NOTE: End date changed to 1/24/2026 per HHC element/JSC (Ed., 4/8/21)

NOTE: End date changed to 9/30/2025 per PI (Ed., 12/21/19)

SPECIFIC AIMS: Conducting SANS research on two-month, six-month, and one-year crewmembers will enable us to objectively generate data to help NASA determine if and how SANS findings change with mission duration. Data from these missions will enable the development of a non-linear trend model that can be extrapolated to make predictions for spaceflights that are up to three years in duration. Therefore, the results of the "Investigating Structure and Function of the Eye" (iSAFE) study will help NASA to define the risk posture for future interplanetary expeditions and to identify possible countermeasures. Specific Aim 1: To determine if ocular structural changes develop to a greater degree (frequency or magnitude) during long-duration one-year spaceflight missions compared to findings during shorter length missions, and if recovery is prolonged after longer missions. Specific Aim 2: To determine if ocular vascular structure is altered to a greater degree during long-duration one-year spaceflight missions, and if recovery is more prolonged. Specific Aim 3: To determine if ocular function is altered to a greater degree during long duration one-year spaceflight missions, and the recovery profile. Specific Aim 4: To determine if measures of vascular structure and function are altered to a greater degree during long-duration one-year spaceflight missions, and if these vascular adaptations correlate with alterations in ocular structure and function. RELEVANCE AND MAP TO THE NASA HUMAN RESEARCH ROADMAP: This multi-project proposal is in response to NASA research announcement Human Exploration Research Opportunities (HERO), 80JSC017N0001-BPBA, Appendix C, Topic 1: Analyses of the Temporal Nature of Human Adaptation to Long-Duration Low-Earth Orbit Mission Virtual NASA Specialized Center of Research (VNSCOR). This proposal addresses multiple Human Research Program (HRP) Integrated Research Plan Gaps, including:

• SANS101: Determine the relationship between fluid shifts (intravascular, interstitial, CSF) and ocular manifestations in astronauts during spaceflight.

• SANS102: Determine the relationship between the fluid-shifts induced ocular changes and fluid shifts in the CNS, including whether elevated intracranial pressure or brain edema play a role.

PURPOSE The purpose of this study is to evaluate whether spaceflight mission duration influences SANS incidence and severity and whether vascular changes during weightlessness relate to SANS findings. Specifically, we will test the hypotheses that ocular tissue structure, ocular vascular structure, and ocular function are altered in spaceflight. Cervicothoracic vasculature will be evaluated for volume increase in both incidence and magnitude with mission duration, as well as the magnitude of vascular adaptation and its correlation with ocular findings. Moreover, we will test the hypothesis that a genetic predisposition to SANS is conferred by 1-carbon metabolism pathway-associated gene variants that compromise vascular structure and function by perturbing of B-vitamin and related metabolite levels.

METHODS Advanced techniques will be used to study the eyes, cervicothoracic vasculature, and 1-carbon pathway genetics and biochemistry in 30 astronauts scheduled to participate in missions on the International Space Station (ISS). Subjects will be divided into 3 cohorts (n=10/cohort) based on mission duration, specified as Short (~2 months), Standard (~6 months), or Extended (~1 year). Ocular structure and function will be evaluated using magnetic resonance imaging (MRI) and 3D structural analysis, optical coherence tomography (OCT), OCT angiography (OCTA), electroretinography (ERG), visual field analysis, pneumotonometry (PTM, intraocular pressure/IOP), visual field analysis, optical biometry, and dynamic vessel analysis (DVA). Ultrasound will be used to investigate variables associated with the cervicothoracic vasculature, including stroke volume, cardiac output, and internal jugular vein morphology/pressure and carotid intima-media thickness. In addition, MRI will be used to assess brain structural changes. Many of the experiments will be performed before, during, and after flight (Table 1). Some of the data collected on the ground (i.e., before and after flight) will be acquired in the seated and supine postures to simulate the fluid shift experienced upon transition from 1 g to weightlessness. To complement the research measures, medically relevant test results already collected by the Space Medicine Operations Division will be requested.

