vascular beds, contributes to vision alterations.

Hypothesis 4: Splanchnic venous congestion (detected by portal vein size) contributes to headward volume shift, but is not in communication with the veins of head and neck. Thus, there should be a different level of venous congestion in these two compartments.

Specific Aim II: To correlate in-flight alterations of eye structure, ocular vascular parameters, and vision with headward fluid shifts, vascular dimensions, and flow patterns.

Hypothesis 5: Space flight-induced fluid shifts will have an upregulating effect on ICP and will alter ocular refraction / visual acuity. These changes will vary in magnitude and respectively, in their resolution pattern after space flight.

Hypothesis 6: In-flight ICP-related measures, IOP, venous and arterial morphometric and flow characteristics, vascular resistance of ocular vascular beds, and optic nerve anatomy will trend towards normal-gravity levels temporarily during and residually after fluid sequestration (LBNP) interventions.

Specific Aim III: To determine systemic and ocular factors of individual susceptibility to the development of ICP elevation and/or vision alterations.

Hypothesis 7: Subjects with greater fluid shifts (as measured by the ultrasound method in Aim 1) during pre-flight testing will experience greater fluid shifts in-flight and will be more susceptible to flight-induced vision alterations.

Hypothesis 8: Subjects who are resistant to the reversal of in-flight symptoms and physiological status through the application of LBNP will be more susceptible to persistent flight-induced vision alterations.

Hypothesis 9: Propensity towards more severe changes in-flight and the more indolent postflight resolution pattern will correlate with a range of individual characteristics of the crewmembers, such as anatomical and microanatomical and physiological features and potentially, hitherto unsuspected factors.

NOTE: This study was merged with investigations from Dr. Alan Hargens (Fluid distribution before, during and after prolonged space flight) and Dr. Michael Stenger (Distribution of Body Fluids during Long Duration Space Flight and Subsequent Effects on Intraocular Pressure and Vision Disturbance ) 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).

Erik Hougland, our International Space Station Medical Projects (ISSMP) flight project manager, continues to coordinate our bi-weekly FS team telecons. Over the past year we have provided inputs to updated versions of the FS Experimental Document (ED), recently revised and under review as of March 2016. The ISSMP team has done an excellent job coordinating crew ICBs, training, and testing as well as coordinating Russian activities. The FS team has collectively responded to changes in circumstances (inflight schedules, Russian travel limitations, etc.) that have required a review of existing experiment requirements. The team has reasoned through multiple such scenarios to solve the dilemma and preserve scientific value.

We have continued to work with the University of Texans Medical Branch (UTMB) Victory Lakes 3T MRI (magnetic resonance imaging) facility to employ scanning protocols that maximize science return while capitalizing on the existing MRID (MED B) sequences. Over the past year Dr. Larry Kramer has been added to the team to assist with data analysis. MRI analysis methods continue to be refined to optimize both collected data as well as analysis resources. Medical Operations has made the decision to use contrast agent during MED B MRI scans as the preferred protocol. Our team has worked closely with the NASA medical community to accommodate this change in protocol to preserve comparability with our existing FS MRI protocol while capitalizing on the use of contrast agent in these scans.

Since Russian and European Space Agency (ESA) crews are also “direct return” to their home countries, they are not available in Houston for immediate postflight testing, requiring reproduction and testing of the imaging procedure and protocol elements at the additional scanning locations in Moscow (Research Center of Neurology) and Cologne (DLR/envihab:). Our team has been especially involved with the process of providing 15-degree foam wedges to both the Russian scanning facility and the ESA scanning facility. Terry Guess (Wyle STE) was once again instrumental in this process, specifically in the rapid construction of a second wedge to ensure that a wedge was available for postflight testing on the Russian One Year Mission crewmember. Thanks to extensive coordination and technical exchanges, the Fluid Shifts 3Tesla MRI protocol was successfully completed on the Russian one-year crewmember on March 10, 2016 in Moscow. Based on prior parabolic flight work, the team developed procedures for “free-floating” use of the OCT device for in-flight measurements. An inflight free-float practice run was successfully completed in April 2015, demonstrating that this approach is feasible and would result in valuable data collected on crewmembers while in Chibis. The team has proceeded to collect six sets of data during the One Year Mission using this technique, which has resulted in similar exam times and data quality when compared to the traditional chinrest method.

