Gap BMed-102: Given exposures to spaceflight hazards (space radiation, isolation), how do we identify individual susceptibility, monitor molecular/biomarkers and acceptable thresholds, and validate behavioral health and CNS/neurological/neuropsychological performance measures and domains of relevance to exploration class missions?
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Last Published:  07/30/20 02:45:13 PM (Central)
Responsible Element: Human Factors and Behavioral Performance (HFBP)
Status: Open
Description
Given the extended duration and/or distance from Earth of future spaceflight missions, crewmembers will be exposed to multiple individual and simultaneous spaceflight hazards (e.g., space radiation, isolation, altered gravity) for extended periods of time. However, there is a lack of human epidemiology data on which to estimate these risks, making projection based on scaling to human data not currently possible for central nervous system (CNS) risks. Possible acute (within mission) risks to the central nervous system (CNS) from galactic cosmic rays (GCR) and solar particle events (SPE) are a documented concern for human exploration of space, as are risks due to isolation and confinement, circadian dysregulation, and cerebral fluid shifts in altered gravity.  Acute CNS risks include: altered cognitive function, reduced motor function, behavioral and neuropsychological changes, all of which may affect performance and human health.  Research specific to the spaceflight environment using animal and cell models using near-term experimental research focused on low dose-rate relevant types and exposures of GCR must be compiled to calculate the magnitude of this risk by scaling these results to human data while assessing potential synergistic risks of multiple stressors.  Since it is anticipated that exploration class missions will become increasingly autonomous, a largely different model of psychological care provided to crewmembers is needed. This increased autonomy will increase the need to identify and validate measures to monitor behavioral health and performance during exploration class missions to determine acceptable thresholds for these measures.  There is a need for objective, reliable, and sensitive methods or tools for monitoring and measuring changes in individual behavioral and cognitive health and performance so that flight surgeons and operational psychologists can provide support. Objective assessments of the crewmember's psychological well-being in conjunction with the crewmember's subjective reports can provide the context needed to more accurately assess the astronaut’s cognitive and behavioral health and performance. In addition, evidence indicates that gathering objective information would be highly valuable in astronaut selection and training and can provide mission planners and operators with critical information on individual adaptation and functioning so that if decrements are detected these can be evaluated on a case-by-case basis and a more personalized countermeasure approach can be provided.  The contributions of individual sensitivity (genetic, epigenetic, previous injury, age, sex/gender, etc.) to possible acute and late risks to the CNS from space radiation exposure, isolation, circadian dysregulation, and brain morphology shifts in altered gravity on overall crew health and performance are undetermined. While it is necessary to determine the impact of environmental factors on sleep and performance, as well as the mission requirements that disrupt circadian rhythms and sleep, there are varied ways through which individuals respond to stressors. Recent studies have documented that there are large stable (trait-like) differences among individuals in the degree of cognitive deficits experienced during sleep loss.  Such evidence is needed to identify, establish, and validate performance outcome limits (POLs) and Permissible Exposure Limits (PELs) for these hazards individually and in combination. 
