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New Findings: What is the central question of this study? Cerebrovascular reactivity (CVR) is a common functional test to assess brain health, and impaired CVR has been associated with all-cause cardiovascular mortality: does the duration of the CO 2 stimulus and the time point used for data extraction alter the CVR outcome measure? What is the main finding and its importance? This study demonstrated CVR measures calculated from 1 and 2 min CO 2 stimulus durations were significantly higher than CVR calculated from a 4 min CO 2 stimulus. CVRs calculated from the first 2 min of the CO 2 stimulus were significantly higher than CVR values calculated from the final minute if the duration was ≥4 min. This study highlights the need for consistent methodological approaches., Abstract: Cerebrovascular reactivity to carbon dioxide (CVR) is a common functional test to assess brain vascular health, though conflicting age and fitness effects have been reported. Studies have used different CO 2 stimulus durations to induce CVR and extracted data from different time points for analysis. Therefore, this study examined whether these differences alter CVR and explain conflicting findings. Eighteen healthy volunteers (24 ± 5 years) inhaled CO 2 for four stimulus durations (1, 2, 4 and 5 min) of 5% CO 2 (in air) via the open-circuit Douglas bag method, in a randomized order. CVR data were derived from transcranial Doppler (TCD) measures of middle cerebral artery blood velocity (MCAv), with concurrent ventilatory sensitivity to the CO 2 stimulus ( V ̇ E , C O 2 ). Repeated measures ANOVAs compared CVR and V ̇ E , C O 2 measures between stimulus durations and steady-state time points. An effect of stimulus duration was observed (P = 0.002, η² = 0.140), with 1 min (P = 0.010) and 2 min (P < 0.001) differing from 4 min, and 2 min differing from 5 min (P = 0.019) durations. V ̇ E , C O 2 sensitivity increased ∼3-fold from 1 min to 4 and 5 min durations (P < 0.001, η² = 0.485). CVRs calculated from different steady-state time points within each stimulus duration were different (P < 0.001, η² = 0.454), specifically for 4 min (P = 0.001) and 5 min (P < 0.001), but not 2 min stimulus durations (P = 0.273). These findings demonstrate that methodological differences alter the CVR measure., (© 2020 The Authors. Experimental Physiology © 2020 The Physiological Society.)

Key Points: Aerobic exercise elicits increases in cerebral blood flow (CBF), as well as core body temperature; however, the isolated influence of temperature on CBF regulation during exercise has not been investigated The present study assessed CBF regulation and neurovascular coupling during submaximal cycling exercise and temperature-matched passive heat stress during isocapnia (i.e. end-tidal P C O 2 was held constant) Submaximal cycling exercise and temperature-matched passive heat stress provoked ∼16% increases in vertebral artery blood flow, independent of changes in end-tidal P C O 2 and blood pressure External carotid artery blood flow increased by ∼43% during both exercise and passive heat stress, with no change in internal carotid artery blood flow Neurovascular coupling (i.e. the relationship between local increases in cerebral metabolism and appropriately matched increases in regional cerebral blood flow) is preserved during both exercise and temperature-matched passive heat stress ABSTRACT: Acute moderate-intensity exercise increases core temperature (T c ; +0.7-0.8°C); however, such exercise increases cerebral blood flow (CBF; +10-20%) mediated via small elevations in arterial P C O 2 and metabolism. The present study aimed to isolate the role of T c from P C O 2 on CBF regulation during submaximal exercise. Healthy adults (n = 11; 10 males/one female; 26 ± 4 years) participated in two interventions each separated by ≥48 h: (i) 60 min of semi-recumbent cycling (EX; 50% workload max) and (ii) 75 min of passive heat stress (HS; 49°C water-perfused suit) to match the exercise-induced increases in T c (EX: Δ0.75 ± 0.33°C vs. HS: Δ0.77 ± 0.33°C, P = 0.855). Blood flow (Q) in the internal and external carotid arteries (ICA and ECA, respectively) and vertebral artery (VA) (Duplex ultrasound) was measured. End-tidal P C O 2 and P O 2 were effectively clamped to resting values within each condition. The Q ICA was unchanged with EX and HS interventions (P = 0.665), consistent with the unchanged end-tidal P C O 2 (P = 0.327); whereas, Q VA was higher throughout both EX and HS (EX: Δ16 ± 21% vs. HS: Δ16 ± 23%, time effect: P = 0.006) with no between condition differences (P = 0.785). These increases in Q VA contributed to higher global CBF throughout both EX and HS (EX: Δ12 ± 20% vs. HS: Δ14 ± 14%, time effect: P = 0.029; condition effect: P = 0.869). The Q ECA increased throughout both EX and HS (EX: Δ42 ± 58% vs. HS: Δ53 ± 28%, time effect: P < 0.001; condition effect: P = 0.628). Including blood pressure as a covariate did not alter these CBF findings (all P > 0.05). Overall, these data provide new evidence for temperature-mediated elevations in posterior CBF during exercise that are independent of changes in P C O 2 and blood pressure., (© 2020 The Authors. The Journal of Physiology © 2020 The Physiological Society.)