Our team has made great advances in the analysis of otoacoustic emission (OAE) data over the past year. Dr. David Kemp (the first to experimentally document OAEs) and Rozela Melgoza (a Johnson Space Center audiology intern) joined the team this past year and have been instrumental in data analysis and interpretation. Dr. Kemp has graciously guided the FS OAE team through development of novel analysis techniques for OAE data, and Ms. Melgoza has performed analysis on all available data, culminating in a poster presentation of the FS OAE data at the 2016 Human Research Program (HRP) Workshop. Of particular interest are the consistent phase shifts of transient evoked OAE (TEOAE) in response to posture change and lower body negative pressure. TEOAE phase shifts are consistent with intracranial pressure changes across a relatively broad frequency range, and appear to be consistent across multiple subjects. Further, TEOAE phase shifts are largely consistent with CCFP results.

The team has coordinated closely with the Twins study to ensure the most efficient and effective data collection for both Fluid Shifts and Twins study. Sessions corresponding with preflight, a single mid-mission inflight, and postflight have been completed on the ground twin.

Our team attended the NASA HRP Investigators’ Workshop in Galveston, TX in February 2016, presenting an overall project poster for Fluid Shifts and participating in many Vision Impairment and Intracranial Pressure (VIIP)-related sessions and discussions, including the VIIP modelling breakout session. Our team also presented an otoacoustic emissions poster based on the data collected for Fluid Shifts.

Presentations (past year):

1) Stenger M, Hargens A, Dulchavsky S, Ebert D, Lee S, Laurie S, Garcia K, Sargsyan A, Martin D, Lui J, Macias B, Arbeille P, Danielson R, Chang D, Gunga H-C, Johnston S, Westby C, Ploutz-Snyder R, Smith S. Fluid Shifts. Presented at 2016 NASA Human Research Program Investigators’ Workshop, Galveston, TX. February 8-11, 2016.

2) Melgoza R, Kemp D, Ebert D, Danielson R, Stenger M, Hargens A, Dulchavsky S. Fluid Shifts: Otoacoustic Emission Changes in Response to Posture and Lower Body Negative Pressure. Presented at 2016 NASA Human Research Program Investigators’ Workshop, Galveston, TX. February 8-11, 2016.

3) Ebert D, Garcia K, Sargsyan A, Young M, Dulchavsky S, Dentinger M. The Hydrostatic Gradient, Individual Responses, and Other Challenges. Presented at 2016 NASA Human Research Program Investigators’ Workshop VIIP Modelling Session, Galveston, TX. February 8-11, 2016.

Fifty percent of American astronauts have developed ocular refraction change after long duration space flight on the International Space Station (ISS). Recent findings have also included structural changes of the eye (papilledema, globe flattening, choroidal folds) and the optic nerve (sheath dilatation, tortuosity, and kinking), as well as imaging signs and lumbar puncture data indicative of elevated intracranial pressure (ICP). While short duration space flight is also characterized by vision disturbances, these are generally transient and do not appear to have lasting impacts on the structure or function of the eye. Changes in vision, eye, and adnexa morphology, are hypothesized to be the result of space flight-induced cephalad fluid shifts and transiently elevated intracranial pressure. This hypothesis, however, has not been systematically tested. In earlier anecdotal publications, ICP elevation in long-duration space flight has been inferred but without association with structural or functional changes of the eye. Furthermore, while fluid shifts and compartmentalization during short-duration space flight (Space Shuttle missions) have been studied, the fluid distribution patterns and their effects on intracranial pressure or the structure and function of the sensory organs in the course of long-duration space flight are not well known.

Several ISS crewmembers have reported consistent worsening of nasal congestion and associated symptoms in late afternoon hours, necessitating topical and systemic decongestant use. Although several explanations have been entertained, food (salt) and water intake are likely to have provoked these symptoms through postprandial modification of fluid balance or increase in the circulating volume that manifests in the most susceptible individuals.

The purpose of the proposed work is to objectively characterize the changes in fluid distribution, including intra/extracellular and intra/extravascular fluid shifts, by applying advanced non-invasive assessment technologies before, during, and after long duration space flight. Additionally, we will examine the relationship between the type and magnitude of the fluid shift with any effects on eye morphology and vision disturbances, intraocular pressure (IOP), and measures of intracranial pressure. Further, we seek to determine whether the magnitude of fluid shifts during space flight, as well as the above effects of those shifts can be predicted based upon crewmember baseline data and responses to acute head-down tilt tests performed before launch. Finally, we propose to evaluate the effect of lower body negative pressure (LBNP) on the above parameters.