Approach: Ground-based, peer-reviewed research using cell and animal models to acquire necessary knowledge for accurate risk quantification and uncertainty reduction for central nervous system (CNS) adverse changes due to space radiation exposure. Where feasible, identify biomarkers of cognitive/CNS/behavioral performance changes and/or disease prognosis/progression and outcome pathways for use in monitoring early, in-mission, or adverse late operationally-relevant outcomes.  Research approaches are establishing the molecular basis of operationally-relevant, cognitive performance/CNS reactions to HZE nuclei exposure.  An integrated research approach is needed that focuses on the potential synergistic impacts to the central nervous system (CNS), impacts of isolation on Behavioral Medicine (B), and the sensorimotor (S) and broader cognitive impacts of altered gravity (i.e., CBS Integrated Research Plan).  The CBS Integrated Research Plan is a systems biology approach focused on the potential CNS adverse outcome pathways that form a basis for animal to human extrapolation, and relies on an understanding of molecular and physiological changes in the CNS caused by individual or potentially synergistic actions of space radiation, isolation, and altered gravity, and how these changes relate to adverse operationally-relevant performance outcomes. This approach will rely on understanding of molecular and physiological changes in the cognitive/CNS domains caused by space radiation. Intermediate CNS models of important pathways and processes that contribute to cognitive/CNS risks including synapse dysfunction, impaired neurogenesis, proteinopathies, neurodegeneration, chronic oxidative stress, neuro-inflammation, etc., will be generated and developed into a model for operationally-relevant cognitive/CNS risk assessment. In conjunction with this effort, it is necessary to set exploration-class mission acceptable levels (thresholds) for the key behavioral health and performance indicators. The astronaut corps is comprised of highly selected, motivated and skilled individuals who out-perform other healthy adults while working operationally. Therefore thresholds will need to be normed to the astronaut population. A threshold represents a level above or below which would indicate a meaningful or reliable change and thus can trigger mitigation action. The change could be a percentage change in a set of behaviors from baseline levels or at specific times during the mission (e.g., third quarter). We will then develop and validate the measures and tools that are sensitive, reliable, and feasible to monitor behavioral health and performance. We will utilize high fidelity analogs to validate the set of effective measures for monitoring. These measures will be vetted with SMEs and evidence will be updated accordingly. During the development and validation of those tools, a critical step is to establish a baseline for thresholds regarding individual behavioral health and performance for exploration class missions.  This will enable experts (e.g., flight surgeons, BHP Operations) and astronauts themselves, to more accurately monitor and manage crewmember behavioral health status. Setting crewmember thresholds is important to the understanding and mitigating of off-nominal individual behaviors during exploration missions of varying duration (e.g., <6; 6-12; >12 months). Currently, such metrics do not exist for ISS missions, and neither do astronaut norms for many of the parameters of import. The goal is to develop astronaut norms where needed and to standardize metrics to provide the ability to objectively detect, assess, and manage off-nominal events, and predict future off-nominal events that may compromise a mission and increase the risk of behavioral health and performance decrements. Individualized, real-time tools that provide rapid feedback and assessment will be needed for exploration class missions. From the key threats and promoters of behavioral health identified and baselined for Earth-levels, current measures and readiness levels of research deliverables (tools and technologies) will be reviewed. The baseline will allow for future monitoring of long duration crews. Astronaut norms will need to be developed for this set of behaviors where possible, or extrapolated from healthy, astronaut-like population. The tools for detecting and assessing cognitive and behavioral health status will need to be tested in high fidelity analogs for sensitivity, reliability as well as feasibility and acceptability for astronauts. Finally an integrated testing of countermeasures will test the full suite of integrated countermeasures.
Metrics for Interim Progress:
Determine impact of individual susceptibility on space radiation dose responses, possible dose thresholds, latency to onset and severity of acute and late operationally-relevant cognitive/CNS and behavioral performance outcomes.
     