Developing near-infrared spectroscopy (NIRS) parameter recovery techniques to more specifically resolve brain physiology from that of the overlying tissue is an important part of improving the clinical utility of the technology. The Valsalva maneuver (VM) involves forced expiration against a closed glottis causing widespread venous congestion within the context of a fall in cardiac output. Due to the specific anatomical confines and metabolic demands of the brain we believe a properly executed VM has the ability to separate haemodynamic activity of brain tissue from that of the overlying scalp as observed by NIRS, and confirmed by functional magnetic resonance imaging (fMRI). Healthy individuals performed a series of standing maximum effort VMs under separate observation by frequency domain near-infrared spectroscopy (FD-NIRS) and fMRI. Nine individuals completed the clinical protocol (6 males, age 21-40). During the VMs, brain and extracranial tissue targeted signal were significantly different (opposite direction of change) in both fMRI and NIRS (p=0.00025 and 0.00115 respectively), with robust cross correlation of parameters between modalities. Four of these individuals performed further VMs after infiltrating 2% xylocaine/1:100,000 epinephrine (vasoconstrictor) into scalp tissue beneath the probes. No significant difference in the cerebrally derived parameters was observed. The maximum effort VM has the ability to separate NIRS observable physiology of the brain from the overlying extracranial tissue. Observations made by this FD cerebral NIRS device are comparable with fMRI in this context., Competing Interests: The views expressed are those of the authors and not necessarily those of the NIHR or the Department of Health and Social Care., (© 2020 Optical Society of America under the terms of the OSA Open Access Publishing Agreement.)

New Findings: What is the central question of this study? Does habitual resistance and endurance exercise modify dynamic cerebral autoregulation? What is the main finding and its importance? To the authors' knowledge, this is the first study to directly assess dynamic cerebral autoregulation in resistance-trained individuals, and potential differences between exercise training modalities. Forced oscillations in blood pressure were induced by repeated squat-stands, from which dynamic cerebral autoregulation was assessed using transfer function analysis. These data indicate that dynamic cerebral autoregulatory function is largely unaffected by habitual exercise type, and further document the systemic circulatory effects of regular exercise., Abstract: Regular endurance and resistance exercise produce differential but desirable physiological adaptations in both healthy and clinical populations. The chronic effect of these different exercise modalities on cerebral vessels' ability to respond to rapid changes in blood pressure (BP) had not been examined. We examined dynamic cerebral autoregulation (dCA) in 12 resistance-trained (mean ± SD, 25 ± 6 years), 12 endurance-trained (28 ± 9 years) and 12 sedentary (26 ± 6 years) volunteers. The dCA was assessed using transfer function analysis of forced oscillations in BP vs. middle cerebral artery blood velocity (MCAv), induced via repeated squat-stands at 0.05 and 0.10 Hz. Resting BP and MCAv were similar between groups (interaction: both P ≥ 0.544). The partial pressure of end-tidal carbon dioxide ( P ETC O 2 ) was unchanged (P = 0.561) across squat-stand manoeuvres (grouped mean for absolute change +0.6 ± 2.3 mmHg). Gain and normalized gain were similar between groups across all frequencies (both P ≥ 0.261). Phase showed a frequency-specific effect between groups (P = 0.043), tending to be lower in resistance-trained (0.63 ± 0.21 radians) than in endurance-trained (0.90 ± 0.41, P = 0.052) and -untrained (0.85 ± 0.38, P = 0.081) groups at slower frequency (0.05 Hz) oscillations. Squat-stands induced mean arterial pressure perturbations differed between groups (interaction: P = 0.031), with greater changes in the resistance (P < 0.001) and endurance (P = 0.001) groups compared with the sedentary group at 0.05 Hz (56 ± 13 and 49 ± 11 vs. 35 ± 11 mmHg, respectively). The differences persisted at 0.1 Hz between resistance and sedentary groups (49 ± 12 vs. 33 ± 7 mmHg, P < 0.001). These results indicate that dCA remains largely unaltered by habitual endurance and resistance exercise with a trend for phase to be lower in the resistance exercise group at lower fequencies., (© 2019 The Authors. Experimental Physiology © 2019 The Physiological Society.)

New Findings: What is the central question of the study? What are the effects of acute mental stress on the mechanisms regulating cerebral blood flow? What is the main finding and its importance? The major new findings are as follows: (i) high mental stress and hypercapnia had an interactive effect on mean middle cerebral artery blood velocity; (ii) high mental stress altered the regulation of cerebral blood flow; (iii) the increased cerebrovascular hypercapnic reactivity was not driven by changes in mean arterial pressure alone; and (iv) this increased perfusion with mental stress appeared not to be justified functionally by an increase in oxygen demand (as determined by near-infrared spectroscopy-derived measures)., Abstract: In this study, we examined the effects of acute mental stress on cerebrovascular function. Sixteen participants (aged 23 ± 4 years; five female) were exposed to low and high mental stress using simple arithmetic (counting backwards from 1000) and more complex arithmetic (serial subtraction of 13 from a rapidly changing four-digit number), respectively. During consecutive conditions of baseline, low stress and high stress, end-tidal partial pressure of CO 2 ( P ET , C O 2 ) was recorded at normocapnia (37 ± 3 mmHg) and clamped at two elevated levels (P < 0.01): 41 ± 1 and 46 ± 1 mmHg. Mean right middle cerebral artery blood velocity (MCAv mean ; transcranial Doppler ultrasound), right prefrontal cortex haemodynamics (near-infrared spectroscopy) and mean arterial blood pressure (MAP; finger photoplethysmography) were measured continuously. Cerebrovascular hypercapnic reactivity (ΔMCAv mean /Δ P ET , C O 2 ), cerebrovascular conductance (CVC; MCAv mean /MAP), CVC CO 2 reactivity (ΔCVC/Δ P ET , C O 2 ) and total peripheral resistance (MAP/cardiac output) were calculated. Acute high mental stress increased MCAv mean by 7 ± 7%, and more so at higher P ET , C O 2 (32 ± 10%; interaction, P = 0.03), illustrating increased sensitivity to CO 2 (i.e. its major regulator). High mental stress also increased MAP (17 ± 9%; P ≤ 0.01), coinciding with increased near-infrared spectroscopy-derived prefrontal haemoglobin volume and saturation measures. High mental stress elevated both cerebrovascular hypercapnic and conductance reactivities (main effect of stress, P ≤ 0.04). These findings indicate that the cerebrovascular response to acute high mental stress results in a coordinated regulation between multiple processes., (© 2019 The Authors. Experimental Physiology © 2019 The Physiological Society.)

