Table 2.

Stage 2, In-Flight: Stressors and resilience factors in-flight and in aging that likely contribute to neural dysfunction and adaptations.

STAGE 2		IN-FLIGHT	NEW EXPERIENCES AS AN ADULT1
STRESSORS		Microgravity Radiation exposure Uncomfortable temperatures, constant noise, lack of fresh air Increased ambient CO2ST, SP (Zuj et al., 2012) Lack of sleep and altered circadian rhythmsREV, HA (Basner et al., 2013) IsolationREV / ST, AN (Pagel and Choukèr, 2016; Stahn et al., 2019) Headward fluid shiftsST, SP (Petersen et al., 2019) Emotional stress Heavy workload (i.e., 8+ hour work days; 2.5 hours exercise) Space motion sickness Altered and reduced somatosensory and vestibular inputsST, SP (Lowrey et al., 2014) Altered diet Decreased cardiovascular reactivity Visual impairments / Spaceflight Associated Neuro-Ocular Syndrome (SANS) Biological agingREV, HA (Seidler et al., 2010)	Vascular disease Biological aging
RESILIENCE		Spaceflight euphoria In-flight exerciseST, AN (Koppelmans et al., 2015) Reduction in disordered sleep and snoringST, SP (Elliott et al., 2001) Psychological counseling Receiving care packages from family Access to leisure activities (e.g., group movies and keyboard guitar) Crew discretionary events (i.e., a private conversation with a person of their choosing) Artificial gravity countermeasures Cognitive engagement (e.g., spacewalks, station maintenance, science experiments)	New learning Social / intellectual engagement Exercise Cognitive training Meditation
DYSFUNCTION	Behavior	Impaired balanceST, SP (Layne et al., 2001; Cohen et al., 2012) Impaired locomotionST, SP (Bloomberg and Mulavara, 2003; Miller et al., 2010; Mulavara et al., 2010; Cohen et al., 2012) Impaired functional mobilityST, SP/AN/AN (Mulavara et al., 2010; Koppelmans et al., 2015; Lee et al., 2019a) Impaired stretch reflex, dynamic balance, and functional mobilityST, AN (Reschke et al., 2009) Increased manual tracking errors under cognitive load (Manzey et al., 2000; Bock et al., 2010) Reduced mass discrimination abiliitesST, SP (Ross et al., 1984) In-flight spatial disorientation and dizzinessST, SP (Young et al., 1984) Changes in gaze-holdingST, SP (Clément et al., 1993; Kornilova et al., 1983) Changes in perception of self-motionST, SP (De Saedeleer et al., 2013) Impaired dual tasking abilityST, SP (Manzey et al., 1993, 1995, 1998; Bock et al., 2010) Mental slowing and poor concentrationST, AN (Welch et al., 2009)	Declining cognitive abilities
	Brain Structure	Fluid shifts, including an upward shift of the brain within the skull and ventricular expansionST, SP (Koppelmans et al., 2016; Roberts et al., 2017; Van Ombergen et al., 2019; Hupfeld et al., 2020b) Widespread gray matter decreases in frontal regionsST, AN (Koppelmans et al., 2017a) Crowding of cerebrospinal fluid around the vertex and upward shift of the brain within the skullST, AN (Roberts et al., 2015) Free water increases in frontal-temporal regions and decreases in posterior-parietal areasST, AN (Koppelmans et al., 2017b) Widespread gray matter volume decreases, including large areas covering the temporal and frontal poles and around the orbitsST, SP (Koppelmans et al., 2016) Declines in white matter integrity and structural connectivityST, SP (Lee et al., 2019b; Riascos et al., 2019) Increased total brain volume and increased CSFST, SP (Kramer et al., 2020) Increased periventricular white matter hyperintensitiesST, SP (Alperin et al., 2017) Larger brain fluid shift changes for twelve versus six months on the ISSST, SP (Hupfeld et al., 2020b) Decreased hippocampal volumeST, AN (Stahn et al., 2019)	Cortical thinning Regional atrophy Loss of white matter integrity Dopamine depletion Amyloid/tau burden
	Brain Function	Possible detrimental changes in resting state vestibular and sensorimotor networksST, SP (Demertzi et al., 2016) Reduced neural efficiency during vestibular processingST, AN (Yuan et al., 2018b) Reduced neural efficiency for dual task processingST, AN (Yuan et al., 2016) Changes in cerebral blood flow due to microgravity exposureST, SP (Bondar et al., 1993)	Dedifferentiation Decreased memory-related recruitment of medial temporal regions Dysregulation of default mode network Declines in resting state network specificity
ADAPTATION	Behavior	Reductions in tactile sensitivity and sensory reweightingST, SP (Lowrey et al., 2014) Adaptive central reinterpretation of visual, vestibular, and proprioceptive informationREV, SP (Reschke et al., 1998) Facilitation of cognitive processing speedST, AN (Lee et al., 2019a)	Slowing of cognitive decline Use of compensatory strategies Learning of new skills
	Brain Structure	Localized gray matter increases in somatosensory and motor cortical regions where the lower limbs are representedST, SP (Koppelmans et al., 2016) Widespread gray matter increases in posterior parietal regions; increased gray matter volume in somatosensory cortex and cerebellar lobule V; association of greater increases in gray matter in precuneus and pre-/post-central gyri with less post- bed rest balance declineST, AN (Koppelmans et al., 2017a) Astronauts returning from longer duration missions show smaller decreases in cerebellar white matter structure; white matter may become more robust to microgravity effects over longer durationsST, SP (Lee et al., 2019b)	Unclear if aging is associated with any structural brain adaptations
	Brain Function	Increased motor cortex excitabilityST, AN (Roberts et al., 2007) Association of greater post-bed rest brain activation during foot tapping with better post-bed rest balance and mobility (suggesting a neural compensatory response)ST, AN (Yuan etal., 2018a) Evidence for adaptive functional neural changes within the vestibular and spatial working memory systems (Hupfeld et al. 2020a; Salazar et al., 2020)ST, AN Possible sensory reweighting and changes in functional connectivityST, SP (Pechenkova et al., 2019) EEG evidence for in-flight sensory reweighting (Cheron et al., 2014; Cebolla et al., 2016) Changes in motor, somatosensory, and vestibular functional networks with bed rest; correlations of several connectivity changes with sensorimotor and spatial working memory performance (suggesting that these are adaptive functional changes)ST, AN (Cassady et al., 2016)	Bilateral recruitment Enhanced fronto-parietal recruitment Strengthened connectivity Recruitment of new regions Neurogenesis