To our knowledge, this is the first attempt to systematically determine the impact of the fluid distribution in microgravity on a comprehensive set of structural and functional measures including, but not limited to, those related to intracranial pressure, vision, morphology of the eye and its adnexa, and the vascular systems of the head and neck, during and after long duration space flight. The study design and methodology are based on the extensive relevant experience of the Investigators, including many successful ground-based, space flight analogue, and space flight projects and investigations.

Primary Hypothesis

Prolonged microgravity-induced, headward volume, and pressure shifts promote elevation of intracranial pressure and result in alterations in crewmembers’ vision.

Specific Aims

Specific Aim I: To characterize fluid distribution and compartmentalization before, during, and after long-duration space flight.

Hypothesis 1: Fluid distribution measured by dilution techniques will reflect a headward fluid shift and an intra- to extra-vascular fluid shift during space flight, returning to pre-flight condition after landing.

Hypothesis 2: Regional headward fluid shifts in-flight are documented by increased cephalad venous dimensions (jugular veins) and flow characteristics, skin and soft tissue thickness.

Hypothesis 3: Fluid re-distribution towards the eye (detected in choroid, retina, and optic nerve head using ultrasonography and optical coherence tomography), and in arteries supplying ocular vascular beds, contributes to vision alterations.

Hypothesis 4: Splanchnic venous congestion (detected by portal vein size) contributes to headward volume shift, but is not in communication with the veins of head and neck. Thus, there should be a different level of venous congestion in these two compartments.

Specific Aim II: To correlate in-flight alterations of eye structure, ocular vascular parameters, and vision with headward fluid shifts, vascular dimensions, and flow patterns.

Hypothesis 5: Space flight-induced fluid shifts will have an upregulating effect on ICP and will alter ocular refraction / visual acuity. These changes will vary in magnitude and respectively, in their resolution pattern after space flight.

Hypothesis 6: In-flight ICP-related measures, IOP, venous and arterial morphometric and flow characteristics, vascular resistance of ocular vascular beds, and optic nerve anatomy will trend towards normal-gravity levels temporarily during and residually after fluid sequestration (LBNP) interventions.

Specific Aim III: To determine systemic and ocular factors of individual susceptibility to the development of ICP elevation and/or vision alterations.

Hypothesis 7: Subjects with greater fluid shifts (as measured by the ultrasound method in Aim 1) during pre-flight testing will experience greater fluid shifts in-flight and will be more susceptible to flight-induced vision alterations.

Hypothesis 8: Subjects who are resistant to the reversal of in-flight symptoms and physiological status through the application of LBNP will be more susceptible to persistent flight-induced vision alterations.

Hypothesis 9: Propensity towards more severe changes in-flight and the more indolent postflight resolution pattern will correlate with a range of individual characteristics of the crewmembers, such as anatomical and microanatomical and physiological features and potentially, hitherto unsuspected factors.

NOTE: This study was merged with investigations from Dr. Alan Hargens (Fluid distribution before, during and after prolonged space flight) and Dr. Michael Stenger (Distribution of Body Fluids during Long Duration Space Flight and Subsequent Effects on Intraocular Pressure and Vision Disturbance ) 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).

At the request of the NASA Element office we succeeded in merging three flight projects. We worked to integrate our proposed ground and flight measures among the combined research team (Dulchavsky et al., Hargens et al., and Stenger et al.), and have now finalized our research testing protocols for ISS crewmembers We have completed studies demonstrating that our proposed testing sessions can be successfully completed within the allotted crew time. Representatives from the entire Fluid Shifts (FS) team visited NASA-JSC in March 2014 for ground feasibility tests to successfully integrate vascular ultrasound and ocular measurements. In the process of developing our protocols, several “feasibility study” test subjects completed the protocols (or portions thereof).

Erik Hougland, our International Space Station Medical Projects (ISSMP) flight project manager, has been coordinating our bi-weekly FS team telecons. We have provided input to the baseline version of the “Fluid Shifts” Experimental Document (ED) as well as updated versions, most recently approved in January 2015. The ISSMP team has also done an excellent job coordinating crew ICBs (inflight crew briefing), training, and testing as well as coordinating hardware development and Russian activities.