Both acute and regular exercise influence vascular and cognitive function. Upright aquatic exercise increases mean middle cerebral artery blood velocity (MCAv mean ) and has been suggested as favorable for cerebrovascular adaptations. However, MCAv mean has not been reported during swimming. Thus, we examined the cerebrovascular and cognitive effects of swimming. Ten land-based athletes (22 ± 5 years) and eight swimmers (19 ± 1 years) completed three cognitive tasks and four conditions that were used to independently and collectively delineate the swimming-related factors (i.e., posture, immersion, CO 2 retention [end-tidal CO 2 ; PETCO 2 ], and motor involvement). Measurements of MCAv mean and PETCO 2 were taken throughout each condition. Prone posture increased MCAv mean by 11% (P < 0.01 vs. upright land). Water immersion independently increased MCAv mean when upright (12%; P < 0.01) but not prone (P = 0.76). The consequent rise in PETCO 2 during head-out, breast-stroke swimming (50% heart rate range) independently increased MCAv mean by 14% (P < 0.01), while the motor involvement of swimming per se did not significantly change MCAv mean (P = 0.32). While accounting for sex, swimmers had ~17% lower MCAv mean during all rest conditions (P ≤ 0.05). However, in a subset of participants, both groups had similar internal carotid artery diameters (P = 0.99) and velocities (P = 0.97). Water immersion per se did not alter cognition (P ≥ 0.15), but 20 min of moderate-intensity swimming improved visuomotor performance by 4% (P = 0.03), regardless of athlete group (P = 0.12). In conclusion, breast-stroke swimming increased MCAv mean mostly due to postural and PETCO 2 effects, with minimal contributions from water immersion or motor activity. Lastly, swimming improved cognitive functioning acutely, regardless of athlete group. Future research should explore the chronic effects of swimming on cerebrovascular function and cognition, particularly in aging., (© 2019 The Authors. Physiological Reports published by Wiley Periodicals, Inc. on behalf of The Physiological Society and the American Physiological Society.)

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.)

Nicotinamide adenine dinucleotide (NAD + ) is modulated by conditions of metabolic stress and has been reported to decline with aging in preclinical models, but human data are sparse. Nicotinamide riboside (NR) supplementation ameliorates metabolic dysfunction in rodents. We aimed to establish whether oral NR supplementation in aged participants can increase the skeletal muscle NAD + metabolome and if it can alter muscle mitochondrial bioenergetics. We supplemented 12 aged men with 1 g NR per day for 21 days in a placebo-controlled, randomized, double-blind, crossover trial. Targeted metabolomics showed that NR elevated the muscle NAD + metabolome, evident by increased nicotinic acid adenine dinucleotide and nicotinamide clearance products. Muscle RNA sequencing revealed NR-mediated downregulation of energy metabolism and mitochondria pathways, without altering mitochondrial bioenergetics. NR also depressed levels of circulating inflammatory cytokines. Our data establish that oral NR is available to aged human muscle and identify anti-inflammatory effects of NR., (Copyright © 2019 The Author(s). Published by Elsevier Inc. All rights reserved.)

Introduction: The time of day when cardiovascular events are most likely to occur is thought to be aligned with the circadian rhythm of physiological variables. Chronotype has been shown to influence the time of day when cardiovascular events happen, with early chronotypes reported to be more susceptible in the morning and late chronotypes in the evening. However, no studies have investigated the influence of chronotype on physiological variables responsible for cardiovascular regulation in healthy individuals. Methods: 312 individuals completed the Munich ChronoType Questionnaire to assess chronotype. Twenty participants were randomly selected to continue into the main study. In a repeated-measures experiment, participants were tested between 08:00 and 10:00 h and again between 18:00 and 20:00 h. Measurements of mean arterial pressure, heart rate and vascular endothelial vasodilation via flow-mediated dilatation (FMD) were obtained at each session. Results: Individual diurnal differences in mean arterial pressure and heart rate show no significant relationship with chronotype. Diurnal differences in FMD showed a significant correlation ( p = 0.010), driven by a clear significant relationship in the evening and not the morning ( p < 0.001). Conclusion: These preliminary data indicate that chronotype influences the diurnal variation of endothelial vasodilation measured using flow-mediated dilatation. Furthermore, we show that the influence of chronotype is much stronger in the evening, highlighting an increased susceptibility for later types. These findings are consistent with the diurnal rhythm in cardiovascular events and uncover potential mechanisms of local mediators that may underpin the influence of chronotype in the onset of these events.

