NOTE: End date changed to 03/31/2029 per L. Juliette/JSC (Ed., 5/3/22).

Specific Aim 1: Characterize the recovery and long-term ocular structural changes up to 5 years following 6-month spaceflight missions. Specific Aim 2: Characterize the recovery and long-term ocular functional changes up to 5 years following 6-month spaceflight missions. Specific Aim 3: Characterize the recovery and long-term brain structural changes up to 5 years following 6-month spaceflight missions. Specific Aim 4: Characterize the recovery and long-term brain functional changes up to 5 years following 6-month spaceflight missions. Specific Aim 5: Characterize the structural and functional changes to the eye, brain, and cognition in crewmembers who participated in past missions, calling them back several years after their flights. Specific Aim 6: Integration and characterization of the relationships across ocular and brain measures, crewmembers, and time.

This project will evaluate the persistence of spaceflight-induced ocular, brain, and behavioral changes, as well as quantify their association with long-term health and performance. We will quantify regional changes and recovery in brain structure, brain fluid distribution, changes in brain activation and functional connectivity, glymphatic clearance, and optic nerve head structure; we will also assess visual function, sensorimotor function, cognitive function, and quality of life. Finally, we will determine the molecular signatures of brain changes. Investigating these parameters is critically important as we prepare to extend the duration and distance of space travel.

This project will be comprised of two arms: (1) a prospective spaceflight arm that includes a 5-year postflight follow-up and (2) a call-back arm in which crew who have flown a ~6-month standard duration mission (or longer) > 5 years earlier will be invited to participate. In the prospective flight arm, long-term structural and functional changes to the eye and brain will be characterized for up to 5 years in 10 crewmembers completing approximately 6-month spaceflight missions. Crewmember data will be compared to similar data from 10 age- and sex-matched controls. Eye and brain structure and function will be assessed before, during, and after spaceflight. The call-back arm will recruit 20 crewmembers who have previously participated in a long-duration (≥ 6 month) mission and 20 controls with no spaceflight experience to further characterize the lasting structural and functional effects of long-duration spaceflight in a cross-sectional population. Ocular testing will include optical coherence tomography, electroretinography, intraocular pressure, visual field analysis, optical biometry, and orbital magnetic resonance imaging (MRI). Multi-modal brain MRI will assess changes in brain activation during tasks, functional connectivity via task and resting state functional MRI, brain volume, lateral ventricle size, and pituitary gland deformation. Comprehensive neurological examination and neuropsychology testing will be performed to correlate MRI findings with cognitive and neurological functioning. Blood samples will be obtained to identify key neurotrophins and neurodegenerative biomarkers.

This project has been combined with the work of three other Principal Investigators (PIs) who responded to the same solicitation with independent proposals. The protocols and aims from all four PIs have been integrated into a revised proposal that was delivered to NASA Human Health Countermeasures (HHC) and Human Factors and Behavioral Performance (HFBP) Element Scientists in January 2022. For information on the four related investigations, see:

• The Long-Term Consequences of Spaceflight on Brain and Eye Health (PI: Bershad). • Long-Term Brain Structural and Functional Consequences of Spaceflight (PI: Basner, this taskbook entry). • Investigating Long-term Structural and Functional Changes in the Eye and Brain After Spaceflight (PI: Macias). • Recovery Timeline of Spaceflight-Induced Central Nervous System Changes (PI: Seidler).

The “LTH Call Back” retrospective arm will focus on investigating the structural and functional changes in the eye, brain, and cognition in astronauts who previously participated in long-duration missions, calling them back at least 5 years after their previous flights to determine changes that may endure long after return from spaceflight. We have limited involvement in this arm of the study. Major accomplishments during this reporting period for this sub-study include:

• The Lifetime Surveillance of Astronaut Health (LSAH) data share request was approved by the LSAH Advisory Board. • An LSAH epidemiologist was added to the study team to help with data analysis. • The MRI facility contract was finalized, and two MRI dry runs were completed at Houston Physicians’ Hospital. • One internal dry run was completed in the Cardiovascular and Vision Laboratory. • The neuropsychological and neurological Co-PI team completed a dry run at NASA Johnson Space Center (JSC). • The Crew Office approved the Informed Consent Briefing (ICB). • Recruitment efforts were initiated by ROI and are ongoing. • The Test Readiness Review (TRR) package was developed and is undergoing internal review.

Ongoing forward work with ROI for “LTH Call Back” includes:

• Approval of the TRR package (planned for December 2024). • Initiate recruitment and testing of astronauts and matched control TSS participants.

