NOTE: End date changed to 5/31/2017 per NSBRI (Ed., 1/27/16)

Specific Aim I: To determine whether previous spaceflight experience predisposes astronauts to lower venous compliance and/or the development of the spaceflight-associated neuro-ocular syndrome (SANS). This study was designed originally with an arm that sought to acquire ocular and cardiovascular parameters from astronauts completing a long-duration International Space Station (ISS) mission. During the course of the project, NASA's research priorities were realigned such that the flight portion of this study was removed from the flight queue. However, control data were collected in 7 astronauts who at the time of the study had not flown in space. The study designed was modified such that the test protocol included similar measures as an existing flight study (Fluid Shifts), allowing important comparisons between veteran astronauts and those without spaceflight experience. Also, these never-flown astronauts participated in two tests separated by 4-6 months to determine the stability of these measures across an interval similar to the duration of a long-duration ISS mission. While results from a veteran group of astronauts are not yet available from which to determine the effects of a prior spaceflight mission, importantly our data in never-flown astronauts suggest that our measures of arterial and venous compliance do not change over the same time frame as an ISS mission when subjects are not exposed to spaceflight.

Specific Aim II: To evaluate the effect of 14-days of 6 degrees head-down tilt bed rest, a model of spaceflight, and aging on vascular compliance after using a test subject population similar to younger (25-35 yrs) and older (45-55 yrs) astronaut cohorts. Exposure to head-down tilt bed rest, a well-accepted analog to induce cardiovascular adaptations similar to spaceflight, has not resulted in findings representative of SANS that have been observed in some astronauts participating in long-duration ISS missions. Factors other than the cephalad fluid shift observed during spaceflight and bed rest have been hypothesized to contribute to the development of SANS but had not been tested. This bed rest study sought to investigate two of these, age and diet, with regard to vascular compliance and ocular measures. Specifically, 7 younger men and 4 older men participated in a 6 degrees head-down bed rest study under standard conditions, with the exception that a higher than normal sodium intake was prescribed to match the intake of ISS astronauts. Dietary sodium intake in this study was approximately 40% higher than in previous bed rest studies. For the majority of cardiovascular and ocular variables studied, there was no significant effect of bed rest. The bed rest-induced decrease in plasma volume did not appear to differ from plasma volume losses experience in other bed rest studies using standard dietary practices. Arterial diameters and flow were not different from pre- to post-bed rest at rest during the whole body tilting protocol (-20, -10, 0, +10, +20 degrees of tilt). Similarly, axial length and retinal nerve fiber layer were not different after bed rest. In contrast, internal jugular vein area was lower after bed rest in the head-down tilt postures, suggesting a decrease in venous compliance. This effect was transient and recovered to pre-bed rest levels after three days of normal ambulation. Unfortunately, we were unable to recruit a sufficient number of older subjects to test the interactions between aging and bed rest on the parameters studied. These results suggest that, even with a diet more closely matching that of astronauts during spaceflight, short-duration bed rest is not a good model for SANS. Future studies should address other factors specific to spaceflight which might produce a valid ground-based analog.

Specific Aim III: To determine whether previous spaceflight experience or training in high performance jet aircraft predisposes astronauts to lower venous compliance and/or the development of the Vision Impairment and Intracranial Pressure (VIIP) syndrome. Cardiovascular and ocular data acquired from 41 astronauts during medically-required testing were released from the Lifetime Surveillance of Astronaut Health to the Cardiovascular and Vision Laboratory to test for associations between cardiovascular health, high performance aircraft exposures, and ocular findings. Unfortunately, data regarding high performance aircraft exposures were not of sufficient quality and quantity to include this factor in our analyses. Of all the associations tested between the Framingham Risk Score and ocular outcomes, the only association was with visual acuity. Given the age of the astronaut population, this may reflect aging-associated decrements in cardiovascular health and vision. These results, in combination with the other flight and ground-based studies conducted by our group, will inform the development and inflight testing of countermeasures against SANS.

