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Background: Hypoxia and hyperoxia can affect the acute psycho-physiological response to exercise. Recording various perceptual responses to exercise is of particular importance for investigating behavioral changes to physical activity, given that the perception of exercise-induced pain, discomfort or unpleasure, and a low level of exercise enjoyment are commonly associated with a low adherence to physical activity. Therefore, this study aimed to compare the acute perceptual and physiological responses to aerobic exercise under intermittent hypoxia-hyperoxia (IHHT), hypoxia-normoxia (IHT), and sustained normoxia (NOR) in young, recreational active, healthy males., Methods: Using a randomized, single-blinded, crossover design, 15 males (age: 24.5 ± 4.2 yrs) performed 40 min of submaximal constant-load cycling (at 60% peak oxygen uptake, 80 rpm) under IHHT (5 × 4 min hypoxia and hyperoxia), IHT (5 × 4 min hypoxia and normoxia), and NOR. Inspiratory fraction of oxygen during hypoxia and hyperoxia was set to 14% and 30%, respectively. Heart rate (HR), total hemoglobin (tHb) and muscle oxygen saturation (S m O 2 ) of the right vastus lateralis muscle were continuously recorded during cycling. Participants' peripheral oxygen saturation (S p O 2 ) and perceptual responses ( i.e ., perceived motor fatigue, effort perception, perceived physical strain, affective valence, arousal, motivation to exercise, and conflict to continue exercise) were surveyed prior, during (every 4 min), and after cycling. Prior to and after exercise, peripheral blood lactate concentration (BLC) was determined. Exercise enjoyment was ascertained after cycling. For statistical analysis, repeated measures analyses of variance were conducted., Results: No differences in the acute perceptual responses were found between conditions ( p ≥ 0.059, η p 2 ≤ 0.18), while the physiological responses differed. Accordingly, S p O 2 was higher during the hyperoxic periods during the IHHT compared to the normoxic periods during the IHT ( p < 0.001, η p 2 = 0.91). Moreover, HR ( p = 0.005, η p 2 = 0.33) and BLC ( p = 0.033, η p 2 = 0.28) were higher during IHT compared to NOR. No differences between conditions were found for changes in tHb ( p = 0.684, η p 2 = 0.03) and S m O 2 ( p = 0.093, η p 2 = 0.16)., Conclusion: IHT was associated with a higher physiological response and metabolic stress, while IHHT did not lead to an increase in HR and BLC compared to NOR. In addition, compared to IHT, IHHT seems to improve reoxygenation indicated by a higher S p O 2 during the hyperoxic periods. However, there were no differences in perceptual responses and ratings of exercise enjoyment between conditions. These results suggest that replacing normoxic by hyperoxic reoxygenation-periods during submaximal constant-load cycling under intermittent hypoxia reduced the exercise-related physiological stress but had no effect on perceptual responses and perceived exercise enjoyment in young recreational active healthy males., Competing Interests: The authors declare that they have no competing interests., (© 2024 Behrendt et al.)

Objective: To evaluate, under replicable, blinded and standardised conditions, the effect of acute exposure to hypobaric hypoxia (HH) (equivalent to 200 or 3000 or 5000 m above sea level (asl)) on selected cognitive domains and physiological parameters in personnel of helicopter emergency medical service (HEMS)., Methods: We conducted a randomized clinical trial using a single-blind crossover design in an environmental chamber ( terraXcube ) to induce HH in 48 HEMS personnel. Participants performed cognitive tests (CT) before the ascent, after 5 min at altitude, and after simulated cardiopulmonary resuscitation (SCR). CT evaluated: sustained attention using the psychomotor vigilance test (PVT) that included measurement of reaction time (RT); risky decision making using the balloon analogue risk task (BART), and attention and speed of processing using the digit symbol substitution test (DSST). CT performance was subjectively rated with a visual analogue scale (VAS). Physiological data were recorded with a physiological monitoring system. Data were analysed using a linear mixed model and correlation analysis., Results: Mean reaction time was significantly slower ( p = 0.002) at HH (5000 m asl), but there were no independent effects of HH on the other parameters of the PVT, BART or DSST. Participants did not detect subjectively the slower RT at altitude since VAS performance results showed a positive correlation with mean RT ( p = 0.009). DSST results significantly improved ( p = 0.001) after SCR., Conclusion: Acute exposure of HEMS personnel to HH induced a slower RT but no changes in any other investigated measures of cognition. The reduced RT was not detected subjectively by the participants. Trial number 3489044136, ClinicalTrials.gov trial registration.

This study investigates how cognitive performance is affected by the combination of two stressors that are operationally relevant for helicopter pilots: heat load and hypobaric hypoxia. Fifteen participants were exposed to (1) no stressors, (2) heat load, (3) hypobaric hypoxia, and (4) combined heat load and hypobaric hypoxia. Hypobaric hypoxia (13,000 ft) was achieved in a hypobaric chamber. Heat load was induced by increasing ambient temperature to ∼28 °C. Cognitive performance was measured using two multitasks, and a vigilance task. Subjective and physiological data (oxygen saturation, heart rate, core- and skin temperature) were also collected. Mainly heat load caused cognitive performance decline. This can be explained by high subjective heat load and increased skin temperature, which takes away cognitive resources from the tasks. Only the arithmetic subtask was sensitive to hypobaric hypoxia, whereby hypobaric hypoxia caused a further performance decline in addition to the decline caused by heat load. Practitioner summary: Little is known about how multiple environmental stressors interact. This study investigates the combined effects of heat load and hypobaric hypoxia on cognitive performance. An additive effect of heat load and hypobaric hypoxia was found on a arithmetic task, which may be attributed to independent underlying mechanisms.

We tested the hypothesis that ingestion of cocoa flavanols would improve cognition during acute hypoxia equivalent to 5,500 m altitude (partial pressure of end-tidal oxygen = 45 mmHg). Using placebo-controlled double-blind trials, 12 participants ingested 15 mg·kg -1 of cocoa flavanols 90 min before completing cognitive tasks during normoxia and either poikilocapnic or isocapnic hypoxia (partial pressure of end-tidal carbon dioxide uncontrolled or maintained at the baseline value, respectively). Cerebral oxygenation was measured using functional near-infrared spectroscopy. Overall cognition was impaired by poikilocapnic hypoxia (main effect of hypoxia, P = 0.008). Cocoa flavanols improved a measure of overall cognitive performance by 4% compared with placebo (effect of flavanols, P = 0.033) during hypoxia, indicating a change in performance from "low average" to "average." The hypoxia-induced decrease in cerebral oxygenation was two-fold greater with placebo than with cocoa flavanols (effect of flavanols, P = 0.005). Subjective fatigue was increased by 900% with placebo compared with flavanols during poikilocapnic hypoxia (effect of flavanols, P = 0.004). Overall cognition was impaired by isocapnic hypoxia (effect of hypoxia, P = 0.001) but was not improved by cocoa flavanols (mean improvement = 1%; effect of flavanols, P = 0.72). Reaction time was impaired by 8% with flavanols during normoxia and further impaired by 11% during isocapnic hypoxia (effect of flavanols, P = 0.01). Our findings are the first to show that flavanol-mediated improvements in cognition and mood during normoxia persist during severe oxygen deprivation, conferring a neuroprotective effect. NEW & NOTEWORTHY We show for the first time that cocoa flavanols exert a neuroprotective effect during severe hypoxia. Following acute cocoa flavanol ingestion, we observed improvements in cognition, cerebral oxygenation, and subjective fatigue during normoxia and severe poikilocapnic hypoxia. Cocoa flavanols did not improve cognition during severe isocapnic hypoxia, suggesting a possible interaction with carbon dioxide.

Background: Decreased SpO 2 during hypoxia can cause cognitive function impairment, and the effects of acute hypoxia on high-order brain functions such as executive processing remain unclear. This study's goal was to examine the impact of an acute normobaric hypoxia breathing session on executive function and biological markers., Methods: Thirty-two healthy subjects participated in a blind study performing two sessions of single 30 min breathing bouts under two conditions (normoxia (NOR) and normobaric hypoxia (NH), FIO 2 = 0.135). The Stroop test was applied to assess cognitive function., Results: No significant difference was observed in the Stroop interference in the "reading" part of the test in either condition; however, there was a significant increase in the "naming" part under NH conditions ( p = 0.003), which corresponded to a significant decrease in SpO 2 ( p < 0.001). There was a significant increase ( p < 0.013) in the brain-derived neurotrophic factor (BDNF) level after NH conditions compared to the baseline, which was not seen in NOR. In addition, a significant drop ( p < 0.001) in cortisol levels in the NOR group and a slight elevation in the NH group was noticed., Conclusions: According to these findings, acute hypoxia delayed cognitive processing for motor execution and reduced the neural activity in motor executive and inhibitory processing. We also noted that this negative effect was associated with decreased SpO 2 irrespective of a rise in BDNF.