Mission Impact The Investigating Structure and Function of the Eye (iSAFE) research study will advance NASA’s understanding of SANS, an important human health and performance risk through the following specific aims: 1) The relationships between mission duration and SANS development, progression, and recovery will be defined. 2) Experiments will identify whether optic disc edema is accompanied by leakage of the retinal vasculature. 3) With the implementation of ERG, visual function will be measured during spaceflight for the first time and will be related to the development of optic disc edema. 4) Possible mechanisms underlying SANS will be evaluated, including vascular adaptations in weightlessness and 1-carbon pathway genetics.

This research will narrow the SANS101 and SANS102 knowledge gaps described in the Human Research Roadmap and, in turn, will help NASA to evaluate this spaceflight-associated risk more accurately and refine its approach to SANS countermeasure development.

Study Progress in this reporting period includes a total of 8 of 10 crew assigned to standard duration missions (4-6 months) who have consented to participate. Forward work includes continuing to support all phases of preflight, inflight, and postflight data collection and training of crew members.

NOTE: End date changed to 1/24/2026 per HHC element/JSC (Ed., 4/8/21)

NOTE: End date changed to 9/30/2025 per PI (Ed., 12/21/19)

SPECIFIC AIMS: Conducting SANS research on two-month, six-month, and one-year crewmembers will enable us to objectively generate data to help NASA determine if and how SANS findings change with mission duration. Data from these missions will enable the development of a non-linear trend model that can be extrapolated to make predictions for spaceflights that are up to three years in duration. Therefore, the results of the "Investigating Structure and Function of the Eye" (iSAFE) study will help NASA to define the risk posture for future interplanetary expeditions and to identify possible countermeasures. Specific Aim 1: To determine if ocular structural changes develop to a greater degree (frequency or magnitude) during long-duration one-year spaceflight missions compared to findings during shorter length missions, and if recovery is prolonged after longer missions. Specific Aim 2: To determine if ocular vascular structure is altered to a greater degree during long-duration one-year spaceflight missions, and if recovery is more prolonged. Specific Aim 3: To determine if ocular function is altered to a greater degree during long duration one-year spaceflight missions, and the recovery profile. Specific Aim 4: To determine if measures of vascular structure and function are altered to a greater degree during long-duration one-year spaceflight missions, and if these vascular adaptations correlate with alterations in ocular structure and function. RELEVANCE AND MAP TO THE NASA HUMAN RESEARCH ROADMAP: This multi-project proposal is in response to NASA research announcement Human Exploration Research Opportunities (HERO), 80JSC017N0001-BPBA, Appendix C, Topic 1: Analyses of the Temporal Nature of Human Adaptation to Long-Duration Low-Earth Orbit Mission Virtual NASA Specialized Center of Research (VNSCOR). This proposal addresses multiple Human Research Program (HRP) Integrated Research Plan Gaps, including:

• SANS101: Determine the relationship between fluid shifts (intravascular, interstitial, CSF) and ocular manifestations in astronauts during spaceflight.

• SANS102: Determine the relationship between the fluid-shifts induced ocular changes and fluid shifts in the CNS, including whether elevated intracranial pressure or brain edema play a role.

Within the past year, "Investigating Structure and Function of the Eye" (ISAFE) has achieved multiple milestones, including successful completion of the first preflight ground sessions, first inflight sessions with the first use of new electroretinography (ERG) and pneumotonometry (PTM, intraocular pressure (IOP)) hardware for data collection on the International Space Station (ISS), first implementation of the postflight optical coherence tomography (OCT) intravenous fluorescein angiography (IVFA) test, and first postflight ground sessions. As it was the first use of several of the modalities (ERG, PTM, and dynamic vessel analysis (DVA)) with crewmembers and, for ERG and PTM, on the ISS, several issues were encountered during early sessions which have since been mitigated through modifications to procedures and the operators’ approach. The first OCT IVFA session was successfully completed. Preparation for this session included the data collection team traveling to University of California, San Diego (UCSD) to train with collaborators at the Shiley Eye Institute, as well as training activities at NASA Johnson Space Center (JSC).

