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Acute high‐altitude exposure can lead to impaired neurocognitive function. However, it remains unclear if the duration of exposure impacts the degree of impairment or if acclimatization improves performance over time. We hypothesized that measures of sustained attention and reaction time would be impaired by acute high‐altitude exposure and would improve over three days of acclimatization. 14 participants (n=9 men; n=5 women) were included in the study. Participants completed a 30 minute cognitive function test battery (Cognition by Joggle Research) at sea level and each morning over three days at 3800 m elevation. Half of the participant group completed baseline sea‐level cognitive function testing before ascent to high altitude and half completed baseline tests at least 2 days after returning to sea level. The cognitive test battery evaluated sensory motor speed, visual learning, working memory and spatial working memory, abstraction, spatial orientation, complex scanning and visual tracking, risk decision making, and vigilant attention. Mean reaction time on the Psychomotor Vigilance Task (PVT) was higher at high‐altitude compared to sea level (SL: 199 ± 27 ms; Day 1 Alt: 224 ± 33 ms; p=0.005) and did not improve over three days of acclimatization. However, mean reaction time on the Line Orientation Task (LOT) was lower at high‐altitude compared to sea level (SL: 6076 ± 1831 ms; Day 1 Alt: 5173 ± 988 ms; p=0.02) and remained lower throughout acclimatization. The number of correct responses on the LOT did not change significantly upon ascent. Reaction times on the Digit Symbol Substitution Task (DSST) decreased (R=‐0.33, p=0.04) and the number of correct responses increased (R=0.32, p=0.04) throughout acclimatization. Mean reaction time on the Balloon Analog Risk Task (BART) decreased throughout acclimatization (R=‐0.35, p=0.02). These data suggest that while some cognitive domains including complex scanning and visual tracking (DSST) improve with acclimatization, behavioral alertness and sustained attention (PVT) remain impaired. Furthermore, spatial orientation measured by the LOT was improved at high altitude, consistent with studies showing no change, or improvements in visuospatial perception, under mild stress. Further work is required to determine the mechanisms underlying the effects of acclimatization on cognitive function, the domains in which improvement occurs, the time course of these changes, and whether interventions can impact these processes. Support or Funding Information This work was funded by the University of California, Riverside, School of Medicine.
Inflammation plays a critical role in the physiological response to hypoxic stress. Evolutionary conserved inflammatory responses to oxygen limitation promote adaptation to the hypoxic environment. However, these responses may also become maladaptive during chronic exposure if not properly resolved, possibly contributing to pathologies such as Acute or Chronic Mountain Sickness. We hypothesize that pro‐inflammatory gene expression increases upon acute high‐altitude exposure, followed by a subsequent blunting of the inflammatory profile with acclimatization. We compared the inflammatory profiles in whole blood samples collected in the morning during fasting at sea level and after one and three nights at high altitude (3800 m elevation) in 15 healthy sojourners (5 women, 10 men). RNA sequencing was coupled with a nanoString Human Inflammatory Panel. Previously, we found key components of the TLR4 signaling pathway upregulated under acute high‐altitude exposure. To complement this, we found that IL8, a chemotactic cytokine that induces neutrophil recruitment, was significantly upregulated upon the first and third day at high altitude, and larger increases in IL8 may be associated with lower oxygen saturation (SpO2) at high altitude (R= ‐0.51; p=0.05). Additionally, FASLG, which is essential for immune system regulation, was associated with both SpO2 (R=0.68; p<0.01) and AMS score (R= ‐0.71; p<0.01) at high altitude. The upregulation of TLR4 signaling pathway genes observed during high‐altitude exposure in vivo suggested that hypoxia may exacerbate responses to inflammatory stimuli. To test this, we cultured whole blood in the presence of normoxia or hypoxia with or without a lipopolysaccharide (LPS) stimulus for 24 hours. Cultures were further treated with DMOG (HIF prolyl hydroxylase inhibitor), PX‐478 (HIF inhibitor), or media (control) to determine if any of these outcomes were HIF‐dependent. Preliminary data suggests that, in the presence of both inflammatory stimuli (LPS and hypoxia), TNF production was exacerbated (p=0.03). However, when HIF was inhibited with PX‐478, this exacerbated response was mitigated. Additionally, we found that DMOG abrogated TNF, IL6, and IL8 production in all treatments, suggesting a key role of prolyl hydroxylase activity in inflammation. In conclusion, our results indicate that acute high‐altitude exposure may cause an initial priming of the innate immune system with a synergistic TLR4‐induced sensitization to subsequent inflammatory stimuli and neutrophil activation and recruitment. In the case that the inflammatory response is not properly blunted during acclimatization, this may lead to the development of hypoxia‐induced pathologies. This may be particularly important in the context of pulmonary diseases if hypoxemia initiates an exacerbated inflammatory response to infection.
Introduction Individuals who travel to high altitude experience variable levels of poor sleep quality and sleep disordered breathing, which can have neurocognitive and other systemic impacts. Past studies by our group and others have shown that the apnea hypopnea index (AHI) increases, and nocturnal oxygen saturation decreases at higher altitude. This may change over time with acclimatization to environmental hypoxemia. The aim of this study was to examine the trajectory and variability in high altitude sleep disordered breathing effects in healthy young adult volunteers. Methods Twenty healthy volunteers were recruited from a local university (35% women), mean age 23.5(20.0, 32.2) years and BMI of 30.0(28.0, 35.9) kg/m2. Peripheral Arterial tonometry based home sleep apnea tests (HSAT; WatchPat One) was performed on all subjects at sea level up to three days prior to transportation via car to high altitude (3800m White Mountain Research Center - Barcroft Station, CA). Participants continued HSAT testing for three consecutive nights at high altitude sleeping in any position, without oxygen, acetazolamide, or use of any other medications impacting sleep or breathing. Mixed effects modeling was used to compare sleep parameters across nights. Results Subjects' characteristics: median (IQR)[range] age 23(20,32)[19,39] years, BMI 30(28, 36)[23,48] kg/m2, 35% women. AHI at altitude night 1 (67±4 events/hour) was significantly higher than sea level (7±4 events/hour; P< 0.001). Mean sleep SpO2 at altitude night 1 (79±1%) was significantly lower than sea level (95±1%; P< 0.0001). There was no statistically significant change in AHI or mean sleep SpO2 on nights 1-3; however substantial variability was noted between individual trajectories. Conclusion Healthy young adults exhibit severe Sleep Disordered Breathing when traveling to high altitude. Despite acclimatization, the severity of Sleep Disordered Breathing remained relatively unchanged overall. However substantial differences in individual trajectories were apparent. Larger studies are needed to understand how differences in genetics, sex, and other factors might impact Sleep Disordered Breathing at altitude. In addition, the impacts of (or tolerances to) altitude are likely to be broadly informative towards Sleep Disordered Breathing, hypoxemia, and other areas. Support (if any) N/A
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