Although emerging as a cost and time efficient way to prepare for competition in the heat, recent evidence indicates that "short-term" heat acclimation (<7 days) may not be sufficient for females to adapt to repeated heat stress. Furthermore, self-paced performance following either short-term, or longer (>7 days) heat acclimation has not been examined in a female cohort. Therefore, the aim of this study was to investigate self-paced endurance performance in hot conditions following 4- and 9-days of a high-intensity isothermic heat acclimation protocol in a female cohort. Eight female endurance athletes (mean ± SD, age 27 ± 5 years, mass 61 ± 5 kg, VO 2peak 47 ± 6 ml⋅kg⋅min -1 ) performed 15-min self-paced cycling time trials in hot conditions (35°C, 30%RH) before (HTT1), and after 4-days (HTT2), and 9-days (HTT3) isothermic heat acclimation (HA, with power output manipulated to increase and maintain rectal temperature ( T rec ) at ∼38.5°C for 90-min cycling in 40°C, 30%RH) with permissive dehydration. There were no significant changes in distance cycled ( p = 0.47), mean power output ( p = 0.55) or cycling speed ( p = 0.44) following 4-days HA (i.e., from HTT1 to HTT2). Distance cycled (+3.2%, p = 0.01; +1.8%, p = 0.04), mean power output (+8.1%, p = 0.01; +4.8%, p = 0.05) and cycling speed (+3.0%, p = 0.01; +1.6%, p = 0.05) were significantly greater in HTT3 than in HTT1 and HTT2, respectively. There was an increase in the number of active sweat glands per cm 2 in HTT3 as compared to HTT1 (+32%; p = 0.02) and HTT2 (+22%; p < 0.01), whereas thermal sensation immediately before HTT3 decreased ("Slightly Warm," p = 0.03) compared to ratings taken before HTT1 ("Warm") in 35°C, 30%RH. Four-days HA was insufficient to improve performance in the heat in females as observed following 9-days HA.

The cost and highly invasive nature of brain monitoring modality in traumatic brain injury patients currently restrict its utility to specialist neurological intensive care settings. We aim to test the abilities of a frequency domain near-infrared spectroscopy (FD-NIRS) device in predicting changes in invasively measured brain tissue oxygen tension. Individuals admitted to a United Kingdom specialist major trauma center were contemporaneously monitored with an FD-NIRS device and invasively measured brain tissue oxygen tension probe. Area under the curve receiver operating characteristic (AUROC) statistical analysis was utilized to assess the predictive power of FD-NIRS in detecting both moderate and severe hypoxia (20 and 10 mm Hg, respectively) as measured invasively. Sixteen individuals were prospectively recruited to the investigation. Severe hypoxic episodes were detected in nine of these individuals, with the NIRS demonstrating a broad range of predictive abilities (AUROC 0.68-0.88) from relatively poor to good. Moderate hypoxic episodes were detected in seven individuals with similar predictive performance (AUROC 0.576-0.905). A variable performance in the predictive powers of this FD-NIRS device to detect changes in brain tissue oxygen was demonstrated. Consequently, this enhanced NIRS technology has not demonstrated sufficient ability to replace the established invasive measurement.

A growing body of evidence indicates regular physical activity benefits older adults' cognitive functioning, particularly when a high level of cognitive control is required. Recent research has pointed to improved cerebrovascular function as one mechanism through which such benefits might arise. This study built on previous research by investigating in 51 healthy older adults aged 60-72 years relationships between habitual physical activity, cerebrovascular function (indicated by resting cerebral blood flow velocity in the middle cerebral artery [n = 42], and its responsiveness to hypercapnia [n = 26] and hypocapnia [n = 25]), and cognitive control (inhibition and switching). Linear regression analyses showed moderate positive associations between physical activity and inhibitory control, but not cerebrovascular function. There were also no significant relationships between the cerebrovascular measures and cognitive control. These results indicate that regular engagement in physical activity is associated with superior inhibitory control in older adulthood, but cerebrovascular function was not found to explain those relationships. Taken together, the current findings reinforce reports of positive links between habitual physical activity and cognition in healthy older adults, but also signal that interrelationships with cerebrovascular function may be more complex than currently indicated by the literature, necessitating further research to elucidate the role cerebrovascular function might play in accounting for physical activity-cognition links in healthy older adults., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Recent evidence indicates that cerebral autoregulation (CA) might be more pressure passive than previously thought. That is, cerebral blood flow, traditionally thought to be regulated independently of prevailing mean arterial pressure (MAP), might fluctuate, to some extent, as a function of MAP. However, due to limitations associated with experimental usage of pharmaceuticals to manipulate MAP and inconsistent control of arterial carbon dioxide, questions remain regarding the MAP-cerebral blood flow relationship, especially during typical daily activities that alter MAP. Therefore, the current study aimed to assess CA using a nonpharmacological acute psychological stress task to augment MAP, while at the same time controlling for end-tidal carbon dioxide (P ET CO 2 ). Twenty-five healthy young adults completed a stressful task while continuous measures of MAP, middle cerebral artery blood flow velocity (MCAv), and P ET CO 2 were recorded. Slope values obtained from hierarchical linear regression were used to assess the strength of the MAP-MCAv relationship and control for P ET CO 2 . The stress task significantly increased MAP (p < 0.001) and MCAv (p < 0.001), and decreased P ET CO 2 (p = 0.05). For every 10 mmHg task-induced increase in MAP, MCAv increased by ≈3.5%; task-induced changes in P ET CO 2 did not appreciably change the MAP-MCAv relationship. Greater task-induced MAP responses were significantly related to decreased MAP-MCAv slope values, consistent with CA. These data support the hypothesis that CA is more pressure passive than previously thought and provide initial evidence indicating that a pressure-passive MAP-MCAv relationship may play a role in the observed associations between MAP stress responses, stroke, and cerebrovascular disease., (© 2018 Society for Psychophysiological Research.)