FORWARD WORK

In the next year, we will continue inflight and postflight data collection with our current crew, as well as begin data collection with 1-2 additional crewmembers. We anticipate this support to include the following training and testing sessions:

• 8 ERG/PTM crew classes • 3 Ultrasound crew classes • Certification of 1 additional trainer each for ERG/PTM and ultrasound crew classes • 2 Preflight BDC sessions • 10 Inflight sessions • 3 Postflight IVFA sessions • 9 Postflight sessions

NOTE: End date changed to 1/24/2026 per HHC element/JSC (Ed., 4/8/21)

NOTE: End date changed to 9/30/2025 per PI (Ed., 12/21/19)

SPECIFIC AIMS: Conducting SANS research on two-month, six-month, and one-year crewmembers will enable us to objectively generate data to help NASA determine if and how SANS findings change with mission duration. Data from these missions will enable the development of a non-linear trend model that can be extrapolated to make predictions for spaceflights that are up to three years in duration. Therefore, the results of the "Investigating Structure and Function of the Eye" (iSAFE) study will help NASA to define the risk posture for future interplanetary expeditions and to identify possible countermeasures. Specific Aim 1: To determine if ocular structural changes develop to a greater degree (frequency or magnitude) during long-duration one-year spaceflight missions compared to findings during shorter length missions, and if recovery is prolonged after longer missions. Specific Aim 2: To determine if ocular vascular structure is altered to a greater degree during long-duration one-year spaceflight missions, and if recovery is more prolonged. Specific Aim 3: To determine if ocular function is altered to a greater degree during long duration one-year spaceflight missions, and the recovery profile. Specific Aim 4: To determine if measures of vascular structure and function are altered to a greater degree during long-duration one-year spaceflight missions, and if these vascular adaptations correlate with alterations in ocular structure and function. RELEVANCE AND MAP TO THE NASA HUMAN RESEARCH ROADMAP: This multi-project proposal is in response to NASA research announcement Human Exploration Research Opportunities (HERO), 80JSC017N0001-BPBA, Appendix C, Topic 1: Analyses of the Temporal Nature of Human Adaptation to Long-Duration Low-Earth Orbit Mission Virtual NASA Specialized Center of Research (VNSCOR). This proposal addresses multiple Human Research Program (HRP) Integrated Research Plan Gaps, including:

• SANS101: Determine the relationship between fluid shifts (intravascular, interstitial, CSF) and ocular manifestations in astronauts during spaceflight.

• SANS102: Determine the relationship between the fluid-shifts induced ocular changes and fluid shifts in the CNS, including whether elevated intracranial pressure or brain edema play a role.

NOTE: End date changed to 1/24/2026 per HHC element/JSC (Ed., 4/8/21)

NOTE: End date changed to 9/30/2025 per PI (Ed., 12/21/19)