Bed Rest Study: Data collection for the bed rest study was completed before the closure of the Flight Analogs Research Unit at University of Texas Medical Branch (UTMB) in Galveston, TX, on December 31, 2014. A compressed schedule resulted in study of 13 rather than the planned 20 subjects. Data analysis for the bed rest data was completed during the last funded year of this grant.

Astronaut Ground Study: The study of astronauts who have never flown in space will serve as a control arm for the NASA-funded flight study, Fluid Shifts Before, During and After Prolonged Space Flight and Their Association with Intracranial Pressure and Visual Impairment. In the final year of this study, we recruited 7 astronauts who had never flown to participate in the ground portion of this study. All 7 astronauts participated in testing on two separate occasions, separated by a ~4-6 months (roughly equivalent to a long-duration mission on ISS). Data analysis has been completed.

Data Mining Study: Approval for the data mining study was received from the Johnson Space Center (JSC) Institutional Review Board (IRB) and the Longitudinal Surveillance of Astronaut Health (LSAH) Board. In the final year of this study, a Johnson Space Center biostatistician analyzed in-flight and post-flight ocular outcomes to determine whether any relationships exists with cardiovascular health parameters. Preliminary results from the Bed Rest Study and the Data Mining Study were reported at the 2016 Human Research Program (HRP) Investigators' Workshop. Results from the Astronaut Ground Study will be reported at the 2017 HRP Investigators' Workshop.

NOTE: End date changed to 5/31/2017 per NSBRI (Ed., 1/27/16)

Specific Aim I: To evaluate the effect of 14-days of 6 degrees head-down tilt bed rest, a model of spaceflight, and aging on vascular compliance after using a test subject population similar to younger (25-35 yrs) and older (45-55 yrs) astronaut cohorts. Hypothesis 1: Pre-bed rest vascular compliance in the head and neck will be higher in younger subjects compared to older subjects. Hypothesis 2: Following bed rest, both groups of subjects will exhibit decreased vascular compliance in the head and neck, but vascular compliance will decrease more in the older subjects than in younger subjects. Hypothesis 3: Subjects in this bed rest study will have more pronounced ocular changes/VIIP symptoms than those in a previous 14-day bed rest study due to the increased sodium content in the diet. The data collection portion of the bed rest study was completed before the closure of the Flight Analogs Research Unit at University of Texas Medical Branch (UTMB) in Galveston, TX, on December 31, 2014. Seven young men and 4 older men participated. The compressed schedule from the time of the approval to proceed with work at UTMB, to the closure of the Flight Analogs Unit and difficulties in recruiting subjects who passed the inclusion criteria did not allow us to collect data on the total number of 20 planned subjects. Preliminary data analysis is underway. Final analysis of the bed rest data, with the assistance of the NASA Johnson Space Center (JSC) Biostatistician, will be completed in Year 3. The final report will be submitted to the National Space Biomedical Research Institute (NSBRI), and at least one manuscript will be submitted to a peer-reviewed journal thereafter.

Specific Aim II: To determine whether previous spaceflight experience or training in high performance jet aircraft predisposes astronauts to lower venous compliance and/or the development of the VIIP syndrome. Hypothesis 1: Vascular compliance in the head and neck will be higher in novice crewmembers compared to astronauts with previous flight experience (Astronaut Ground study) Hypothesis 2: Astronauts with training as high performance jet aircraft pilots will have lower vascular compliance, even preflight, than non-pilot astronauts and will have a higher incidence/severity of VIIP syndrome (Data Mining study).

Astronaut Ground Study

We have developed an Informed Consent Briefing to present to potential subjects and are working with International Space Station Medical Project (ISSMP) personnel to schedule the briefing to the Astronaut Office. We plan to recruit 8 astronauts that have never flown or astronaut candidates to participate in research at the Cardiovascular Laboratory at the NASA Johnson Space Center in Houston, TX.