Introduction: The physiological responses on exposure to high altitude are relatively well known, but new discoveries are still being made, and novel prevention and treatment strategies may arise. Basic information has changed little since our previous review in this journal 10 years ago, but considerable more detail on standard therapies, and promising new approaches are now available., Areas Covered: Herein, the authors review the role of pharmacological agents in preventing and treating high-altitude illnesses. The authors have drawn on their own experience and that of international experts in this field. The literature search was concluded in March 2018., Expert Opinion: Slow ascent remains the primary prevention strategy, with rapid descent for the management of serious altitude illnesses. Pharmacological agents are particularly helpful when rapid ascent cannot be avoided or when rapid descent is not possible. Acetazolamide remains the drug of choice for prophylaxis of acute mountain sickness. However, evidence indicates that reduced dosage schemes compared to the current recommendations are warranted. Calcium channel blockers and phosphodiesterase inhibitors remain the drugs of choice for the management of high-altitude pulmonary edema. Dexamethasone should be reserved for the treatment of more severe cases of altitude illnesses such as cerebral edema.

Frostbite and other cold-related injuries commonly develop during prolonged exposure to the low environmental temperatures of polar and mountainous regions. Hypoxia is a potent sympathetic stimulus that causes vasoconstriction of the peripheral blood vessels, which may further compound the risk of developing a cold-related injury during high-altitude exposure. To investigate this, we utilized portable infrared thermographic technology to quantitatively measure changes in the surface temperature of the hands during exposure to increasing levels of normobaric hypoxia in a temperature-controlled high-altitude simulation. Surface temperature was assessed at four anatomical locations on both the left and right hands in a cohort of 10 healthy male participants at a series of predetermined levels of hypoxia (0.20 fraction of inspired oxygen [F I O 2 ] [pre- and postexposure], 0.172 F I O 2 , 0.145 F I O 2 , 0.128 F I O 2 ). Thermographic analysis revealed an overall decrease in peripheral temperature across the anatomical regions of the hands as the hypoxic stimulus increased, with statistically significant reductions observed at all four anatomical sites during exposure to 0.128 F I O 2 (p < 0.05). These findings demonstrate that portable infrared thermography can be used to detect reductions in peripheral surface body temperature during exposure to normobaric hypoxia.

Qualitative clinical assessments of the recovery of awareness after severe brain injury require an assessor to differentiate purposeful behavior from spontaneous behavior. As many such behaviors are minimal and inconsistent, behavioral assessments are susceptible to diagnostic errors. Advanced neuroimaging tools can bypass behavioral responsiveness and reveal evidence of covert awareness and cognition within the brains of some patients, thus providing a means for more accurate diagnoses, more accurate prognoses, and, in some instances, facilitated communication. The majority of reports to date have employed the neuroimaging methods of functional magnetic resonance imaging, positron emission tomography, and electroencephalography (EEG). However, each neuroimaging method has its own advantages and disadvantages (e.g., signal resolution, accessibility, etc.). Here, we describe a burgeoning technique of non-invasive optical neuroimaging-functional near-infrared spectroscopy (fNIRS)-and review its potential to address the clinical challenges of prolonged disorders of consciousness. We also outline the potential for simultaneous EEG to complement the fNIRS signal and suggest the future directions of research that are required in order to realize its clinical potential.

Earlier studies have indicated an important role for cerebral blood flow in the pathophysiology of central sleep apnea (CSA) at high altitude, but were not decisive. To test the hypothesis that pharmacologically altering cerebral blood flow (CBF) without altering arterial blood gas (ABGs) values would alter the severity of CSA at high altitude, we studied 11 healthy volunteers (8M, 3F; 31 ± 7 yr) in a randomized placebo-controlled single-blind study at 5,050 m in Nepal. CBF was increased by intravenous (iv) acetazolamide (Az; 10 mg/kg) plus intravenous dobutamine (Dob) infusion (2-5 μg·kg -1 ·min -1 ) and reduced by oral indomethacin (Indo; 100 mg). ABG samples were collected and ventilatory responses to hypercapnia (HCVR) and hypoxia (HVR) were measured by rebreathing and steady-state techniques before and after drug/placebo. Duplex ultrasound of blood flow in the internal carotid and vertebral arteries was used to measure global CBF. The initial 3-4 h of sleep were recorded by full polysomnography. Intravenous Az + Dob increased global CBF by 37 ± 15% compared with placebo ( P < 0.001), whereas it was reduced by 21 ± 8% by oral Indo ( P < 0.001). ABGs and HVR were unchanged in both interventions. HCVR was reduced by 28% ± 43% ( P = 0.1) during intravenous Az ± Dob administration and was elevated by 23% ± 30% ( P = 0.05) by Indo. During intravenous Az + Dob, the CSA index fell from 140 ± 45 (control night) to 48 ± 37 events/h of sleep ( P < 0.001). Oral Indo had no significant effect on CSA. We conclude that increasing cerebral blood flow reduced the severity of CSA at high altitude; the likely mechanism is via a reduction in the background stimulation of central chemoreceptors. NEW & NOTEWORTHY This work is significant because it shows convincingly for the first time in healthy volunteers that increasing cerebral blood flow will reduce the severity of central sleep apnea in a high-altitude model, without the potentially confounding effects of altering partial pressure of arterial carbon dioxide or the ventilatory response to hypoxia. The proposed mechanism of action is that of increasing the removal of locally produced CO 2 from the central chemoreceptors, causing the reduction in hypercapnic ventilatory response, hence reducing loop gain.