SPECIFIC AIMS: Conducting SANS research on two-month, six-month, and one-year crewmembers will enable us to objectively generate data to help NASA determine if and how SANS findings change with mission duration. Data from these missions will enable the development of a non-linear trend model that can be extrapolated to make predictions for spaceflights that are up to three years in duration. Therefore, the results of the "Investigating Structure and Function of the Eye" (iSAFE) study will help NASA to define the risk posture for future interplanetary expeditions and to identify possible countermeasures. Specific Aim 1: To determine if ocular structural changes develop to a greater degree (frequency or magnitude) during long-duration one-year spaceflight missions compared to findings during shorter length missions, and if recovery is prolonged after longer missions. Specific Aim 2: To determine if ocular vascular structure is altered to a greater degree during long-duration one-year spaceflight missions, and if recovery is more prolonged. Specific Aim 3: To determine if ocular function is altered to a greater degree during long duration one-year spaceflight missions, and the recovery profile. Specific Aim 4: To determine if measures of vascular structure and function are altered to a greater degree during long-duration one-year spaceflight missions, and if these vascular adaptations correlate with alterations in ocular structure and function. RELEVANCE AND MAP TO THE NASA HUMAN RESEARCH ROADMAP: This multi-project proposal is in response to NASA research announcement Human Exploration Research Opportunities (HERO), 80JSC017N0001-BPBA, Appendix C, Topic 1: Analyses of the Temporal Nature of Human Adaptation to Long-Duration Low-Earth Orbit Mission Virtual NASA Specialized Center of Research (VNSCOR). This proposal addresses multiple Human Research Program (HRP) Integrated Research Plan Gaps, including:

• SANS101: Determine the relationship between fluid shifts (intravascular, interstitial, CSF) and ocular manifestations in astronauts during spaceflight.

• SANS102: Determine the relationship between the fluid-shifts induced ocular changes and fluid shifts in the CNS, including whether elevated intracranial pressure or brain edema play a role.

• The Test Readiness Review (TRR) document supporting the implementation of the iSAFE Study activities in NASA Johnson Space Center Building 21 was submitted to ROI.

• The iSAFE PI team supported the TRR for the Payloads Development Laboratory (PDL) in NASA Johnson Space Center Building 9, which is now approved. This TRR permits the use of the PDL for training crewmember operators to perform ERGs and pneumatonometry.

• Supported the informed consent briefings (ICB) for 5 potential CIPHER subjects (03/04/2021, 04/29/2021 [x2], 11/15/2021, 12/01/2021) and developed an iSAFE overview video that has been integrated into the CIPHER ICB presentation.

• Supported a hardware checkout of the ERG units designated for flight, flight backup, ground use by ROI, and for baseline data collection.

• ERG and pneumatonometry flight hardware/units passed Science Verification Testing (SVT) and are now on the International Space Station.

• Two iSAFE operators completed Telescience Center orientation in preparation for remote guidance activities, and remote guidance scripts were drafted for ERG and pneumatonometry.

• Completed the Payloads Training Dry Run (PTDR) that was overseen by NASA Marshall Space Flight Center, certifying proficiency of Cardiovascular and Vision Laboratory (CVL) personnel (Co-Investigator Scott Greenwald) to train crewmember operators for ERG and pneumatonometry.

• Two crewmember operators have completed the “Training” sessions for ERG and pneumatonometry (11/03/2021, 11/12/2021).

• Preliminary dry runs of baseline data collection were completed in the NASA Cardiovascular and Vision Laboratory.

• Steps have been taken to ensure readiness for implementation of inflight OCT angiography, which include obtaining the flight version of the OCT software and conducting preliminary remote guidance training for CVL personnel.

• Preliminary training occurred for iSAFE operators on Dynamic Vessel data collection and analysis.

• The plans for iSAFE were presented at the 2021 Human Research Program Investigators’ Workshop and at the JSC Chapter of the NASA Alumni League, both virtual.

• Substantial progress has been made towards finalizing the iSAFE data analysis plan.

• Substantial progress has been made towards finalizing the suite of standard operating procedures (SOPs) and operator logs.

NOTE: End date changed to 9/30/2025 per PI (Ed., 12/21/19)

SPECIFIC AIMS

Conducting Spaceflight Associated Neuro-ocular Syndrome (SANS) research on one-year, six-month, and short-duration (2-month) crew members will enable us to objectively generate data to help NASA determine if and how SANS symptoms worsen with mission duration. These new data from longer missions will enable us to develop a non-linear trend model that can be extrapolated to make predictions for even longer missions, up to three years, and therefore help NASA to define the risk posture for future interplanetary expeditions, and to identify possible countermeasures by the following specific aims:

Specific Aim 1: To determine if ocular structural changes develop to a greater degree (frequency or magnitude) during long-duration one-year spaceflight missions compared to findings during shorter length missions and if recovery is prolonged after longer missions.