We compared behavioral and psychoemotional manifestations of young and old male Wistar rats in elevated plus-maze, the levels of corticosterone and testosterone, as well as the resistance to acute hypoxic hypoxia before and after stress exposure (10-min swimming sessions over 10 days). The behavioral characteristics, responses of the main stress hormone corticosterone, and resistance to acute hypoxic hypoxia were identical in both age groups before and after stress. A distinguishing feature was pronounced flattening of the psychoemotional manifestations in old animals. The main adaptive differences between young and old rats were revealed in the response of circulating testosterone to stress., (© 2021. Springer Science+Business Media, LLC, part of Springer Nature.)

This review provides an update on the neurocognitive phenotype of pediatric obstructive sleep apnea (OSA). Pediatric OSA is associated with neurocognitive deficits involving memory, learning, and executive functioning. Adenotonsillectomy (AT) is presently accepted as the first-line surgical treatment for pediatric OSA, but the executive function deficits do not resolve postsurgery, and the timeline for recovery remains unknown. This finding suggests that pediatric OSA potentially causes irreversible damage to multiple areas of the brain. The focus of this review is the hippocampus, 1 of the 2 major sites of postnatal neurogenesis, where new neurons are formed and integrated into existing circuitry and the mammalian center of learning/memory functions. Here, we review the clinical phenotype of pediatric OSA, and then discuss existing studies of OSA on different cell types in the hippocampus during critical periods of development. This will set the stage for future study using preclinical models to understand the pathogenesis of persistent neurocognitive dysfunction in pediatric OSA., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2020 International Anesthesia Research Society.)

Sleep apnea disrupts physiologic homeostasis and causes neuronal dysfunction. In addition to signs of mental disorders and cognitive dysfunction, patients with sleep apnea have a higher anxiety rate. Here, we examined the mechanisms underlying this critical health issue. We used a mouse model with sleep-associated chronic intermittent hypoxia (IH) to verify the effects of sleep apnea on neuronal dysfunction. To evaluate how IH alters neuronal function to yield anxiety-like behavior and cognitive dysfunction, we examined synaptic plasticity and neuronal inflammation in related brain areas, including the medial prefrontal cortex (mPFC), striatum, and hippocampus. Mice subjected to chronic IH for 10 days exhibited significant anxiety-like behaviors in the elevated plus maze test. IH mice spent less travel time in open arms and more travel time in enclosed arms compared to control mice. However, cognitive impairment was minimal in IH mice. Increased glutamate N-methyl-D-aspartate (NMDA) receptor subunits 2B (GluN2B) and phosphorylated-ERK1/2 were seen in the mPFC, striatum, and hippocampus of IH mice, but no significant microglial and astrocyte activation was found in these brain areas. Chronic IH in mice induced compensatory increases in GluN2B to disturb neuronal synaptic plasticity, without neuronal inflammation. The altered synaptic plasticity subsequently led to anxiety-like behavior in mice. Treatment with the NMDA receptor antagonist dextromethorphan attenuated chronic IH-induced anxiety-like behavior and GluN2B expression. Our findings provide mechanistic evidence of how IH may provoke anxiety and support for the importance of early intervention to alleviate anxiety-associated complications in patients with chronic sleep apnea.

Preclinical investigations into neuroprotective agents for traumatic brain injury (TBI) have shown promise when administered before or very early after experimental TBI. However clinical trials of therapeutics demonstrating preclinical efficacy for TBI have failed to replicate these results in humans, a lost in translation phenomenon. N-acetylcysteine (NAC) is a potent anti-oxidant with demonstrated efficacy in pre-clinical TBI when administered early after primary injury. Utilizing our clinically relevant mouse model, we hypothesized that NAC administration in a clinically relevant timeframe could improve the brain's resilience to the secondary insult of hypoxemia. NAC or vehicle administered daily starting 2 h prior to hypoxemia (24 h after controlled cortical impact) for 3 doses in male mice reduced short-term axonal injury and hippocampal neuronal loss. Six month behavioral assessments including novel object recognition, socialization, Barnes maze, and fear conditioning did not reveal performance differences between sham controls and injured mice receiving NAC or saline vehicle. At 7 months after injury, NAC administered mice had reduced hippocampal neuronal loss but no reduction in lesion volume. In summary, our preclinical trial to test the neuroprotective efficacy of NAC against a secondary hypoxic insult after TBI demonstrated short and long-term neuropathological evidence of neuroprotection but a lack of detectable differences in long-term behavioral assessments between sham controls and injured mice limits conclusions on its impact on long-term neurobehavioral outcomes., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Many countries across the globe utilized medical and non-medical facemasks as non-pharmaceutical intervention for reducing the transmission and infectivity of coronavirus disease-2019 (COVID-19). Although, scientific evidence supporting facemasks' efficacy is lacking, adverse physiological, psychological and health effects are established. Is has been hypothesized that facemasks have compromised safety and efficacy profile and should be avoided from use. The current article comprehensively summarizes scientific evidences with respect to wearing facemasks in the COVID-19 era, providing prosper information for public health and decisions making., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

This study aims to investigate the mechanisms through which fructose diphosphate (FDP) causes anti-hypoxia and anti-fatigue effects and improves learning and memory. Mice were divided into three groups: low-dose FDP (FDP-L), high-dose FDP (FDP-H), and a control group. Acute toxic hypoxia induced by carbon monoxide, sodium nitrite, and potassium cyanide and acute cerebral ischemic hypoxia were used to investigate the anti-hypoxia ability of FDP. The tests of rod-rotating, mouse tail suspension, and swimming endurance were used to explore the anti-fatigue effects of FDP. The Morris water maze experiment was used to determine the impact of FDP on learning and memory ability. Poisoning-induced hypoxic tests showed that mouse survival time was significantly prolonged in the FDP-L and FDP-H groups compared with the control group ( p < 0.05). In the exhaustive swimming test, FDP significantly shortened struggling time and prolonged the time of mass-loaded swimming; the rod-rotating test showed that endurance time was significantly prolonged by using FDP ( p < 0.05). FDP significantly decreased lactate and urea nitrogen levels and increased hepatic and muscle glycogen and glucose transporter-4 and Na + -K + -ATPase ( p < 0.05). To conclude, FDP enhances hypoxia tolerance and fatigue resistance and improves learning and memory ability through regulating glucose and energy metabolism.

Background: Aircrew members are required to attend hypoxia awareness training regularly to strengthen their memory of their personal hypoxia symptoms by undergoing training inside a hypobaric chamber. The aim of this study was to examine the association between hypoxia symptoms experienced during two training sessions that were 4 years apart., Methods: This was a crossover study to compare hypoxia symptoms and self-reported physiological effects of trapped gas between a previous training session and a current training session in an altitude chamber. The subjects were military crew members who undertook a 25,000-feet refresher training course in 2018. We used a structured questionnaire to obtain the target information before and during hypoxia exposure. Data were analyzed using SPSS software., Results: A total of 341 trainees participated in this survey and completely filled out the questionnaire. Gastrointestinal tract discomfort caused by the expansion of trapped gas was the main physiological reaction during the previous and current training sessions. Frequently reported symptoms were poor concentration (30.5%), impaired cognitive function (20.5%), visual disturbances (16.4%), hot flashes (15.8%), and paresthesia (12.6%) during both exposures. However, the proportions of participants reporting poor concentration (P = 0.378) and visual disturbances (P = 0.594) were not significantly different between the recalled and current training sessions. The five most common symptoms among the subjects with less than 1,000 flight hours were poor concentration (29.8%), visual disturbance (27.3%), impaired cognitive function (14.9%), dizziness/lightheadedness (11.6%), and hot flashes (9.9%), which overlapped substantially with the symptoms reported by other subjects. The occurrence of those five most common symptoms in the group with more than 1,000 flight hours did not significantly differ between the recalled training session and the current training session., Conclusions: The most common hypoxia symptoms reported were similar between the recalled and current training sessions in an environment with a low oxygen concentration. This finding was also clearly affected by the duration of flight experience. Moreover, GI effects of the expansion of trapped gas were commonly observed at low atmospheric pressure., Competing Interests: There was no conflicts of interest.