The “Brain Health” component is prospective and will investigate the development and recovery of structural and functional changes in the eye, brain, and cognition in astronauts participating in standard or extended duration missions and will follow them out 5 years postflight. Major accomplishments for the Flight Study during this reporting period include:

• ROI submitted the Feasibility Assessment to the HHC and HFBP Elements and the sub-study was approved for Select for Flight in December 2024. • The LSAH data share request was approved by the LSAH Advisory Board. • An LSAH epidemiologist was added to the study team to help with data analysis.

Ongoing future work with ROI for “Brain Health” includes (pending select for flight determination by HRP): • Completion of two MRI dry runs for the Brain Health MRI scanning protocol. • Development and approval of a TRR package (targeting January 2025). • Development and approval of ICB presentation. • Pitch ICB starting with Crew-12.

NOTE: End date changed to 03/31/2029 per L. Juliette/JSC (Ed., 5/3/22).

In summary, this international project will monitor changes in brain structure and function up to 3-years post-flight to determine 1) whether they persist in some astronauts, 2) if so, for how long, and 3) whether there are any long-term health consequences. It will thus deliver critical insights into the time course of brain changes and their functional relevance observed in astronauts after ISS missions lasting 6-months and longer. Synergies between the projects will be used to provide NASA and DLR/ESA with insights that go beyond the specific aims of the individual projects.

Ed. Note (2/29/24): This project has been combined with the work of three other Principal Investigators (PIs) who responded to the same solicitation with independent proposals. The protocols and aims from all four PIs have been integrated into a revised proposal that was delivered to NASA Human Health Countermeasures (HHC) and Human Factors and Behavioral Performance (HFBP) Element Scientists in January 2022. For information on the four related investigations, see:

• The Long-Term Consequences of Spaceflight on Brain and Eye Health (PI: Bershad). • Long-Term Brain Structural and Functional Consequences of Spaceflight (PI: Basner). • Investigating Long-term Structural and Functional Changes in the Eye and Brain After Spaceflight (PI: Macias). • Recovery Timeline of Spaceflight-Induced Central Nervous System Changes (PI: Seidler).

The “LTH Call Back” retrospective arm will focus on investigating the structural and functional changes in the eye, brain, and cognition in astronauts who previously participated in long-duration missions, calling them back at least 5 years after their previous flights to determine changes that may endure long after return from spaceflight. Major accomplishments during this reporting period for this sub-study include:

• The protocol was approved by the Institutional Review Board (IRB) in August 2023.

• ROI submitted the Feasibility Assessment to the HHC and HFBP Elements and the sub-study was approved for Select for Ground in September 2023.

Ongoing work with ROI for “LTH Call Back” includes:

• The development of a testing schedule for participants.

• ROI submitted the NASA Lifetime Surveillance of Astronaut Health (LSAH) data share request and is awaiting the completion of a Feasibility Assessment by LSAH prior to moving forward with their recruitment effort.

• The development of a list of potential crewmembers who meet the recruitment criteria for this sub-study.

• The development of an Informed Consent Briefing.

• The completion of the MRI facility contract, which is in progress.

The “LTH Flight” component is prospective and will investigate the development and recovery of structural and functional changes in the eye, brain, and cognition in astronauts participating in standard or extended duration missions and will follow them out 5 years postflight. Major accomplishments for the Flight Study during this reporting period include:

• The protocol was approved by the IRB in October 2023.

• Inputs to the ROI Feasibility Assessment.

Ongoing work with ROI for “LTH Flight” includes:

• Providing testing constraints to ROI so they can begin developing testing schedules for participants.

NOTE: End date changed to 03/31/2029 per L. Juliette/JSC (Ed., 5/3/22).

In summary, this international project will monitor changes in brain structure and function up to 3-years post-flight to determine 1) whether they persist in some astronauts, 2) if so, for how long, and 3) whether there are any long-term health consequences. It will thus deliver critical insights into the time course of brain changes and their functional relevance observed in astronauts after ISS missions lasting 6-months and longer. Synergies between the projects will be used to provide NASA and DLR/ESA with insights that go beyond the specific aims of the individual projects.

In summary, this international project will monitor changes in brain structure and function up to 3-years post-flight to determine 1) whether they persist in some astronauts, 2) if so, for how long, and 3) whether there are any long-term health consequences. It will thus deliver critical insights into the time course of brain changes and their functional relevance observed in astronauts after ISS missions lasting 6-months and longer. Synergies between the projects will be used to provide NASA and DLR/ESA with insights that go beyond the specific aims of the individual projects.

[Ed. Note, Sept 2021: HRP Gap numbers listed above are not current. For the current list of HRP Gaps, see updates at the Human Research Roadmap: https://humanresearchroadmap.nasa.gov/ ].