Cocoa flavanols protect cognitive function, cerebral oxygenation, and mental fatigue during severe hypoxia.

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.

Effects of heat load and hypobaric hypoxia on cognitive performance: a combined stressor approach.

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.

Acute Normobaric Hypoxia Lowers Executive Functions among Young Men despite Increase of BDNF Concentration.

BACKGROUND: Decreased SpO2 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), FIO2 = 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 SpO2 (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 SpO2 irrespective of a rise in BDNF.

Comparison of the Adaptive Capacity in Old and Young Wistar Rats to Stress Exposure and Acute Hypoxic Hypoxia.

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.

Intermittent Hypoxia Activates N-Methyl-D-Aspartate Receptors to Induce Anxiety Behaviors in a Mouse Model of Sleep-Associated Apnea.

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.

N-acetylcysteine reduces brain injury after delayed hypoxemia following traumatic brain injury.

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.

Intermittent Hypoxia and Effects on Early Learning/Memory: Exploring the Hippocampal Cellular Effects of Pediatric Obstructive Sleep Apnea.

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.

Retracted: Facemasks in the COVID-19 era: A health hypothesis.

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.

Comparison of hypobaric hypoxia symptoms between a recalled exposure and a current exposure.

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.

Mechanism and effects of fructose diphosphate on anti-hypoxia fatigue and learning memory ability.

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.

Acclimatization to Middle Attitude Hypoxia Masks the Symptoms of Experimental Posttraumatic Stress Disorder, but Does Not Affect Its Pathogenetic Mechanisms.

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.

Percutaneous Closure of PFO in Patients with Reduced Oxygen Saturation at Rest and during Exercise: Short- and Long-Term Results.

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.

Hypobaric hypoxia induced fear and extinction memory impairment and effect of Ginkgo biloba in its amelioration: Behavioral, neurochemical and molecular correlates.

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.

The objective assessment of the effects on cognition functioning among military personnel exposed to hypobaric-hypoxia: A pilot fMRI study.

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.

Treadmill running attenuates neonatal hypoxia induced adult depressive symptoms and promoted hippocampal neural stem cell differentiation via modulating AMPK-mediated mitochondrial functions.

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.

The interactive effects of acute exercise and hypoxia on cognitive performance: A narrative review.

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.

Early postnatal hypoxia induces behavioral deficits but not morphological damage in the hippocampus in adolescent rats.

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.

Effect of Ambient Oxygen Content, Safety Shoe Type, and Lifting Frequency on Subject's MAWL and Physiological Responses.

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.