We have worked with the University of Texans Medical Branch (UTMB) Victory Lakes 3T MRI (magnetic resonance imaging) facility to develop scanning protocols that maximize science return while capitalizing on the existing medically required MRI sequences. Additionally, we developed a 15 degree foam wedge that allows subjects to be scanned in the 15 degree head-down tilted position in the wide-bore Siemens 3T Verio instrument. The wedge fits securely into the patient table yet is lightweight and simple in design, allowing for rapid transitions during subject scanning. Terry Guess (Wyle STE) was instrumental in the design and construction of this wedge. We also visited the upright MRI facility to meet with the members of the FS team as well as Fonar and MRI facility personnel. We also participated in the protocol development and feasibility runs of the proposed MRI measures which include cerebral spinal fluid flow tests. Testing in the two MRI systems was coordinated to acquire mutually complementary data on central nervous system structure, vascular, and cerebrospinal fluid systems.

We provided expertise and coordinated the acquisition of iCare intraocular pressure measurement devices (rebound tonometry). The team decided to use the iCare Pro for FS pre- and postflight studies due to its ability to collect tonometry data (eye pressure) in the supine position (without rolling the subject’s head to the side), as well as the fact that it does not require eye anesthesia. The team would have preferred using the iCare TA01i inflight, however Human Research Program (HRP) and MedOps chose not to fly this additional hardware.

Also, we provided feedback on acquisition and flight development of the Marchbanks Cerebral and Cochlear Fluid Pressure (CCFP) units. The Marchbanks device received a CE mark and the NASA research unit was shipped on 1/30/2014. In addition, two of the CCFP flight units arrived at NASA JSC on 12/29/2014. These flight units have now passed all flight hardware testing and certification and one unit has been delivered for packing onto the SpaceX6 vehicle in preparation for delivery to ISS. We have held conferences with Drs. Mike Williams and Bob Marchbanks to learn lessons from their experiments and assembly of our CCFP units to facilitate implementation of the CCFP hardware into our ISS flight project. In addition, we have worked with Dr. Alan Hargens’ lab in developing the CCFP data analysis protocol.

Parabolic flights were conducted in April 2014 under the Flight Opportunities Program “Microgravity Health Care” project to evaluate CCFP, Otoacoustic Emissions (OAE), and the iCare tonometer in microgravity. All three devices performed well in micro-, partial, and hypergravity, eliminating any concerns regarding proper operation once delivered to ISS. No major usability or ergonomic concerns were discovered. Physiological data was collected on multiple subjects, and a significant effect of gravity on intraocular pressure was found. OAE data quality was negatively affected by aircraft noise, but OAE and CCFP data are still being analyzed.

Our study will utilize the Russian Chibis device; we have been in close contact with our Russian collaborators, Irina Alferova and Zhanna Yarmanova, to coordinate ISS Chibis operations and study implementation. We had a productive meeting with Drs. Alferova and Yarmanova to coordinate our planned physiological measures in the Russian ISS segment during Chibis operations at NASA JSC this past year. The ISSMP team continues to work Russian operational issues such as inverter use, safety certifications, and camera placements, among other topics.

We provided feedback on the acquisition of the research Spectralis Optical Coherence Tomography (OCT) device with anterior segment module. A major milestone completed this year was acquisition and modification of an adjustable arm for OCT measurements in the upright, supine, and head-down-tilt positions. Terry Guess, a Wyle team member, did an excellent job working with the OCT manufacturer (Heidelberg Engineering) to verify that this was the correct solution and make the further modifications that made this an optimal OCT device for use in our experiment. We continue to work with Heidelberg to finalize automated, quantitative, and objective measures of ocular structures; however, it appears that automated choroid analysis will require a complete re-configuration of the current Heidelberg software. We understand that Heidelberg is still developing this software but the timeline has been significantly delayed. Therefore, we are pursuing other options for choroid analysis including collaboration with Dr. Nimesh Patel at University of Houston (UH) School of Optometry, and potentially Dr. Brian Samuels at the University of Alabama at Birmingham (UAB).

Testing and training have been initiated to enable “free-floating” of the OCT device for in-flight measurements. Prior work by members of our group tested the feasibility of using the OCT scanner in free-float (without the use of the chin rest and stage); parabolic flights were conducted in November 2013 that established that this mode was feasible. This information opened up options for scanning locations other than the Maintenance Work Area (MWA) which would include scanning in the Russian Service Module while in Chibis. An inflight (ISS) free-float practice run is scheduled for April 2, 2015. All training sessions and preflight baseline data collection (BDC) have been completed for both one year mission crewmembers (including one cosmonaut); training and preflight BDC has also been completed for the one year mission US backup crewmember. These include MRI, dilution measures, ultrasound, OCT, tonometry, NIR (near infrared), CCFP, and OAE measures. Ocular and transcranial ultrasound analysis is complete on all data collected to date.