Identifying individual factors that mediate the degree to which an external stressor affects the individual will inform individual countermeasure recommendations.

Can we identify/validate advancing technological innovations in areas of Brain-Computer Interface (BCI), Artificial Intelligence (AI), neurophysiological processes, workload and cognitive performance thresholds for autonomous, long-duration expeditionary/exploration missions?

Use multiple research approaches involving neuroergonomics that uses non-invasive neurophysiological tools to measure known correlates of mental effort to assess workload during a task as well as machine learning to classify mental workload states via brain activity to identify cognitive performance thresholds. 

Use ground-based, peer-reviewed research using cell and animal models conducted to acquire necessary knowledge for accurate risk calculation and uncertainty reduction for acute adverse cognitive/CNS behavioral performance outcome measures due to mission-relevant individual or combined exposures (e.g., space radiation, isolation, altered gravity).
    
-Identify appropriate experimental models, paradigms and endpoints for assessment of acute radiation effects on the CNS.     
-Identify the pathophysiological mechanisms underlying functional CNS change.     
-Determine the space radiation dose responses and existence of threshold doses for functional CNS changes using appropriate animal model systems (e.g. rodent, NHP)     
-Broaden initial experiments to investigate higher fidelity radiation fields (e.g., a larger number of GCR particle types and energies including mixed fields) representative of GCR and different shielding configurations including the Martian surface.

Determine impact of previous CNS injury on space radiation dose responses, possible dose thresholds, latency to onset and severity of acute and late CNS effects.

Determine feasibility of indexed biomarker approaches for monitoring individual susceptibility for monitoring acute (in-mission) and late (post-mission) operationally-relevant cognitive/CNS and behavioral performance outcomes.

Identified behavioral and/or physiological marker(s) for individual vulnerabilities and resiliencies to sleep loss and circadian rhythm disruption based on the amount of variance seen in performance, across individuals in controlled experimental studies.

Acquire data from astronauts to relate space radiation exposure and individual sensitivity to acute and late operationally-relevant cognitive/CNS and behavioral performance outcomes.

Define risk domains and appropriate metrics that encompass operationally-relevant performance decrements of concern (e.g. memory, attention and executive functions, motor skills, reasoning/decision making, reaction time, other neuropsychological or neurobehavioral domains, etc). 

Develop intermediate cognitive/CNS/behavioral performance models of important outcome pathways and processes that contribute to CNS risks, including synaptic dysfunction, proteinopathies, chronic oxidative stress, impaired neurogenesis, neurodegeneration, neuro-inflammation, etc.

Combine cognitive/CNS process impacts and operationally-relevant change due to exposure to spaceflight hazards exposures to create a model for cognitive/CNS and behavioral risk assessment.

Operationally-relevant cognitive and behavioral performance model validation and documentation. 
Target for Closure
Determine the operational significance of adverse changes elicited by mission-relevant space radiation, isolation, circadian disruption, etc. exposures.
Quantify the spectrum and dose responses for acute (mission timescale) functional cognitive/CNS/Behavioral operationally-relevant performance changes from space radiation and isolation exposures.     
-Organize cognitive/CNS reactions to radiation exposure into adverse outcome pathway(s) related to known diseases and biomarkers.     
-Identify behavioral and/or physiological biomarkers linking individual vulnerabilities and resiliency to sleep loss and circadian rhythm and sensitivity to other mission relevant exposures (e.g., space radiation, isolation, altered gravity) and outcome measures.     
-Identification of factors that would affect individual risk (both acute, inflight, and post-mission) to the cognitive/CNS/behavioral status from mission-relevant exposures (e.g., space radiation, isolation, altered gravity) and assessment of these factors in a study in astronauts.     
-Model cognitive/CNS/operationally-relevant performance reactions to radiation and isolation exposures to identify adverse outcome pathway(s) related to known cognitive or behavioral risks, or conditions of impaired performance, and link to biomarkers at molecular, cellular, tissue levels of organization.

Identification and validation of an integrated suite of minimally obtrusive tools that have been verified (meets functional requirements) and validated (content, construct, and where applicable, criterion-related validity), as well as evaluated for feasibility and acceptability in high fidelity ground analogs and/or spaceflight, to monitor and measure operationally-relevant performance changes due to mission-relevant exposures, to include measures of sleep and associated changes to performance and cognitive function unobtrusively, while providing operationally relevant feedback related to sleep and operationally-relevant performance.

Monitoring measures validated for feasibility and acceptability in high fidelity ground analogs of different durations (<6 months; 6-12 months; >12 months).

Quantified and validated set of mission acceptable thresholds for individual behavioral health and performance during exploration class missions. 

Identified and incorporated standard exposure conditions and reference measures.
Mappings
Risk Risk of Adverse Cognitive or Behavioral Conditions and Psychiatric Disorders
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