Data Mining Study

We received full approval from all necessary boards to proceed with data release from Lifetime Surveillance of Astronaut Health (LSAH). We have received almost all of the requested data; data from 3 astronauts who have flown recently has yet to be delivered. With each data release from LSAH to the JSC Cardiovascular Laboratory, data were verified for validity and incorporated into the study's database. Final data analysis will be completed with the NASA JSC Biostatistician in Year 3. The final report will be submitted to NSBRI, and at least one manuscript will be submitted to a peer-reviewed publication thereafter.

Data Mining: The data mining study is in progress. The JSC Institutional Review Board (IRB) approved the renewal of the data mining study (expiration date - December 31, 2015). The consent process has been completed. Initial data sets have been provided to the Principal Investigator team by Lifetime Surveillance of Astronaut Health (LSAH). We are in the process of preparing the data for analysis.

Bed Rest: Eleven (7 younger men, 4 older men) of 20 planned subjects completed participation in this study before the closure of the Flight Analogs Research Unit at the University of Texas, Medical Branch (UTMB) in Galveston, TX on December 31, 2014. Due to the closure of the facility, we were not able to complete the 20 planned male subjects. Plasma volume, vascular measures (area and diameter of head and neck vessels among other ultrasound measures), and ocular measures (intraocular pressure, optical coherence tomography, and ocular ultrasound) were collected on all 11 men. We collected non-invasive internal jugular venous pressure using a novel device, VeinPress, in 6 of 11 subjects. Invasive left internal jugular venous pressure was measured using a catheter inserted into the internal jugular vein in 2 of these 6 during their pre-bed rest testing session.

Ground: We recently renewed the IRB approval for this study (expiration - April 30, 2016). We are in the process of scheduling an Informed Consent Briefing to be presented to the astronaut corps. The International Space Station Medical Project (ISSMP) will assist with recruiting astronauts who have never flown or astronaut candidates.

The purpose of this proposal is to use non-invasive methodologies (ultrasound) to track changes in venous and arterial compliance in vessels of the head and neck and relate these changes to development of the recently identified Vision Impairment and Intracranial Pressure (VIIP) syndrome in astronauts. The study is composed of four research objectives (bed rest, astronaut ground, astronaut flight, and data mining), which encompass three specific aims.

Specific Aim I: To determine whether noninvasive measures of venous and arterial compliance are altered by long-duration spaceflight exposure in ISS astronauts and whether these changes are related to the development of the VIIP syndrome. Hypothesis 1: Venous and arterial compliance in the head and neck will be decreased following long-duration exposure to the environment of spaceflight in International Space Station (ISS) astronauts. Hypothesis 2: Venous and arterial compliance in the arm (used as a control for fluid shifts and pressure redistribution) will not be changed after long-duration spaceflight in ISS astronauts. Hypothesis 3: Astronauts who experience the greatest decreases in vascular compliance also will have more severe cases of the VIIP syndrome as classified by Space Medicine Clinical Practice Guidelines.

Specific Aim II: Using 14-days of 6 degrees head-down tilt bed rest as a model of spaceflight, to evaluate the effect of aging on vascular compliance using a subject population similar to younger (25-35 yrs) and older (45-55 yrs) astronaut cohorts. Hypothesis 1: Pre-bed rest vascular compliance in the head and neck will be higher in younger subjects compared to older subjects. Hypothesis 2: Following bed rest, both groups of subjects will decrease vascular compliance in the head and neck, but will decrease more in the older subjects than younger subjects. Hypothesis 3: Subjects in this bed rest study will have more pronounced ocular changes/VIIP symptoms than those in a previous 14-day bed rest study due to the increased sodium content in the diet.