Specific Aim 2: To determine if ocular vascular structure is altered to a greater degree during long-duration one-year spaceflight missions, and if recovery is more prolonged.

Specific Aim 3: To determine if ocular function is altered to a greater degree during long duration one-year spaceflight missions, and the recovery profile.

Specific Aim 4: To determine if measures of vascular structure and function are altered to a greater degree during long-duration one-year spaceflight missions and if these vascular adaptations correlate with alterations in ocular structure and function.

RELEVANCE & MAP TO HUMAN RESEARCH ROADMAP

This multi-project proposal is in response to NASA research announcement Human Exploration Research Opportunities (HERO), 80JSC017N0001-BPBA, Appendix C, Topic 1: Analyses of the Temporal Nature of Human Adaptation to Long-Duration Low-Earth Orbit Mission Virtual NASA Specialized Center of Research (VNSCOR). This proposal addresses multiple Human Research Program (HRP) Integrated Research Plan Gaps, including: SANS101: Determine the relationship between fluid shifts (intravascular, interstitial, CSF) and ocular manifestations in astronauts during spaceflight. SANS102: Determine the relationship between the fluid-shifts induced ocular changes and fluid shifts in the CNS, including whether elevated intracranial pressure or brain edema play a role.

• The iSAFE Principal Investigator (PI) team has worked with NASA Research Operations and Integration (ROI) Element to integrate this project into the Compliment of Integrated Protocols for Human Exploration Research on varying mission durations (CIPHER) project. The CIPHER study has received select-for-flight approval by the Human Research Program Control Board.

• We completed an informed consent briefing (ICB) with a crewmember while iSAFE had a select-for-flight status for the 6-month duration mission cohort. This status was reversed due to flight schedule conflicts, at which point iSAFE was integrated into the prime CIPHER study, as mentioned above.

• Supported the CIPHER Study PI “Face-to-Face” meeting (1/31/2020), which represented a major step toward coordinating the full complement of studies. Based on the outcome of this meeting, we updated our Institutional Review Board documents and experiment procedures to ensure compatibility and appropriate data sharing with the other studies.

• Optical biometry hardware was acquired for ground baseline data collection.

• The FORUM electronic medical records system was implemented for analyzing and securely storing visual field analysis data.

• Worked with ROI to achieve milestones that have made research hardware (i.e., Electroretinography and pneumotonometry systems) flight ready.

• Worked with ROI to baseline the Experimental Document for iSAFE 6-month cohort.

• The plans for iSAFE were presented at the 2020 Human Research Program Investigators’ Workshop in Galveston, TX.

• Substantial progress has been made towards completing the iSAFE data analysis plan.

• Substantial progress has been made towards completing the Standard operating procedures (SOPs) and workflows for the collection of electroretinography, optical coherence tomography, pneumotonometry (intraocular pressure), and visual field analysis data.

• We supported presentations to control boards to earn an accelerated select for flight status for initiating research with the 6-month duration cohort.

• The drafting of operator logs to capture activity during ground and in flight data collection sessions is in progress.

• Substantial progress has been made in drafting of the iSAFE Test Readiness Review document.

SPECIFIC AIMS

Conducting Spaceflight Associated Neuro-ocular Syndrome (SANS) research on one-year, six-month, and short-duration (2-month) crew members will enable us to objectively generate data to help NASA determine if and how SANS symptoms worsen with mission duration. These new data from longer missions will enable us to develop a non-linear trend model that can be extrapolated to make predictions for even longer missions, up to three years, and therefore help NASA to define the risk posture for future interplanetary expeditions, and to identify possible countermeasures by the following specific aims:

Specific Aim 1: To determine if ocular structural changes develop to a greater degree (frequency or magnitude) during long-duration one-year spaceflight missions compared to findings during shorter length missions and if recovery is prolonged after longer missions.