Regulated fear and extinction memory is essential for balanced behavioral response. Limbic brain regions are susceptible to hypobaric hypoxia (HH) and are putative target for fear extinction deficit and dysregulation. The present study aimed to examine the effect of HH and Ginkgo biloba extract (GBE) on fear and extinction memory with the underlying mechanism. Adult male Sprague-Dawley rats were evaluated for fear extinction and anxious behavior following GBE administration during HH exposure. Blood and tissue (PFC, hippocampus and amygdala) samples were collected for biochemical, morphological and molecular studies. Results revealed deficit in contextual and cued fear extinction following 3 days of HH exposure. Increased corticosterone, glutamate with decreased GABA level was found with marked pyknosis, decrease in apical dendritic length and number of functional spines. Decline in mRNA expression level of synaptic plasticity genes and immunoreactivity of BDNF, synaptophysin, PSD95, spinophilin was observed following HH exposure. GBE administration during HH exposure improved fear and extinction memory along with decline in anxious behavior. It restored corticosterone, glutamate and GABA levels with an increase in apical dendritic length and number of functional spines with a reduction in pyknosis. It also improved mRNA expression level and immunoreactivity of neurotrophic and synaptic proteins. The present study is the first which demonstrates fear extinction deficit and anxious behavior following HH exposure. GBE administration ameliorated fear and extinction memory dysregulation by restoration of neurotransmitter levels, neuronal pyknosis and synaptic connections along with improved neurotrophic and synaptic protein expressions., Competing Interests: Declaration of Competing Interest There are no competing interests, financial or otherwise., (Copyright © 2020. Published by Elsevier B.V.)

Background: A patent foramen ovale (PFO) is a rare cause of hypoxemia and clinical symptoms of dyspnea. Due to a right-to-left shunt, desaturated blood enters the systemic circulation in a subset of patients resulting in dyspnea and a subsequent reduction in quality of life (QoL). Percutaneous closure of PFO is the treatment of choice., Objectives: This retrospective multicentre study evaluates short- and long-term results of percutaneous closure of PFO in patients with dyspnea and/or reduced oxygen saturation., Methods: Patients with respiratory symptoms were selected from databases containing all patients percutaneously closed between January 2000 and September 2018. Improvement in dyspnea, oxygenation, and QoL was investigated using pre- and postprocedural lung function parameters and two postprocedural questionnaires (SF-36 and PFSDQ-M)., Results: The average follow-up period was 36 [12-43] months, ranging from 0 months to 14 years. Percutaneous closure was successful in 15 of the 16 patients. All patients reported subjective improvement in dyspnea immediately after device deployment, consistent with their improvement in oxygen saturation (from 90 ± 6% to 94 [92-97%] on room air and in upright position) ( p < 0.05). Both questionnaires also indicated an improvement of dyspnea and QoL after closure. The two early and two late deaths were unrelated to the procedure., Conclusion: PFO-related dyspnea and/or hypoxemia can be treated successfully with a percutaneous intervention with long-lasting benefits on oxygen saturation, dyspnea, and QoL., Competing Interests: The authors declare that there are no conflicts of interest regarding the publication of this paper., (Copyright © 2020 Céline De Cuyper et al.)

Neonatal hypoxia can induce the persisting brain dysfunctions and subsequently result in the behavioral abnormalities in adulthood. Improving mitochondrial functions were suggested as the effective strategy for brain functional recovery. In this study, we tested the effects of physical exercise, a well-established way benefits mitochondrion, for its functions to prevent hypoxia induced adult behavioral dysfunctions and the underlying molecular mechanism. Mice was induced with hypoxia and treadmill running were then administrated until the adulthood. The treadmill running resulted in the improved behavioral performance in depressive and anxiety tests together with the enhancement of hippocampal neurogenesis. We then detected treadmill running restored the mitochondrial morphology in adult neural stem cells (NSCs) as well as the ATP production in hippocampal tissue. In addition, activity of AMPK, which playing key roles in regulating mitochondrial functions, was also elevated by treadmill running. Blockage of AMPK with selective inhibitor compound C prohibited effects of treadmill running in attenuating neonatal hypoxia induced neurogenic impairment and antidepressant behavioral deficits in adulthood. In conclusion, treadmill running could prevent neonatal hypoxia induced adult antidepressant dysfunctions and neurogenic dampening via AMPK-mediated mitochondrial regulation., Competing Interests: Declaration of competing interest All authors listed in this study entitled “Treadmill Running Attenuates Neonatal Hypoxia Induced Adult Depressive Symptoms and Promoted Hippocampal Neural Stem Cell Differentiation via Modulating AMPK-Mediated Mitochondrial Functions” have no conflict interest., (Copyright © 2019 Elsevier Inc. All rights reserved.)

The effects of acclimatization to middle attitude hypoxia on the resistance to acute emotional stress were studied on the model of posttraumatic stress disorder in rats. Anxyolitic, but not anxiogenic effect was observed in acclimatized rats. However, acclimatized rats with posttraumatic stress disorder were characterized by hypofunction of the pituitary-adrenocortical axis, which is typical of this pathology, and reduction in corticosterone/dehydroepiandrosterone ratio. At the neuroendocrine level, up-regulation of glucocorticoid receptors and a decrease in the level of corticotropin-releasing hormone in the hippocampus were revealed. The observed modifications of regulatory mechanisms can underlie hypofunction of the pituitary-adrenocortical axis. It was concluded that acclimatization to middle attitude hypoxia masks behavioral symptoms of posttraumatic stress disorder, but does not alter its pathogenetic neuroendocrine mechanisms.

Acute moderate intensity exercise has been shown to improve cognitive performance. In contrast, hypoxia is believed to impair cognitive performance. The detrimental effects of hypoxia on cognitive performance are primarily dependent on the severity and duration of exposure. In this review, we describe how acute exercise under hypoxia alters cognitive performance, and propose that the combined effects of acute exercise and hypoxia on cognitive performance are mainly determined by interaction among exercise intensity and duration, the severity of hypoxia, and duration of exposure to hypoxia. We discuss the physiological mechanism(s) of the interaction and suggest that alterations in neurotransmitter function, cerebral blood flow, and possibly cerebral metabolism are the primary candidates that determine cognitive performance when acute exercise is combined with hypoxia. Furthermore, acclimatization appears to counteract impaired cognitive performance during prolonged exposure to hypoxia although the precise physiological mechanism(s) responsible for this amelioration remain to be elucidated. This review has implications for sporting, occupational, and recreational activities at terrestrial high altitude where cognitive performance is essential. Further studies are required to understand physiological mechanisms that determine cognitive performance when acute exercise is performed in hypoxia., (© 2019 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Hypoxia is one of the major pathological factors affecting brain function. The aim of the present study was to describe the effect of neonatal hypobaric hypoxia on the behavior of rats and to analyze its effect on hippocampal neurodegeneration. Hypobaric hypoxia at a simulated altitude of 9000 m was induced for one hour in neonatal rat pups (PND7 and PND9) of both sexes. Subsequently, the rats underwent behavioral testing on PND25 and PND35 using a LABORAS apparatus to assess spontaneous behavior. Hypoxia did not cause any morphological damage in the hippocampus of rats. However, hypoxia on PND7 led to less horizontal locomotor activity both, in males (on PND25) and females (on PND35). Hypoxia on PND9 led to higher rearing in females on PND25. Hypoxic males exhibited higher grooming activity, while females lower grooming activity on PND35 following hypoxia induced on PND7. In females, hypoxia on PND9 resulted in higher grooming activity on PND25. Sex differences in the effect of hypoxia was observed on PND35, when hypoxic males compared to hypoxic females displayed more locomotor, rearing and grooming activity. Our data suggest that hypoxia on PND7 versus PND9 differentially affects locomotion and grooming later in adolescence and these effects are sex-dependent.

Objective: To identify regions of the brain affected during cognitive working memory during tasks to assess attention, planning and decision making among military aviation personnel who have chronic intermittent exposure to high altitude environment., Method: A case-control study was conducted in the Universiti Putra Malaysia among eight military personnel, four of whom had chronic intermittent exposure to high altitude training. They were divided into two groups, chronic intermittent exposure group (CE) (n=4) and a control group (n=4). They underwent a task-based functional magnetic resonance imaging (fMRI) that utilised spatial working memory task to objectively evaluate the neural activation in response to the Tower of London paradigm. Each correct answer was given a score of one and the maximum achievable score was 100%., Results: A consecutive dichotomised group of CE (4/8) and control (4/8) of age-matched military aviation personnel with a mean age of 37.23±5.52 years; showed significant activation in the right middle frontal gyrus (MFG). This in turn was positively correlated with response accuracy. A significant difference in the response accuracy was noted among both the groups at p<0.05., Conclusion: At the minimum results of power analysis of this preliminary fMRI study, our group of aviation personnel who had chronic intermittent exposure to hypobaric hypoxic environment, did not have any significant decrease in cognitive function namely attention, decision-making and problem solving compared to controls during a working memory task.