Specific Aim III: To determine whether previous spaceflight experience or training in high performance jet aircraft predispose astronauts to lower venous compliance and/or the development of the VIIP syndrome. Hypothesis1: Vascular compliance in the head and neck will be higher in novice crewmembers compared to astronauts with previous flight experience. Hypothesis 2: Astronauts with training as high performance jet aircraft pilots will have lower vascular compliance, even preflight, than non-pilot astronauts and will have a higher incidence/severity of VIIP syndrome (data mining effort).

To date, we have not had any reportable results as we have been submitting paperwork and performing pre- data collection tasks to start the four independent but related studies. For the next year, the JSC Cardiovascular Laboratory will make progress on all four components of this study.

Proposed research milestones for funding year 2

Data Mining: We have received full approval from all necessary boards and individuals to proceed with data release from Lifetime Surveillance of Astronaut Health (LSAH). LSAH has provided a timeline of data release starting May 1, 2014. Data from already consented astronauts will be released in three phases. Astronauts were previously consented as part of a LSAH project to pre-consent to use all their data without stipulations. Remote consenting of astronauts who didn't previously consent without knowledge of the specific study objectives will begin in May 2014. The data from newly consented astronauts or those in-flight during the duration of this study will be provided in later phases of data release. As each data release is received by the JSC Cardiovascular Laboratory, data will be entered into databases and/or spreadsheets, data entry will be verified per Wyle verification procedures, and data mining will be performed on each subset of data.

Bed Rest: After we receive General Clinical Research Center Institutional Review Board approval for testing at the Flight Analogs Research Unit at the University of Texas, Medical Branch (UTMB) in Galveston, TX, we plan to recruit up to 10 subjects to participate in bed rest testing. A Test Readiness Review (TRR) package must be completed and TRR board approval received prior to the start of testing at UTMB. A TRR is the final safety review prior to any human testing.

Ground: We plan to recruit 8 astronauts that have never flown or astronaut candidates to participate in research at the Cardiovascular Laboratory at the NASA Johnson Space Center in Houston, TX. A TRR package must be completed and TRR board approval received prior to the start of testing.

Flight: We plan to submit the flight protocol to the NASA JSC Institutional Review Board in May 2014. A Feasibility Assessment is being performed by the International Space Station Medical Project (ISSMP). Any necessary flight certification of hardware will be initiated by ISSMP. All documentation and presentations required for flight studies will be completed as requested by members of ISSMP. Documentation includes an Experiment Document and an approved TRR package. Presentations include Select for Flight, Astronaut Briefings, and training.

Data Mining: The data mining study is in progress. The JSC Institutional Review Board (IRB) approved the data mining study on December 12, 2013 (expiration - December 31, 2014). The data for use in the data mining study will be provided to the Principal Investigator team by Lifetime Surveillance of Astronaut Health (LSAH). The data that we are requesting is attributable to individual crewmembers to those familiar with the space program. Due to the nature of the data, we presented our data request at the LSAH Advisory Board meeting on February 4, 2014, which was approved by the Advisory Board. Following all necessary approvals, consent of crewmembers was discussed. Approximately 20 astronauts have consented to the use of their data without further information required. Members of LSAH have contacted the study team with a timeline for data release for the currently consented astronauts.

Bed Rest: The JSC IRB approved the bed rest study on December 12, 2013 (expiration - December 31, 2014). The JSC Institutional Review Board reviewed the Bed Rest complement at the IRB meeting on April 17, 2014. Many discussions have occurred as to which facility should be used to perform the bed rest study. As of April 28, 2014, half of the subjects will be completed at the Flight Analogs Research Unit at the University of Texas, Medical Branch (UTMB) in Galveston, TX.

Ground: The JSC IRB approved the study on April 17, 2014 (expiration - April 30, 2015). The International Space Station Medical Project (ISSMP) will assist with recruiting astronauts who have never flown or astronaut candidates.

Flight: The flight study is undergoing review by ISSMP. Prior to accepting flight studies, a Feasibility Assessment is performed. We have met with members of ISSMP to answer questions they had to complete the feasibility assessment. The flight study will be submitted to the JSC IRB shortly.