Specific Aim 2: To determine if ocular vascular structure is altered to a greater degree during long-duration one-year spaceflight missions, and if recovery is more prolonged.

Specific Aim 3: To determine if ocular function is altered to a greater degree during long duration one-year spaceflight missions, and the recovery profile.

Specific Aim 4: To determine if measures of vascular structure and function are altered to a greater degree during long-duration one-year spaceflight missions and if these vascular adaptations correlate with alterations in ocular structure and function.

RELEVANCE & MAP TO HUMAN RESEARCH ROADMAP

This multi-project proposal is in response to NASA research announcement Human Exploration Research Opportunities (HERO), 80JSC017N0001-BPBA, Appendix C, Topic 1: Analyses of the Temporal Nature of Human Adaptation to Long-Duration Low-Earth Orbit Mission Virtual NASA Specialized Center of Research (VNSCOR). This proposal addresses multiple Human Research Program (HRP) Integrated Research Plan Gaps, including: SANS1: We do not know the etiological mechanisms and contributing risk factors for ocular structural and functional changes seen in-flight and postflight. SANS12: We do not know whether ground-based analogs and/or models can simulate Space Associated Neuro-ocular Syndrome.

• Results from this study are anticipated to lead to a temporal model of SANS progression during long-term missions and to inform the development of countermeasures.

• Given the unique environment of the International Space Station (ISS), commonly used ophthalmic instruments are being implemented in novel operational environments. This work may lead to clinical practice adopting these new hardware, software, or protocol elements, benefiting patients on Earth.

• SANS shares characteristics with several terrestrial ophthalmic diseases, such as papilledema, and iSAFE study results could provide new insights into mechanisms underlying these conditions.

SPECIFIC AIMS

Conducting Spaceflight Associated Neuro-ocular Syndrome (SANS) research on one-year, six-month, and short-duration (2-month) crew members will enable us to objectively generate data to help NASA determine if and how SANS symptoms worsen with mission duration. These new data from longer missions will enable us to develop a non-linear trend model that can be extrapolated to make predictions for even longer missions, up to three years, and therefore help NASA to define the risk posture for future interplanetary expeditions, and to identify possible countermeasures by the following specific aims:

Specific Aim 1: To determine if ocular structural changes develop to a greater degree (frequency or magnitude) during long-duration one-year spaceflight missions compared to findings during shorter length missions and if recovery is prolonged after longer missions.

Specific Aim 2: To determine if ocular vascular structure is altered to a greater degree during long-duration one-year spaceflight missions, and if recovery is more prolonged.

Specific Aim 3: To determine if ocular function is altered to a greater degree during long duration one-year spaceflight missions, and the recovery profile.

Specific Aim 4: To determine if measures of vascular structure and function are altered to a greater degree during long-duration one-year spaceflight missions and if these vascular adaptations correlate with alterations in ocular structure and function.

RELEVANCE & MAP TO HUMAN RESEARCH ROADMAP

This multi-project proposal is in response to NASA research announcement Human Exploration Research Opportunities (HERO), 80JSC017N0001-BPBA, Appendix C, Topic 1: Analyses of the Temporal Nature of Human Adaptation to Long-Duration Low-Earth Orbit Mission Virtual NASA Specialized Center of Research (VNSCOR). This proposal addresses multiple Human Research Program (HRP) Integrated Research Plan Gaps, including: SANS1: We do not know the etiological mechanisms and contributing risk factors for ocular structural and functional changes seen in-flight and postflight. SANS12: We do not know whether ground-based analogs and/or models can simulate Space Associated Neuro-ocular Syndrome.