Objective: The purpose of this study was to evaluate the lifting capabilities of individuals in hypoxia when they wear different types of safety shoes and to investigate the behavior of the physiological responses induced by the lifting process associated with those variables., Methods: An experimental design was used, based on two sessions. The first was training and acclimatization session, then an experimental lifting phase. A total of ten male students of King Saud University were recruited in the study. A four-way repeated measures design, with four independent variables and six dependent variables, was used in this research. The independent variables that were studied in the experimental lifting phase were: ambient oxygen content (15%, 18%, and 21%), safety shoes type (light-duty, medium-duty, and heavy-duty), lifting frequency (1 and 4 lifts/min), and replication (first and second trials). The dependent variables were also: maximum acceptable weights lifting using the psychophysical technique, heart rate (HR), electromyography (EMG) of (biceps brachii, trapezius, anterior deltoid, and erector spinae), safety shoes discomfort rating, rating of perceived exertion, and ambient oxygen discomfort rating., Results: The maximum acceptable weights lifting that were selected by participants at lower levels of the independent variables (ambient oxygen content 21%, lifting frequency 1 lift/min, and first replication) were significantly higher than at high levels of the independent variables (ambient oxygen content 15%, lifting frequency 4 lift/min, and second replication). Several interaction effects were also significant., Conclusions: It provides evidence that the ambient oxygen content increases the intensity of workload in lifting tasks. It showed that oxygen content affects the psychophysical selection of maximum acceptable weights lifting and the physiological responses represented in muscular activities and heart rate. It suggests that ambient oxygen content must be considered along with the type of safety shoes worn when the lifting task at altitudes occurs.

Prenatal hypoxia often results in dramatic alterations in developmental profiles and behavioral characteristics, including learning and memory, in later life. Despite the accumulation of considerable amounts of experimental data, the mechanisms underlying developmental deficits caused by prenatal hypoxia remain unclear. In the present study, we investigated whether prenatal hypoxia on embryonic day 14 (E14) affected synaptic properties in the hippocampus and hippocampal-related cognitive functions in young rats. We found that 20- to 30-d-old rats subjected to prenatal hypoxia had significantly disturbed basal synaptic transmission in CA3-CA1 synapses and a two-fold decrease in hippocampal long-term synaptic potentiation. These alterations were accompanied by a significant decline in the protein level of GluN2B but not GluN2A NMDA receptor subunits. In addition, the number of synaptopodin-positive dendritic spines in the CA1 area of the hippocampus was reduced in the rats exposed to prenatal hypoxia. These changes resulted in significant learning and memory deficits in a novel object recognition test., (Copyright © 2019 Elsevier Inc. All rights reserved.)

INTRODUCTION: Paragliding is an emerging discipline of aviation, with recreational pilots flying distances over 100 km. It remains risky. Accidents typically relate to pilot error rather than equipment failure. We measured cognition and physiological responses during simulated flight, to investigate whether errors might be due to pilot impairment, rather than misjudgment. METHODS: There were 10 male paraglider pilots (aged 19-58 yr) who undertook a simulated flight in an environmental chamber from sea level (0.209 F I o₂) to 1524 m (0.174 F I o₂), 2438 m (0.156 F I o₂), and 3658 m (0.133 F I o₂), over approximately 2 h. They experienced normobaric hypoxia, environmental cooling and headwind, completing logical reasoning, mannikin, mathematical processing, Stroop Color-Word and Tower Puzzle tasks; as well as measures of risk-taking (BART), mood (POMS), and subjective experience. RESULTS: Results were compared to ten controls, matched by age, sex, and flying experience. Physiological measures were oxygen consumption, carbon dioxide production, ventilation, heart rate, oxygen saturation, rectal and skin temperatures, blood glucose, blood lactate, and urine production. There were no significant differences between pilots and controls at any altitude. Results were heterogenous within and between individuals. As altitude increased, oxygen consumption and minute volume increased significantly, while oxygen saturations fell (98.3% [baseline] to 88.5% [peak]). Rectal temperatures fell by a statistically (but not clinically) significant amount (37.6°C to 37.3°C), while finger skin temperatures dropped steeply (32.2°C to 13.9°C). DISCUSSION: Results suggest cognitive impairment is unlikely to be a primary cause of pilot error during paragliding flights (of less than 2 h, below 3658 m), though hand protection requires improvement. Wilkes M, Long G, Massey H, Eglin C, Tipton MJ. Cognitive function in simulated paragliding flight. Aerosp Med Hum Perform. 2019; 90(10):851-859.

New Findings: What is the central question of this study? What are the independent effects of hypoxia and hypocapnia on cerebral haemodynamics and cognitive function? What is the main finding and its importance? Exposure to hyperventilation-induced hypocapnia causes cognitive impairment in both normoxia and hypoxia. In addition, supplementation of carbon dioxide during hypoxia alleviates the cognitive impairment and reverses hypocapnia-induced vasoconstriction of the cerebrovasculature. These data provide new evidence for the independent effect of hypocapnia on the cognitive impairment associated with hypoxia., Abstract: Hypoxia, which is accompanied by hypocapnia at altitude, is associated with cognitive impairment. This study examined the independent effects of hypoxia and hypocapnia on cognitive function and assessed how changes in cerebral haemodynamics may underpin cognitive performance outcomes. Single reaction time (SRT), five-choice reaction time (CRT) and spatial working memory (SWM) tasks were completed in 20 participants at rest and after 1 h of isocapnic hypoxia (IH, end-tidal oxygen partial pressure ( P ET O 2 ) = 45 mmHg, end-tidal carbon dioxide partial pressure ( P ETC O 2 ) clamped at normal) and poikilocapnic hypoxia (PH, P ET O 2  = 45 mmHg, P ETC O 2 not clamped). A subgroup of 10 participants were also exposed to euoxic hypocapnia (EH, P ET O 2  = 100 mmHg, P ETC O 2 clamped 8 mmHg below normal). Middle cerebral artery velocity (MCAv) and prefrontal cerebral haemodynamics were measured with transcranial Doppler and near infrared spectroscopy, respectively. IH did not affect SRT and CRT performance from rest (566 ± 50 and 594 ± 70 ms), whereas PH (721 ± 51 and 765 ± 48 ms) and EH (718 ± 55 and 755 ± 34 ms) slowed response times (P < 0.001 vs. IH). Performance on the SWM task was not altered by condition. MCAv increased during IH compared to PH (P < 0.05), which was unchanged from rest. EH caused a significant fall in MCAv and prefrontal cerebral oxygenation (P < 0.05 vs. baseline). MCAv was moderately correlated to cognitive performance (R 2  = 0.266-0.289), whereas prefrontal cerebral tissue perfusion and saturation were not (P > 0.05). These findings reveal a role of hyperventilation-induced hypocapnia per se on the development of cognitive impairment during normoxic and hypoxic exposures., (© 2019 The Authors. Experimental Physiology © 2019 The Physiological Society.)

We investigated whether perceptually-regulated high-intensity intervals in hypoxia are associated with slower running velocities versus normoxia, when physiological responses and exercise-related sensations remain the same. Nineteen trained runners (33.4 ± 9.1 years) completed a high-intensity interval running protocol (4 × 4-min intervals at a clamped perceived rating exertion of 16 on the 6-20 Borg scale, 3-min passive recoveries) in either hypoxic (HYP; FiO 2 15.0%) or normoxic (NOR; FiO 2 20.9%) conditions. Participants adjusted to a progressively slower running velocity from interval 1-4 (-7.0%), and more so in HYP vs. NOR for intervals 2, 3 and 4 (-4.6%, -6.4% and - 7.9%, respectively; p < .01). Heart rate increased from interval 1-4 (+4.8%; p < .01), independent of condition. Arterial oxygen saturation was lower in HYP vs. NOR (86.0% vs. 94.8%; p < .01). Oxyhemoglobin (-23.7%) and total hemoglobin (-77.0%) decreased, whilst deoxyhemoglobin increased (+44.9%) from interval 1-4 (p < .01), independent of condition. Perceived recovery (-41.6%) and motivation (-21.8%) were progressively lower from interval 1-4, and more so in HYP vs. NOR for intervals 2, 3 and 4 (recovery: -8.8%, -24.2% and - 29.3%; motivation: -5.3%, -20.3% and - 22.4%, respectively; p < .01). Perceived breathlessness (+18.6%), limb discomfort (+44.0%) and pleasure (-32.2%) changed from interval 1-4, with significant differences (+21.8%, +11.3% and - 31.3%, respectively) between HYP and NOR (p < .01). Slower interval running velocities in hypoxia achieve similar heart rate and muscle oxygenation responses to those observed in normoxia when perceptually-regulated, yet at the expense of less favourable exercise-related sensations., (Copyright © 2019 Elsevier Inc. All rights reserved.)

