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As future deep space missions to Mars, moons, or asteroids will also exceed current LEO stay durations and are estimated to require up to 3\u00a0years, we review recent evidence with contemporary and historic spaceflight case studies addressing implications for long-duration missions. To highlight the need for specific further investigations, we provide neuropsychological considerations integrating cognitive and motor functions, neuroimaging, neurological biomarkers, behavior changes, and mood and affect to construct a multifactorial profile to explain performance variability, subjective experience, and potential risks. 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