Note. Here we list negative (stressor) and positive (resilience) in-flight factors that likely influence brain changes with spaceflight. Items without citations indicate factors hypothesized to elicit brain changes with spaceflight; however, these hypotheses have yet to be tested and constitute areas for future research (Koppelmans et al., 2015; Manzey et al., 1993; Pagel and Choukèr, 2016; Reschke et al., 2009; Riascos et al., 2019; Stahn et al., 2019; Welch et al., 2009; Wood et al., 2010).

¹All listed aging factors are adapted from the previously-established Scaffolding Theory of Aging and Cognition-Revised (STAC-r) model where they are referred to as resource enriching and depleting factors, respectively (Reuter-Lorenz and Park, 2014).

^REVreview paper.

^STexperimental study.

^HAstudies that have tested effects of the listed factor on the brain in healthy adults; indicates an area where research should be conducted in astronauts.

^SPstudies that have tested effects of the listed factor on the brain with spaceflight. Most of the factors listed for these spaceflight studies are changes measured post-flight; however, we (and the spaceflight human research community) infer these to be spaceflight-induced changes, rather than changes associated with re-adaptation to Earth’s environment.

^ANstudies that have tested effects of the listed factor on the brain with spaceflight analog environments (e.g., head-down-tilt bed rest or Antarctic isolation).