The current study investigated how experimentally induced acute normobaric hypoxia affects attentional control functions during easy, monotonous visual sustained attention and response inhibition (modified Continuous Performance Task) and executive control tasks (number-size Stroop task). Along with behavioral efficiency, task-relevant and task-irrelevant information processing were investigated by measuring event related brain potentials (ERP) evoked by target stimuli (Target P3), task-relevant stimuli with no response needed (NoGo P3), and task-irrelevant novel stimuli (Novelty P3) during acute hypoxia exposure. Normobaric hypoxia was induced by adjusting the O 2 content of the breathing mixture to obtain 80% peripheral oxygen saturation, equivalent of 5500 m above sea level. Here we report decreased Novelty P3 during acute normobaric hypoxia exposure, while Target P3 and NoGo P3, as well as behavioral efficiency remained intact. Our paper is the first to provide evidence for impaired novelty processing along with intact task-relevant information processing and response inhibition during normobaric hypoxic exposure., (Copyright © 2019. Published by Elsevier Inc.)

Background: Additional benefits of passive exposures to intermittent hypoxia and hyperoxia on cognitive performance and functional exercise capacity have been demonstrated in geriatric patients who performed a multimodal training program. The main goal of the present study was to evaluate effects of adding intermittent hypoxic-hyperoxic training (IHHT) to a multimodal training intervention (MTI) on mobility and perceived health in old individuals at a Geriatric Day Hospital., Methods: Thirty-four patients between 64 and 92 years participated in the double blind, randomized and controlled clinical trial. The elderly patients attended in a 5-7 weeks lasting MTI (strength, endurance, balance, reaction, flexibility, coordination, and cognitive exercises) and performed IHHT (breathing 10-14% oxygen for 4-7 min followed by 2-4 min 30-40% oxygen) in the Hypoxic Group (HG) or placebo treatment with ambient air in the Normoxic Group (NG) in parallel. Before and after all treatments, mobility was assessed by the Tinetti Mobility Test (TMT), the Timed-Up-and-Go Test (TUG) and Barthel-Index, while perceived health was assessed by one part of the EQ-5D Test, the EQ visual analogue scale (EQ VAS)., Results: After the MTI plus IHHT or normoxia sessions, results of the TMT, TUG, Barthel Index and EQ-VAS revealed no significant difference between HG and NG (+ 14.9% vs + 15.4%, p = 0.25; - 21% vs - 26.3%, p = 0.51; + 4.2% vs + 3.6%, p = 0.56; + 37.9% vs + 33.9%, p = 0.24;)., Conclusions: IHHT added to MTI did not elicit additional improvements in perceived health and mobility compared to MTI alone.

Introduction: Intermittent hypoxia and sleep fragmentation are critical pathophysiological processes involved in obstructive sleep apnea-hypopnea syndrome (OSAHS). Those manifestations independently affect similar brain regions and contribute to OSAHS-related comorbidities that are known to be related to the host gut alteration microbiota. We hypothesized that gut microbiota disruption may cross talk the brain function via the microbiota-gut-brain axis. Thus, we aim to survey enterotypes and polysomnographic data of patients with OSAHS., Methods: Subjects were diagnosed by polysomnography, from whom fecal samples were obtained and analyzed for the microbiome composition by variable regions 3-4 of 16S rRNA pyrosequencing and bioinformatic analyses. We examined the fasting levels of interleukin-6 and tumor necrosis factor-alpha of all subjects., Results: Three enterotypes Bacteroides, Ruminococcus, and Prevotella were identified in patients with OSAHS. Arousal-related parameters or sleep stages are significantly disrupted in apnea-hypopnea index (AHI) ≥15 patients with Prevotella enterotype; further analysis this enterotype subjects, obstructive, central, and mixed apnea indices, and mean heart rate are also significantly elevated in AHI ≥15 patients. However, blood cytokines levels of all subjects were not significantly different., Conclusions: This study indicates the possibility of pathophysiological interplay between enterotypes and sleeps structure disruption in sleep apnea through a microbiota-gut-brain axis and offers some new insight toward the pathogenesis of OSAHS., (© 2019 The Authors. Brain and Behavior published by Wiley Periodicals, Inc.)

Hypoxic encephalopathy of the newborn is a major cause of long-term neurological sequelae. We have previously shown that CEP-701 (lestaurtinib), a drug with an established safety profile in children, attenuates short-term hyperexcitability and tropomyosin-related kinase B (TrkB) receptor activation in a well-established rat model of early life hypoxic seizures (HS). Here, we investigated the potential long-term neuroprotective effects of a post-HS transient CEP-701 treatment. Following exposure to global hypoxia, 10 day old male Sprague-Dawley pups received CEP-701 or its vehicle and were sequentially subjected to the light-dark box test (LDT), forced swim test (FST), open field test (OFT), Morris water maze (MWM), and the modified active avoidance (MAAV) test between postnatal days 24 and 44 (P24-44). Spontaneous seizure activity was assessed by epidural cortical electroencephalography (EEG) between P50 and 100. Neuronal density and glial fibrillary acidic protein (GFAP) levels were evaluated on histological sections in the hippocampus, amygdala, and prefrontal cortex at P100. Vehicle-treated hypoxic rats exhibited significantly increased immobility in the FST compared with controls, and post-HS CEP-701 administration reversed this HS-induced depressive-like behavior (p < 0.05). In the MAAV test, CEP-701-treated hypoxic rats were slower at learning both context-cued and tone-signaled shock-avoidance behaviors (p < 0.05). All other behavioral outcomes were comparable, and no recurrent seizures, neuronal loss, or increase in GFAP levels were detected in any of the groups. We showed that early life HS predispose to long-lasting depressive-like behaviors, and that these are prevented by CEP-701, likely via TrkB modulation. Future mechanistically more specific studies will further investigate the potential role of TrkB signaling pathway modulation in achieving neuroprotection against neonatal HS, without causing neurodevelopmental adverse effects., (Copyright © 2019 Elsevier Inc. All rights reserved.)

We examined the hypothesis that an expiratory resistance mask containing a small amount of dead space (ER/DS) would reduce the apnea-hypopnea index (AHI) during sleep, attenuate the severity of acute mountain sickness (AMS), and offset decrements in cognitive function compared with a sham mask. In a double-blinded, randomized, sham-controlled, crossover design, 19 volunteers were exposed to two nights of normobaric hypoxia (F I O 2 = 0.125), using a ER/DS mask (3.5 mm restrictive expiratory orifice; 125 mL DS volume) and sham mask (zero-flow resistance; 50 mL DS volume). Cognitive function, AMS, and ventilatory acclimatization were assessed before and after the 12-hour normobaric hypoxia exposure. Polysomnography was conducted during sleep. AHI was reduced using the ER/DS sleep mask compared with the sham (30.1 ± 23.9 events·hr -1 vs. 58.9 ± 34.4 events·hr -1 , respectively; p = 0.01). Likewise, oxygen desaturation index and headache severity were reduced (both p < 0.05). There were also benefits on limiting the hypoxia-induced reductions in select measures of reaction speed and attention (p < 0.05). Our study indicates that a simple noninvasive and portable ER/DS mask resulted in reductions (49%) in AHI, and reduced headache severity and aspects of cognitive decline. The field applications of this ER/DS mask should be investigated before recommendations can be made to support its benefit for travel to high altitude.

The relationship between three markers of chronic hypoxia (altitude, smoking and chronic obstructive pulmonary disease (COPD)) and suicide risk has not been well-studied. We conducted a population-based cohort study evaluating the association between chronic hypoxia and suicide risk. Patients entered the cohort in their first year with a documented healthcare encounter and remained in the cohort until their death or the end of the study period. Generalized estimating equation (GEE) methodology was used to assess the association between suicide and three risk markers of chronic hypoxia. Findings were summarized using odds ratio (OR) and 95% confidence intervals (CI). Among the 9,620,944 patients in the cohort, there were 22,403 suicide deaths. There was a statistically significant progression of suicide risk as altitude rose in increments of 1000 m (OR: 1.22). There was a strong association between the number of hypoxic conditions and the odds of suicide. Patients with three markers of chronic hypoxia was nearly four times more likely to die by suicide than patients with no markers (OR: 3.96). Chronic hypoxia is a risk factor for suicide and having multiple indicators of hypoxia confers a greater risk for suicide, indicating a dose-response relationship., (Published by Elsevier B.V.)

Low atmospheric pressure may increase depression and suicide through inducing hypoxia. Previous studies have not evaluated the geographic variation of this relationship across the United States. Analyses were based on three groupings of age-adjusted completed suicide rates (all suicide, firearm-related suicide, non-firearm-related suicide) from 2286 counties in the United States. Multiple regression was used to determine the overall relationship between atmospheric pressure and completed suicide rates. Geographically weighted regression (GWR) models were used to obtain local coefficient estimates. A negative correlation between atmospheric pressure and completed suicide rates was observed for all three suicide groupings (p-value <0.0001). Significant, negative GWR coefficient estimates were located in the West and Northeast for the all suicides and firearm-related suicides, and in the Midwest for non-firearm-related suicides., Competing Interests: The authors have declared that no competing interests exist.