Healthy ageing is associated with decline in cognitive abilities such as language. Aerobic fitness has been shown to ameliorate decline in some cognitive domains, but the potential benefits for language have not been examined. In a cross-sectional sample, we investigated the relationship between aerobic fitness and tip-of-the-tongue states. These are among the most frequent cognitive failures in healthy older adults and occur when a speaker knows a word but is unable to produce it. We found that healthy older adults indeed experience more tip-of-the-tongue states than young adults. Importantly, higher aerobic fitness levels decrease the probability of experiencing tip-of-the-tongue states in healthy older adults. Fitness-related differences in word finding abilities are observed over and above effects of age. This is the first demonstration of a link between aerobic fitness and language functioning in healthy older adults.

Objective: To assess whether acetazolamide (Az), used prophylactically for acute mountain sickness (AMS), alters exercise capacity at high altitude., Methods: Az (500 mg daily) or placebo was administered to 20 healthy adults (aged 36±20 years, range 21-77), who were paired for age, sex, AMS susceptibility and weight, in a double-blind, randomised manner. Participants ascended over 5 days to 4559 m, then exercised to exhaustion on a bicycle ergometer, while recording breath-by-breath gas measurements. Comparisons between groups and matched pairs were done via Mann-Whitney U and Pearson's χ 2 tests, respectively., Results: Comparing paired individuals at altitude, those on Az had greater reductions in maximum power output (P max ) as a percentage of sea-level values (65±14.1 vs 76.6±7.4 (placebo); P=0.007), lower VO 2max (20.7±5.2 vs 24.6±5.1 mL/kg/min; P<0.01), smaller changes from rest to P max for VO 2 (9.8±6.2 vs 13.8±4.9 mL/kg/min; P=0.04) and lower heart rate at P max (154±25 vs 167±16, P<0.01) compared with their placebo-treated partners. Correlational analysis (Pearson's) indicated that with increasing age P max ( r =-0.83: P<0.005) and heart rate at P max ( r =-0.71, P=0.01) reduced more in those taking Az., Conclusion: Maximum exercise performance at altitude was reduced more in subjects taking Az compared with placebo, particularly in older individuals. The age-related effect may reflect higher tissue concentrations of Az due to reduced renal excretion. Future studies should explore the effectiveness of smaller Az doses (eg, 250 mg daily or less) in older individuals to optimise the altitude-Az-exercise relationships., Competing Interests: Competing interests: None declared.

The brain is highly susceptible to oxidative stress due to its high metabolic demand. Increased oxidative stress and depletion of glutathione (GSH) are observed with aging and many neurological diseases. Exercise training has the potential to reduce oxidative stress in the brain. In this study, nine healthy sedentary males (aged 25 ± 4 years) undertook a bout of continuous moderate intensity exercise and a high-intensity interval (HII) exercise bout on separate days. GSH concentration in the anterior cingulate was assessed by magnetic resonance spectroscopy (MRS) in four participants, before and after exercise. This was a pilot study to evaluate the ability of the MRS method to detect exercise-induced changes in brain GSH in humans for the first time. MRS is a non-invasive method based on nuclear magnetic resonance, which enables the quantification of metabolites, such as GSH, in the human brain in vivo. To add context to brain GSH data, other markers of oxidative stress were also assessed in the periphery (in blood) at three time points [pre-, immediately post-, and post (∼1 hour)-exercise]. Moderate exercise caused a significant decrease in brain GSH from 2.12 ± 0.64 mM/kg to 1.26 ± 0.36 mM/kg (p = .04). Blood GSH levels increased immediately post-HII exercise, 580 ± 101 µM to 692 ± 102 µM (n = 9, p = .006). The findings from this study show that brain GSH is altered in response to acute moderate exercise, suggesting that exercise may stimulate an adaptive response in the brain. Due to the challenges in MRS methodology, this pilot study should be followed up with a larger exercise intervention trial.

The effect that cardiorespiratory fitness has on the dynamic cerebral autoregulatory capacity during changes in mean arterial pressure (MAP) remains equivocal. Using a multiple-metrics approach, challenging MAP across the spectrum of physiological extremes (i.e., spontaneous through forced MAP oscillations), we characterized dynamic cerebral autoregulatory capacity in 19 male endurance athletes and eight controls via three methods: (1) onset of regulation (i.e., time delay before an increase in middle cerebral artery (MCA) conductance [MCA blood velocity (MCAv)/MAP] and rate of regulation, after transient hypotension induced by sit-to-stand, and transfer function analysis (TFA) of MAP and MCAv responses during (2) spontaneous and (3) forced oscillations (5-min of squat-stand maneuvers performed at 0.05 and 0.10 Hz). Reductions in MAP and mean MCAv (MCAV mean ) during initial orthostatic stress (0-30 sec after sit-to-stand) and the prevalence of orthostatic hypotension were also determined. Onset of regulation was delayed after sit-to-stand in athletes (3.1 ± 1.7 vs. 1.5 ± 1.0 sec; P  = 0.03), but rate of regulation was not different between groups (0.24 ± 0.05 vs. 0.21 ± 0.09 sec -1 ; P  = 0.82). While both groups had comparable TFA metrics during spontaneous oscillations, athletes had higher TFA gain during 0.10 Hz squat-stand versus recreational controls ( P  = 0.01). Reductions in MAP ( P  = 0.15) and MCAV mean ( P  = 0.11) during orthostatic stress and the prevalence of initial orthostatic hypotension ( P  = 0.65) were comparable between groups. These results indicate an intact ability of the cerebral vasculature to react to spontaneous oscillations but an attenuated capability to counter rapid and large changes in MAP in individuals with elevated cardiorespiratory fitness., (© 2017 The Authors. Physiological Reports published by Wiley Periodicals, Inc. on behalf of The Physiological Society and the American Physiological Society.)