The team has also provided coordination with the Twins study to ensure the most efficient and effective data collection for both Fluid Shifts and Twins study can be accomplished.

Our team attended the NASA HRP Investigators’ Workshop in Galveston, TX in January 2015, presenting a poster on the FS project and participating in many Vision Impairment and Intracranial Pressure (VIIP) related sessions and discussions.

Recent evidence suggests that a preexisting subclinical pathology or risk factor may determine whether microgravity fluid shifts alone or in combination with other factors cause pathological increases in intracranial pressure (ICP) and sequelae thereof (visual acuity changes, cognitive impairment, retinal pathology). Furthermore, this malady may persist in some crewmembers beyond the rehabilitation phase after flight. Space medicine is therefore facing an occupational medical hazard, with a number of contributing factors challenging to quantify and examine independently (i.e., resistive exercise vs. microgravity fluid shifts).

Over years, the U.S. and the Russian space programs have implemented extensive research to understand the alterations in neurological and cardiovascular physiology secondary to fluid shifts that are induced by microgravity. The investigator team proposes to meet, through this study, the challenge of "how do we understand the effect of fluid shift on cerebrospinal fluid (CSF) dynamics when gold-standard terrestrial technologies are invasive and the true magnitude of microgravity fluid shifts and their pathophysiological effects are not well understood?"

Recent on-orbit long duration studies performed by this team have shown that cephalad venous fluid shifts are permanent in all crewmembers and that external jugular pressures are increased, so that aggressive intra-thoracic pressure maneuvers (i.e., Mueller maneuver) have very little effect on extracranial venous dimensions in all crewmembers examined in space (n=6). Preliminary data from the Braslet Investigation Grant ground experiment (ongoing) find terrestrial supine position to be very different in this regard.

In microgravity, cephalad fluid shifts seem to cause a relative extra-cranial (and therefore intracranial) venous insufficiency and subsequent lymphedema (facial puffiness, loss of olfactory and gustatory sense); several crew members have anecdotally mentioned that Russian thigh venous occlusion cuffs (Braslet, Kentavr nauka, Russian Federation) improve these changes and "help think clearer and perform procedures better." In our experience, venous insufficiency indeed improved when the cuffs were worn for at least 15 minutes: Mueller maneuver was much more readily causing a decrease in jugular venous dimension; cardiac preload was significantly diminishing when measured with echocardiography on-orbit.

The venous thigh occlusion cuffs therefore, though altering the fluid shifts and reducing venous insufficiency, also may effect a change in CSF dynamics in space (that would explain the improvement in cognition and well-being).

The investigators plan to use multiple non-invasive technologies to assess fluid shifts quantitatively, with a commensurate focus on the likelihood and severity of ocular and CSF fluid dynamic changes in microgravity, and identify markers of susceptibility to the development of pathological changes.

Research questions/ Specific Aims:

1. Determining the magnitude and time course of fluid in continuous microgravity.

2. Determining the physiological and potential health effects of microgravity-associated fluid redistribution on the cardiovascular and central nervous (CNS) systems.

3. Assessing the acute fluid volumetric effects of the Braslet and Lower Body Negative Pressure (LBNP) countermeasures on central, peripheral vascular systems, and CNS/ocular systems.

4. Determining best combinations of non-invasive technologies related to fluid shifts and ICP elevation that are most predictive in estimating the absolute ICP and trends thereof during space flight.

NOTE: This study was merged with investigations from Dr. Alan Hargens (Fluid distribution before, during and after prolonged space flight) and Dr. Michael Stenger (Distribution of Body Fluids during Long Duration Space Flight and Subsequent Effects on Intraocular Pressure and Vision Disturbance ) 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).

Major accomplishments:

o Completed the Payload Training Dry Run (PTDR) (certification) events for the Fluid Shifts Science Overview and Ultrasound (USND) training classes. First training is targeted for Scott Kelly on 3/18.

The PI teams have met regularly to review overlapping specific objectives and have attempted to simplify crew training and operative times. We have consolidated the over-arching experiment considerably and are working on finalizing equipment and operational procedures. Specific highlights are included below.