Sleep apnea is associated with testosterone dysregulation as well as increased risk of developing neurodegenerative diseases, such as Alzheimer's disease (AD) and Parkinson's disease (PD). A rodent model of the hypoxemic events of sleep apnea, chronic intermittent hypoxia (CIH), has been previously documented to impair cognitive function and elevate oxidative stress in male rats, while simultaneously decreasing testosterone. Therefore, androgens may modulate neuronal function under CIH. To investigate the role of androgens during CIH, male rats were assigned to one of four hormone groups: 1) gonadally intact, 2) gonadectomized (GDX), 3) GDX + testosterone (T) supplemented, or 4) GDX + dihydrotestosterone (DHT) supplemented. Each group was exposed to either normal room air or CIH exposure for one week, followed by memory and motor task assessments. Brain regions associated with AD and PD (entorhinal cortex, dorsal hippocampus, and substantia nigra) were examined for oxidative stress and inflammatory markers, key characteristics of AD and PD. Gonadally intact rats exhibited elevated oxidative stress due to CIH, but no significant memory and motor impairments. GDX increased memory impairments, regardless of CIH exposure. T preserved memory function and prevented detrimental CIH-induced changes. In contrast, DHT was not protective, as evidenced by exacerbated oxidative stress under CIH. Further, CIH induced significant spatial memory impairment in rats administered DHT. These results indicate androgens can have both neuroprotective and detrimental effects under CIH, which may have clinical relevance for men with untreated sleep apnea., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Although it has been traditionally thought that decreasing SpO 2 with ascent to high altitudes not only induces acute mountain sickness but also can decrease executive function, the relationship between decreased SpO 2 levels and hypoxia-induced lowered executive function is still unclear. Here we aimed to clarify whether hypoxia-induced lowered executive function was associated with arterial oxygen desaturation, using 21 participants performing the color-word Stroop task under normoxic and three hypoxic conditions (FIO 2  = 0.165, 0.135, 0.105; corresponding to altitudes of 2000, 3500, and 5000 m, respectively). Stroop interference significantly increased under severe hypoxic condition (FIO 2  = 0.105) compared with the other conditions. Moreover, there was a negative correlation between Stroop interference and SpO 2 . In conclusion, acute exposure to severe hypoxic condition decreased executive function and this negative effect was associated with decreased SpO 2 . We initially implicated an arterial oxygen desaturation as a potential physiological factor resulting in hypoxia-induced lowered executive function.

Introduction: Exposure to hypoxic conditions is reported to impair cognitive performance. Further, moderate physical exercise improves cognitive function, but little is known about the influence of exercise on cognitive function in hypoxia. Therefore, the current study aimed to examine the influence of hypoxia (HYP) and prolonged exercise (EX) on attentional performance., Methods: A total of 80 participants (female: n = 29; male: n = 51) were assigned to four groups: HYP + EX (n = 15), HYP (n = 25), EX (n = 21) and normoxia (NOR) (n = 21). The Frankfurt Attention Inventory-2 (FAIR-2) was performed at four testing points (day 1, 14, 16 and 18) to assess attentional performance. All groups completed a pretest (D1) and a follow-up test (D18). In HYP + EX conditions, the cognitive task was performed in a hypoxic state after prolonged exercise (D14: 3950 m, D16: 5739 m) during a mountain climb on Mt. Kilimanjaro. Participants in HYP were tested under intermittent hypoxia at rest in a hypoxic chamber (D14: 3500 m, D16: 5800 m), and those in EX were tested under normoxia after prolonged exercise during a 7-day backcountry ski hiking tour. NOR was a control group, and participants completed all tests under normoxia and at rest., Results: Hypoxia impaired the attentional functions performance value (PV) and continuity value (CV) for the HYP + EX (p = 0.000) and HYP (L: p = 0.025; K: p = 0.043) groups at 5739 m and 5800 m, respectively, but not the function quality value (QV). In contrast, the EX group did not exhibit changes in attentional function., Conclusion: The current results suggest that attentional performance is impaired during extreme normobaric and hypobaric hypoxic exposure. We further conclude that greater cognitive impairment under hypobaric hypoxia during a mountain climb compared with normobaric hypoxia at rest is not caused by prolonged exercise, but may be influenced by other factors (e.g. low temperatures, dehydration, or sleep deprivation) that remain to be verified., Competing Interests: The authors have declared that no competing interests exist.

Objective: Sleep apnea has been associated with anxiety, but the mechanisms of the sleep apnea-anxiety relationship are unresolved. Sleep apnea causes oxidative stress, which might enhance anxiety-like behavior in rodents. To clarify the apnea-anxiety connection, we tested the effect of intermittent hypoxia, a model of sleep apnea, on the anxiety behavior of mice., Methods: The rodents were exposed daily to 480 one-minute cycles of intermittent hypoxia to a nadir of 7±1% inspiratory oxygen fraction or to a sham procedure with room air. After 7 days, the mice from both groups were placed in an elevated plus maze and were video recorded for 10 min to allow analysis of latency, frequency, and duration in open and closed arms. Glyoxalase-1 (Glo1) and glutathione reductase-1 (GR1) were measured in the cerebral cortex, hippocampus, and striatum by Western blotting., Results: Compared to controls, the intermittent hypoxia group displayed less anxiety-like behavior, perceived by a statistically significant increase in the number of entries and total time spent in open arms. A higher expression of GR1 in the cortex was also observed., Conclusion: The lack of a clear anxiety response as an outcome of intermittent hypoxia exposure suggests the existence of additional layers in the anxiety mechanism in sleep apnea, possibly represented by sleepiness and irreversible neuronal damage.

Hypobaric Hypoxia (HH) is well-known to cause cognitive impairment and synaptic dysfunction which results in neurodegeneration. Although the role of small conductance calcium-activated potassium channels (SK channels) has been reported in synaptic plasticity, cognition and different neurological disorders; however, the precise role of SK channels in HH-induced memory impairment remains yet to be explored. We, therefore, hypothesized the pivotal role of SK channels in HH-induced cognitive decline and investigated the SK channel expression during different duration of HH exposure (Control, 1, 3, 7 and 14 days) at mRNA and protein level in male Sprague-Dawley rats. Further the role of SK channels in spatial memory and neurodegeneration were explored by inhibiting SK channel through Apamin (a known SK channel blocker). Results from the present study revealed that acute exposure of HH for 3 days leads to significant increase in expression of SK1 and SK3 channels at mRNA and protein levels, which upon chronic exposure restored to normal. Remarkably, SK2 channel expression showed gradual increase from 3 days till 14 days. Immunohistochemical analysis revealed similar pattern in different regions of the hippocampus. Additionally, SK channel inhibition with Apamin prevented HH-induced neurodegeneration and memory impairment as evident from decreased number of Fluoro Jade-positive cells, pyknotic cells, and caspase-3 expression and improved performance in the Morris water maze task. Thus, the present study demonstrates that SK channels play a crucial role in HH-induced cognitive decline and neurodegeneration., (Copyright © 2018 IBRO. Published by Elsevier Ltd. All rights reserved.)

Introduction: Acute cocoa flavanols (CF) intake has been suggested to modulate cognitive function and neurovascular coupling (NVC). Whether increased NVC is solely driven by improved vascular responsiveness or also by neuronal activity remains unknown. This study investigated the effects of acute CF intake on cognitive performance, NVC, and neuronal activity in healthy subjects in normoxia and hypoxia (4000 m simulated altitude; 12.7% O 2 )., Methods: Twenty healthy subjects (age 23.2 ± 4.3 years) performed four trials. Participants performed a Stroop task and "cognition" battery 2 h after acute CF (530 mg CF, 100 mg epicatechin) or placebo intake, and 30 min after initial exposure to hypoxia or normoxia. Electroencephalogram and functional near-infrared spectroscopy were used to analyze hemodynamic changes and neuronal activity., Results: CF enhanced NVC in the right prefrontal cortex during several tasks (risk decision making, visual tracking, complex scanning, spatial orientation), while neuronal activity was not affected. CF improved abstract thinking in normoxia, but not in hypoxia and did not improve other cognitive performances. Hypoxia decreased accuracy on the Stroop task, but performance on other cognitive tasks was preserved. NVC and neuronal activity during cognitive tasks were similar in hypoxia vs. normoxia, with the exception of increased β activity in the primary motor cortex during abstract thinking., Conclusions: Acute CF intake improved NVC, but did not affect neuronal activity and cognitive performance in both normoxia and hypoxia. Most cognitive functions, as well as NVC and neuronal activity, did not decline by acute exposure to moderate hypoxia in healthy subjects.