Exercise and exogenous heat each stimulate multiple adaptations, but their roles are not well delineated, and that of the related stressor, dehydration, is largely unknown. While severe and prolonged hypohydration potentially "silences" the long-term heat acclimated phenotype, mild and transient dehydration may enhance cardiovascular and fluid-regulatory adaptations. We tested the hypothesis that exogenous heat stress and dehydration additively potentiate acute (24 h) cardiovascular and hematological outcomes following exercise. In a randomized crossover study, 10 physically-active volunteers (mean ± SD: 173 ± 11 cm; 72.1 ± 11.5 kg; 24 ± 3 year; 6 females) completed three trials of 90-min orthostatically-stressful calisthenics, in: (i) temperate conditions (22°C, 50% rh, no airflow; CON); (ii) heat (40°C, 60% rh) whilst euhydrated (HEAT), and (iii) heat with dehydration (no fluid ~16 h before and during exercise; HEAT+DEHY). Using linear mixed effects model analyses, core temperature (T CORE ) rose 0.7°C more in HEAT than CON (95% CL: [0.5, 0.9]; p < 0.001), and another 0.4°C in HEAT+DEHY ([0.2, 0.5]; p < 0.001, vs. HEAT). Skin temperature also rose 1.2°C more in HEAT than CON ([0.6, 1.8]; p < 0.001), and similarly to HEAT+DEHY ( p = 0.922 vs. HEAT). Peak heart rate was 40 b·min -1 higher in HEAT than in CON ([28, 51]; p < 0.001), and another 15 b·min -1 higher in HEAT+DEHY ([3, 27]; p = 0.011, vs. HEAT). Mean arterial pressure at 24-h recovery was not consistently below baseline after CON or HEAT ( p ≥ 0.452), but was reduced 4 ± 1 mm Hg after HEAT+DEHY ([0, 8]; p = 0.020 vs. baseline). Plasma volume at 24 h after exercise increased in all trials; the 7% increase in HEAT was not reliably more than in CON (5%; p = 0.335), but was an additional 4% larger after HEAT+DEHY ([1, 8]; p = 0.005 vs. HEAT). Pooled-trial correlational analysis showed the rise in T CORE predicted the hypotension ( r = -0.4) and plasma volume expansion ( r = 0.6) at 24 h, with more hypotension reflecting more plasma expansion ( r = -0.5). In conclusion, transient dehydration with heat potentiates short-term (24-h) hematological (hypervolemic) and cardiovascular (hypotensive) outcomes following calisthenics.

The Near-infrared spectroscopy (NIRS) has not been adopted as a mainstream monitoring modality in acute neurosurgical care due to concerns about its reliability and consistency. However, improvements in NIRS parameter recovery techniques are now available that may improve the quantitative accuracy of NIRS for this clinical context. Therefore, the aim of this study was to compare the abilities of a continuous-wave (CW) NIRS device with a similarly clinically viable NIRS device utilising a frequency-domain (FD) parameter recovery technique in detecting changes in cerebral tissue saturation during stepwise increases of experimentally induced hypoxia. Nine healthy individuals (6M/3F) underwent a dynamic end-tidal forced manipulation of their expiratory gases to induce a stepwise induced hypoxia. The minimum end-tidal oxygen partial pressure (EtO 2 ) achieved was 40 mm Hg. Simultaneous neurological and extra-cranial tissue NIRS reading were obtained during this protocol by both tested devices. Both devices detected significant changes in cerebral tissue saturation during the induction of hypoxia (CW 9.8 ± 2.3 %; FD 7.0 ± 3.4 %; Wilcoxon signed rank test P < 0.01 for both devices). No significant difference was observed between the saturation changes observed by either device (P = 0.625). An observably greater degree of noise was noticed in parameters recovered by the FD device, and both demonstrated equally variable baseline readings (Coefficient of variance 8.4 and 9.7 % for the CW and FD devices, respectively) between individuals tested. No advantageous difference was observed in parameters recovered from the FD device compared with those detected by CW.

Introduction: Aquatic treadmills are used as a rehabilitation method for conditions such as spinal cord injury, osteoarthritis, and stroke, and can facilitate an earlier return to exercise training for athletes. However, their effect on cerebral blood flow (CBF) responses has not been examined. We tested the hypothesis that aquatic treadmill exercise would augment CBF and lower HR compared with land-based treadmill exercise., Methods: Eleven participants completed incremental exercise (crossover design) starting from walking pace (4 km·h, immersed to iliac crest [aquatic], 6 km·h [land]) and increasing 1 km·h every 2 min up to 10 km·h for aquatic (maximum belt speed) or 12 km·h for land. After this, participants completed two 2-min bouts of exercise immersed to midthigh and midchest at constant submaximal speed (aquatic), or were ramped to exhaustion (land; increased gradient 2° every min). Middle cerebral artery blood flow velocity (MCAv) and HR were measured throughout, and the initial 10 min of each protocol and responses at each immersion level were compared., Results: Compared with land-based treadmill, MCAvmean increased more from baseline for aquatic exercise (21% vs 12%, P < 0.001), while being associated with lower overall HR (pooled difference, 11 bpm; P < 0.001). MCAvmean increased similarly during aquatic walking compared with land-based moderate intensity running (~10 cm·s, P = 0.56). Greater water immersion lowered HR (139 vs 178 bpm for midchest vs midthigh), whereas MCAvmean remained constant (P = 0.37)., Conclusion: Findings illustrate the potential for aquatic treadmill exercise to enhance exercise-induced elevations in CBF and thus optimize shear stress-mediated adaptation of the cerebrovasculature.