Provided “final” list of modifications to Manometer (tube length and filter for mouthpieces)

· Upcoming Activities/Actions:

o Baseline Data Collection (BDC) Shakedown TRR (Test Readiness Review) on Friday, March 7

o USND flight-like run through with remote guidance, Tuesday March 11

o Finalization of Distortion-Product Otoacoustic Emission (DPOAE) unit settings for data collection, week of March 10

o Ops Assessment with crew office week of March 17

o Fluid Shifts Implementation TIM April 17

o Dilution Measures training PTDR April 18

The Fluid Shifts Implementation TIM (CDR-like) has been moved to April 17 to deconflict with Planning, Programing, Budget and Execution (PPBE) and Twin Study discussions. We are working within the 3 PI teams to develop input for this meeting in the coming weeks. The plan will be to update the Fluid Shifts ED and Hardware document to “final” requirements for flight implementation.

Recent evidence suggests that a preexisting subclinical pathology or risk factor may determine whether microgravity fluid shifts alone or in combination with other factors causes pathological increases in intracranial pressure (ICP) and sequelae thereof (visual acuity changes, cognitive impairment, retinal pathology). Furthermore, this malady may persist in some crewmembers beyond the rehabilitation phase after flight. Space medicine is therefore facing a an occupational medical hazard, with a number of contributing factors challenging to quantify and examine independently (ie., resistive exercise vs. microgravity fluid shifts).

Over years, the U.S. and the Russian space programs have implemented extensive research to understand the alterations in neurological and cardiovascular physiology secondary to fluid shifts that are induced by microgravity. The investigator team proposes to meet, through this study, the challenge of "how do we understand the effect of fluid shift on cerebrospinal fluid (CSF) dynamics when gold-standard terrestrial technologies are invasive and the true magnitude of microgravity fluid shifts and their pathophysiological effects are not well understood?"

Recent on-orbit long duration studies performed by this team have shown that cephalad venous fluid shifts are permanent in all crewmembers and that external jugular pressures are increased, so that aggressive intra-thoracic pressure maneuvers (i.e., Mueller maneuver) have very little effect on extracranial venous dimensions in all crewmembers examined in space (n=6). Preliminary data from the Braslet Investigation Grant ground experiment (ongoing) find terrestrial supine position to be very different in this regard.

In microgravity, cephalad fluid shifts seem to cause a relative extra-cranial (and therefore intracranial) venous insufficiency and subsequent lymphedema (facial puffiness, loss of olfactory and gustatory sense); several crew members have anecdotally mentioned that Russian thigh venous occlusion cuffs (Braslet, Kentavr nauka, Russian Federation) improve these changes and "help think clearer and perform procedures better." In our experience, venous insufficiency indeed improved when the cuffs were worn for at least 15 minutes: Mueller maneuver was much more readily causing a decrease in jugular venous dimension; cardiac preload was significantly diminishing when measured with echocardiography on-orbit.

The venous thigh occlusion cuffs therefore, though altering the fluid shifts and reducing venous insufficiency, also may effect a change in CSF dynamics in space (that would explain the improvement in cognition and well-being).

The investigators plan to use multiple non-invasive technologies to assess fluid shifts quantitatively, with a commensurate focus on the likelihood and severity of ocular and CSF fluid dynamic changes in microgravity, and identify markers of susceptibility to the development of pathological changes.

Research questions/ Specific Aims:

1. Determining the magnitude and time course of fluid in continuous microgravity.

2. Determining the physiological and potential health effects of microgravity-associated fluid redistribution on the cardiovascular and central nervous (CNS) systems.

3. Assessing the acute fluid volumetric effects of the Braslet and Lower Body Negative Pressure (LBNP) countermeasures on central, peripheral vascular systems and CNS/ocular systems.

4. Determining best combinations of non-invasive technologies related to fluid shifts and ICP elevation that are most predictive in estimating the absolute ICP and trends thereof during space flight.

NOTE: This study was merged with investigations from Dr. Alan Hargens (Fluid distribution before, during and after prolonged space flight) and Dr. Michael Stenger (Distribution of Body Fluids during Long Duration Space Flight and Subsequent Effects on Intraocular Pressure and Vision Disturbance ) 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).

Editor's Note (7/11/2013): NOTE THIS IS A CONTINUATION OF FUNDING FOR NNX13AB42G (Microgravity Associated Compartmental Equilibration (MACE)) WITH THE SAME PRINCIPAL INVESTIGATOR.