Nonpharmacological treatments of stress-induced disorders are promising, since they enhance endogenous stress defense systems, are free of side effects, and have few contraindications. The present study tested the hypothesis that intermittent hypoxia conditioning (IHC) ameliorates behavioral, biochemical, and morphological signs of experimental posttraumatic stress disorder (PTSD) induced in rats with a model of predator stress (10-day exposure to cat urine scent, 15 min daily followed by 14 days of stress-free rest). After the last day of stress exposure, rats were conditioned in an altitude chamber for 14 days at a 1,000-m simulated altitude for 30 min on day 1 with altitude and duration progressively increasing to 4,000 m for 4 h on day 5. PTSD was associated with decreased time spent in open arms and increased time spent in closed arms of the elevated X-maze, increased anxiety index, and increased rate of freezing responses. Functional and structural signs of adrenal cortex degeneration were also observed, including decreased plasma concentration of corticosterone, decreased weight of adrenal glands, reduced thickness of the fasciculate zone, and hydropic degeneration of adrenal gland cells. The thickness of the adrenal fasciculate zone negatively correlated with the anxiety index. IHC alleviated both behavioral signs of PTSD and morphological evidence of adrenal cortex dystrophy. Also, IHC alone exerted an antistress effect, which was evident from the increased time spent in open arms of the elevated X-maze and a lower number of rats displaying freezing responses. Therefore, IHC of rats with experimental PTSD reduced behavioral signs of the condition and damage to the adrenal glands. NEW & NOTEWORTHY Intermittent hypoxia conditioning (IHC) has been shown to be cardio-, vaso-, and neuroprotective. For the first time, in a model of posttraumatic stress disorder (PTSD), this study showed that IHC alleviated both PTSD-induced behavioral disorders and functional and morphological damage to the adrenal glands. Also, IHC alone exerted an antistress effect. These results suggest that IHC may be a promising complementary treatment for PTSD-associated disorders.

Stroke is a leading cause of death and a major contributor to neurological disability in adults. Tissue plasminogen activator is the only approved treatment. However, due to its narrow therapeutic window, <5% of patients receive treatment. Recently, hypoxic postconditioning (HPC) was shown to reduce stroke induced-injury in mice, but the mechanisms and functional outcomes are still unknown. In the current study, male Sprague Dawley rats were subjected to endothelin-1 induced stroke. HPC (8% O 2 , 1 h/d for 5d) or normoxia treatments were started 24 h after stroke. Behavioural tests were performed at various time-points (pre- and post-surgery, 1 and 6 days post stroke) and brains were collected 6 days after stroke for histological and immunoblotting analysis. HPC improved deficits in neurological score, motor and sensory function after stroke. Furthermore, HPC reduced infarct volume and neuronal loss in the cortex, while it increased the number of astrocytes and of Fluoro-Jade-positive cells in the injured hemisphere. We observed a mild increase in HIF-1 and its target gene, glucose transporter-1. Our data suggest that HPC-induced neuroprotection was mediated by enhanced astrocyte function, which may have contributed to functional recovery after stroke., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Postoperative cognitive dysfunction is a common complication associated with anesthesia and surgery. Sevoflurane is a widely used volatile anesthetic in the clinical setting. Preclinical studies show that sevoflurane alone does not appear to cause cognitive dysfunction. Here, we examined whether sevoflurane induces cognitive decline under chronic intermittent hypoxia (CIH) conditions. Rats were exposed to CIH or control for 4 weeks. Two weeks after starting intermittent hypoxia, these animals underwent either 2.6% sevoflurane or vehicle exposure for 4 h. Four weeks after CIH, Morris Water Maze task showed that both groups of CIH rats exhibited significantly longer latency to locate the hidden platform and had shorter dwell-time in the goal quadrant compared with respective controls. Notably, CIH + sevoflurane rats had much higher latency and less dwell-time than CIH + vehicle rats. Molecular studies revealed that pro-inflammatory cytokine expression and activated microglia in the hippocampus were increased in both groups of CIH rats, with greater increases in CIH + sevoflurane rats. No differences in above measured parameters were observed between two control groups. Sevoflurane reduced PPAR-γ expression and activity in both control and CIH rats. Moreover, activated microglia was positively correlated with proinflammatory cytokine expression and negatively correlated with PPAR-γ expression and activity in CIH groups. The results suggest that microglia-mediated neuroinflammation in the hippocampus plays an important role in the pathogenesis of CIH-associated cognitive dysfunction, and that a moderate duration of sevoflurane exaggerates cognitive decline under CIH conditions by aggravating microglia-mediated neuroinflammation via downregulation of PPAR-γ in the hippocampus., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Hypobaric hypoxia (HH) at high altitudes leads to a wide range of cognitive impairments which can handicap human normal activities and performances. However, the underlying mechanism is still unclear. Adenosine A 2A receptors (A 2A Rs) of the brain are pivotal to synaptic plasticity and cognition. Besides, insult-induced up-regulation of A 2A R regulates neuroinflammation and therefore induces brain damages in various neuropathological processes. The present study was designed to determine whether A 2A R-mediate neuroinflammation involves in cognitive impairments under acute HH. A 2A R knock-out and wild-type male mice were exposed to a simulated altitude of 8000 m for 7 consecutive days in a hypobaric chamber and simultaneously received behavioral tests including Morris water maze test and open filed test. A 2A R expression, the activation of microglia and the production of TNF-α were evaluated in the hippocampus by immunohistochemistry and ELISA, respectively. Behavioral tests showed that acute HH exposure caused the dysfunction of spatial memory and mood, while genetic inactivation of A 2A R attenuated the impairment of spatial memory but not that of mood. Double-labeled immunofluorescence showed that A 2A Rs were mainly expressed on microglia and up-regulated in the hippocampus of acute HH model mice. Acute HH also induced the accumulation of microglia and increased production of TNF-α in the hippocampus, which could be markedly inhibited by A 2A R inactivation. These findings indicate that microglia-mediated neuroinflammation triggered by A 2A R activation involves in acute HH-induced spatial memory impairment and that A 2A R could be a new target for the pharmacotherapy of cognitive dysfunction at high altitudes., (Copyright © 2018. Published by Elsevier B.V.)

Brain, being the highest consumer of oxygen, is prone to increased risk of hypoxia-induced neurological insults. In response to hypoxia, microglia, the major resident immune cells of brain switches to an activated phenotype and promote inflammatory responses leading to tissue damage and loss of cognitive functions including working memory impairment. Till date, no proven clinical therapeutics is available to retard the progression of neurodegenerative memory impairment. In the present study, we investigated the therapeutic potential of intranasal small interfering RNA (siRNA) delivery in a mouse model of hypoxia-induced working memory impairment using microglial receptor, Mac-1 as a target gene. Here, we implicate Mac-1 scavenger receptor in microglial phenotype switching, neurodegeneration in prefrontal cortex, hippocampus and working memory impairment. RNA mediated silencing of Mac-1 in both in vitro and in vivo model showed significant impact of it on hypoxia induced altered expression of Mac-1 endogenous ligand, signaling cascade proteins, transcription factors and NADPH oxidase pathway. Efficient degradation of Mac-1 mRNA suppressed expression of M1 phenotypic markers, inflammatory chemokines, and cytokines, but on the other hand, it upregulated M2 phenotypic markers and anti-inflammatory cytokines. Neuronal viability and synaptic plasticity markers were also modulated significantly by this strategy. Behavioral study revealed significant downregulation in the number of working memory errors at a time-dependent manner after silencing the Mac-1 gene during continuous hypoxic exposure. The novel findings of this study for the very first time, unmasked the role of Mac-1 receptor in neurodegenerative disease progression under hypoxic condition and at the same time indicated the potential therapeutic value of this non-invasive siRNA delivery approach for treating working memory loss., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

This study assessed whether hypoxia during high-load resistance exercise could enhance the acute physiological responses related to muscular development. Twelve trained men performed exercise in three conditions: normoxia (fraction of inspired oxygen [F I O 2 ] = 21%), moderate-level hypoxia (F I O 2  = 16%) and high-level hypoxia (F I O 2  = 13%). Exercise comprised high-load squats and deadlifts (5 × 5 using 80% of 1-repetition maximum with 180-s rest). Muscle oxygenation and activation were monitored during exercise. Metabolic stress was estimated via capillary blood sampling. Perceived fatigue and soreness were also quantified following exercise. While the hypoxic conditions appeared to affect muscle oxygenation, significant differences between conditions were only noted for maximal deoxyhaemoglobin in the deadlift (P = 0·009). Blood lactate concentration increased from 1·1 to 1·2 mmol l -1 at baseline to 9·5-9·8 mmol l -1 after squats and 10·4-10·5 mmol l -1 after deadlifts (P≤0·001), although there were no between-condition differences. Perceived fatigue and muscle soreness were significantly elevated immediately and at 24 h following exercise, respectively, by similar magnitudes in all conditions (P≤0·001). Muscle activation did not differ between conditions. While metabolic stress is thought to moderate muscle activation and subsequent muscular development during hypoxic resistance training, it is not augmented during traditional high-load exercise. This may be explained by the low number of repetitions performed and the long interset rest periods employed during this training. These findings suggest that high-load resistance training might not benefit from additional hypoxia as has been shown for low- and moderate-load training., (© 2017 Scandinavian Society of Clinical Physiology and Nuclear Medicine. Published by John Wiley & Sons Ltd.)