Purpose: To compare energy use and substrate partitioning arising from repeated lower- versus upper-body sprints, or endurance exercise, across a 24-h period., Methods: Twelve untrained males (24±4 y) completed three trials in randomized order: (1) repeated sprints (five 30-s Wingate, 4.5-min recovery) on a cycle ergometer (SIT Legs ); (2) 50-min continuous cycling at 65% V̇O 2 max (END); (3) repeated sprints on an arm-crank ergometer (SIT Arms ). Respiratory gas exchange was assessed before and during exercise, and at eight points across 22h of recovery., Results: Metabolic rate was elevated to greater extent in the first 8h after SIT Legs than SIT Arms (by 0.8±1.1kJ/min, p=0.03), and tended to be greater than END (by 0.7±1.3kJ/min, p=0.08). Total 24-h energy use (exercise+recovery) was equivalent between SIT Legs and END (p = 0.55), and SIT Legs and SIT Arms (p=0.13), but 24-h fat use was higher with SIT Legs than END (by 26±38g, p=0.04) and SIT Arms (by 27±43g, p=0.05), whereas carbohydrate use was higher with SIT Arms than SIT Legs (by 32±51g, p=0.05). Plasma volume-corrected post-exercise and fasting glucose and lipid concentrations were unchanged., Conclusion: Despite much lower energy use during five sprints than 50-min continuous exercise, 24-h energy use was not reliably different. However, (i) fat metabolism was greater after sprints, and (ii) carbohydrate metabolism was greater in the hours after sprints with arms than legs, while 24-h energy usage was comparable. Thus, sprints using arms or legs may be an important adjunct exercise mode for metabolic health., (Copyright © 2016 Elsevier Inc. All rights reserved.)

What is the topic of this review? The topic of this review is to consider innovative exercise strategies that optimize neuroprotection in order to combat cognitive decline and neurodegenerative disease in older age. What advances does it highlight? The review summarizes current understanding around exercise mode, duration, frequency and intensity, and then highlights adaptive roles of select stressors that have equal if not indeed greater capacity than exercise per se to induce health-related adaptation in the brain. These stressors include, but are not exclusively limited to, hydrostatic and thermal stress, hypoxia, nutritional supplementation and cognitive loading, and are effective by targeting specific pathways that collectively contribute towards improved brain structure and function. The prevalence of cognitive decline and neurodegenerative diseases (e.g. stroke and dementia) is increasing. Numerous studies show that regular exercise has beneficial effects on brain health in clinical and non-clinical populations, yet adherence to public health exercise guidelines is notoriously poor. Recently, novel exercise strategies have been investigated to allow for more individualized and prescriptive approaches that target the key mechanistic pathways that allow exercise to mediate adaptation. This work exploring alternative approaches to the traditional model of exercise training has demonstrated exciting potential for positive health-related adaptations (especially for metabolic, muscle and cardiovascular function). However, few studies to date have focused on brain adaptations. The aim of this review is to summarize new and innovative interventions that have the potential to optimize exercise for improved brain health (i.e. brain structure and function). First, we briefly summarize current understanding of the nature whereby positive effects of exercise deliver their influence on the brain (i.e. underlying mechanisms and factors affecting its delivery). Second, we introduce the effects of exercise training on cognition and give examples of studies showing the beneficial effects of exercise in clinical populations. Finally, we explore the adaptive roles of individual stressors that may induce greater health-related adaptations in the brain than exercise alone, including environmental stressors (hydrostatic stress, thermal stress and hypoxia), nutritional supplementation and cognitive loading. In summary, optimized interventions that target key mechanistic pathways linked to improved brain structure and function could ultimately protect against and/or ameliorate cognitive decline and neurodegenerative diseases., (© 2016 The Authors. Experimental Physiology © 2016 The Physiological Society.)

Background: The hypoxic ventilatory response (HVR) at sea level (SL) is moderately predictive of the change in pulmonary artery systolic pressure (PASP) to acute normobaric hypoxia. However, because of progressive changes in the chemoreflex control of breathing and acid-base balance at high altitude (HA), HVR at SL may not predict PASP at HA. We hypothesized that resting oxygen saturation as measured by pulse oximetry (Spo₂) at HA would correlate better than HVR at SL with PASP at HA., Methods: In 20 participants at SL, we measured normobaric, isocapnic HVR (L/min · -%Spo₂⁻¹) and resting PASP using echocardiography. Both resting Spo₂ and PASP measures were repeated on day 2 (n = 10), days 4 to 8 (n = 12), and 2 to 3 weeks (n = 8) after arrival at 5,050 m. These data were also collected at 5,050 m in life-long HA residents (ie, Sherpa [n = 21])., Results: Compared with SL, Spo₂ decreased from 98.6% to 80.5% (P < .001), whereas PASP increased from 21.7 to 34.0 mm Hg (P < .001) after 2 to 3 weeks at 5,050 m. Isocapnic HVR at SL was not related to Spo₂ or PASP at any time point at 5,050 m (all P > .05). Sherpa had lower PASP (P < .01) than lowlanders on days 4 to 8 despite similar Spo₂. Upon correction for hematocrit, Sherpa PASP was not different from lowlanders at SL but was lower than lowlanders at all HA time points. At 5,050 m, although Spo₂ was not related to PASP in lowlanders at any point (all R² ≤ 0.05, P > .50), there was a weak relationship in the Sherpa (R² = 0.16, P = .07)., Conclusions: We conclude that neither HVR at SL nor resting Spo₂ at HA correlates with elevations in PASP at HA.