Background: The effects of acute mild hypoxic hypoxia (HH) and physical activity on physiological measures, signs and symptoms, mood, fatigue, cognition, and performance on a simulated flight task were investigated between 8000 (8K; 2438 m) and 14,000 ft (14K; 4267 m)., Method: In a hypobaric chamber, 16 military helicopter pilots were randomly exposed to 4 altitudes and 3 physical exertion levels. After each exercise period, participants identified targets on a designated flight path on a desktop simulator and completed a cognitive test battery. Cerebral regional and finger pulse oxyhemoglobin saturation levels (rSO2 and Spo2), heart and respiration rates were continuously monitored. Participants indicated their symptoms, mood and fatigue., Results: rSO2 and Spo2 were affected by the increase of altitude and exercise level. Target identification accuracy and latency within the simulated flight task showed decrements at 8K, 10K (3048 m), 12K (3658 m), and 14K. Cognitive performance was degraded at 14K. More than 60% of the participants at 8K and 10K and more than 80% at 12K and 14K reported symptoms. Altitude increased symptoms, negative mood, general fatigue, and physical fatigue., Discussion: Our findings indicate a significant influence of mild HH on a number of outcome measures at altitudes above 10K, where operational restrictions are well established. In contrast, there was no clear influence of HH on performance at lower altitudes (i.e., 8K and 10K). The occurrence of HH symptoms and the decrements in target identification latency and accuracy at 8K and 10K may negatively impact flight performance and require further study.Bouak F, Vartanian O, Hofer K, Cheung B. Acute mild hypoxic hypoxia effects on cognitive and simulated aircraft pilot performance. Aerosp Med Hum Perform. 2018; 89(6):526-535.

Exposure to hypoxia appears to depress appetite and energy intake, however the mechanisms are not fully understood. The aim of this review was to determine the magnitude of changes in hunger and energy intake in hypoxic compared with normoxic environments, and establish any alterations in appetite-related hormone concentrations. PubMed and The Cochrane Library as well as MEDLINE, SPORTDiscus, PsycINFO and CINAHL, via EBSCOhost, were searched through 1st April 2017 for studies that evaluated hunger, energy intake and/or appetite-related hormones in normoxia and during hypoxic exposure in a within-measures design. A total of 28 studies (comprising 54 fasted and 22 postprandial comparisons) were included. A random-effects meta-analysis was performed to establish standardised mean difference (SMD) with 95% confidence intervals. Hypoxic exposure resulted in a trivial but significant decrease in postprandial hunger scores (SMD: -0.15, 95% CI: -0.29 to -0.01; n = 14; p = 0.043) and a moderate decrease in energy intake (SMD: -0.50, 95% CI: -0.85 to -0.15; n = 8; p = 0.006). Hypoxic exposure resulted in a decrease (albeit trivial) in postprandial acylated ghrelin concentrations (SMD: -0.16, 95% CI: -0.25 to -0.08; n = 7; p < 0.0005), and a moderate increase in fasted insulin concentrations (SMD: 0.41, 95% CI: 0.17 to 0.65; n = 34; p = 0.001). Meta-regression revealed a decrease in postprandial acylated ghrelin concentrations (p = 0.010) and an increase in fasted insulin concentrations (p = 0.020) as hypoxic severity increased. Hypoxic exposure reduces hunger and energy intake, which may be mediated by decreased circulating concentrations of acylated ghrelin and elevated insulin concentrations. PROSPERO registration number: CRD42015017231., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Background: The high-flow nasal cannula (HFNC) delivers up to 60 l/min of humidified air/oxygen blend at a temperature close to that of the human body. In this study, we tested whether higher temperature and flow decrease patient comfort. In more severe patients, instead, we hypothesized that higher flow might be associated with improved comfort., Methods: A prospective, randomized, cross-over study was performed on 40 acute hypoxemic respiratory failure (AHRF) patients (PaO 2 /FiO 2  ≤ 300 + pulmonary infiltrates + exclusion of cardiogenic edema) supported by HFNC. The primary outcome was the assessment of patient comfort during HFNC delivery at increasing flow and temperature. Two flows (30 and 60 l/min), each combined with two temperatures (31 and 37 °C), were randomly applied for 20 min (four steps per patient), leaving clinical FiO 2 unchanged. Toward the end of each step, the following were recorded: comfort by Visual Numerical Scale ranging between 1 (extreme discomfort) and 5 (very comfortable), together with respiratory parameters. A subgroup of more severe patients was defined by clinical FiO 2  ≥ 45%., Results: Patient comfort was reported as significantly higher during steps at the lower temperature (31 °C) in comparison to 37 °C, with the HFNC set at both 30 and 60 l/min (p < 0.0001). Higher flow, however, was not associated with poorer comfort. In the subgroup of patients with clinical FiO 2  ≥ 45%, both lower temperature (31 °C) and higher HFNC flow (60 l/min) led to higher comfort (p < 0.01)., Conclusions: HFNC temperature seems to significantly impact the comfort of AHRF patients: for equal flow, lower temperature could be more comfortable. Higher flow does not decrease patient comfort; at variance, it improves comfort in the more severely hypoxemic patient.

Brain development is influenced by various prenatal, intrapartum, and postnatal events which may interact with genotype to affect the neural and psychophysiological systems related to emotions, specific cognitive functions (e.g., attention, memory), and language abilities and thereby heighten the risk for psychopathology later in life. Fetal hypoxia (intrapartum oxygen deprivation), hypoxia-related obstetric complications, and hypoxia during the early neonatal period are major environmental risk factors shown to be associated with an increased risk for later psychopathology. Experimental models of perinatal hypoxia/ischemia (PHI) showed that fetal hypoxia-a consequence common to many birth complications in humans-results in selective long-term disturbances of the dopaminergic systems that persist in adulthood. On the other hand, neurotrophic signaling is critical for pre- and postnatal brain development due to its impact on the process of neuronal development and its reaction to perinatal stress. The aim of this review is (a) to summarize epidemiological data confirming an association of PHI with an increased risk of a range of psychiatric disorders from childhood through adolescence to adulthood, (b) to present immunohistochemical findings on human autopsy material indicating vulnerability of the dopaminergic neurons of the human neonate to PHI that could predispose infant survivors of PHI to dopamine-related neurological and/or cognitive deficits in adulthood, and, ((c) to present and discuss older and recent findings on the differential expression of neurotrophins (BDNF, NGF, NT-3, and NT-4) in neonates following hypoxic/ischemic insults and its significance for the development of the human brain and the induction of psychopathology later in life.)

Exposure to elevated concentrations of CO 2 or hypoxia has been widely used in psychiatric research as a panic provoking stimulus. However, the use of these respiratory challenges to model panic-like responses in experimental animals has been less straightforward. Little data is available, from behavioral and endocrine perspectives, to support the conclusion that a marked aversive situation, such as that experienced during panic attacks, was evoked in these animals. We here compared the behavioral responses of male CB57BL/6 mice during exposure to 20% CO 2 or 7% O 2 and its consequence on plasma levels of corticosterone. We also evaluated whether clinically-effective panicolytic drugs affect the behavioral responses expressed during CO 2 exposure. The results showed that whereas hypoxia caused a marked reduction in locomotion, inhalation of CO 2 -enriched air evoked an active escape response, characterized by bouts of upward leaps directed to the border of the experimental cage, interpreted as escape attempts. Corticosterone levels were increased 30min after either of the respiratory challenges used, but it was higher in the hypoxia group. Chronic (21days), but not acute, treatment with fluoxetine or imipramine (5, 10 or 15mg/kg) or a single injection of alprazolam (0.025, 0.05 or 0.1mg/kg), but not of the anxiolytic diazepam (0.025, 0.05 or 0.1 and 1mg/kg) reduced the number of escape attempts, indicating a panicolytic-like effect. Altogether, the results suggest that whereas hypoxia increased anxiety, exposure to 20% CO 2 evoked a panic-like state. The latter condition/test protocol seems to be a simple and validated model for studying in mice pathophysiological mechanisms and the screening of novel drugs for panic disorder., (Copyright © 2017 Elsevier Inc. All rights reserved.)