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Objectives: During apnea diving, a patent foramen ovale may function as a pressure relief valve under conditions of high pulmonary pressure, preserving left-ventricular output. Patent foramen ovale prevalence in apneic divers has not been previously reported. We aimed to determine the prevalence of patent foramen ovale in apneic divers compared to non-divers. Design: Cross sectional.Methods: Apnea divers were recruited from a training camp in Cavtat, Croatia and the diving community of Split, Croatia. Controls were recruited from the population of Split, Croatia and Eugene, Oregon, USA. Participants were instrumented with an intravenous catheter and underwent patent foramen ovale screening utilizing transthoracic saline contrast echocardiography. Appearance of microbubbles in the left heart within 3 cardiac cycles indicated the presence of patent foramen ovale. Lung function was measured with spirometry. Comparison of patent foramen ovale prevalence was conducted using chi-square analysis, p < .05.Results: Apnea divers had a significantly higher prevalence of patent foramen ovale (19 of 36, 53%) compared to controls (9 of 36, 25%) (X2 (1, N = 72) = 5.844, p = .0156).Conclusions: Why patent foramen ovale prevalence is greater in apnea divers remains unknown, though hyperbaria during an apnea dive results in a translocation of blood volume centrally with a concomitant reduction in lung volume and alveolar hypoxia during ascent results in hypoxic pulmonary vasoconstriction. These conditions increase pulmonary arterial pressure, increasing right-atrial pressure allowing for right-to-left blood flow through a patent foramen ovale which may be beneficial for preserving cardiac output and reducing capillary hydrostatic forces.

This study investigated trans-cerebral internal jugular venous-arterial bicarbonate ([HCO3−]) and carbon dioxide tension (PCO2) exchange utilizing two separate interventions to induce acidosis: 1) acute respiratory acidosis via elevations in arterial PCO2 (PaCO2) (n = 39); and 2) metabolic acidosis via incremental cycling exercise to exhaustion (n = 24). During respiratory acidosis, arterial [HCO3−] increased by 0.15 ± 0.05 mmol ⋅ l−1 per mmHg elevation in PaCO2 across a wide physiological range (35 to 60 mmHg PaCO2; P 3−] and PCO2 differences with respiratory acidosis were both related to the hypercapnia-induced elevations in cerebral blood flow (CBF) (both P 3−] exchange (CBF × venous-arterial [HCO3−] difference) was reduced indicating a shift from net release toward net uptake of [HCO3−] (P = 0.004). Arterial [HCO3−] was reduced by −0.48 ± 0.15 mmol ⋅ l−1 per nmol ⋅ l−1 increase in arterial [H+] with exercise-induced acidosis (P 3−] difference and arterial [H+] with exercise-induced acidosis or CBF; therefore, trans-cerebral [HCO3−] exchange was unaltered throughout exercise when indexed against arterial [H+] or pH (P = 0.933 and P = 0.896, respectively). These results indicate that increases and decreases in systemic [HCO3−] – during acute respiratory/exercise-induced metabolic acidosis, respectively – differentially affect cerebrovascular acid-base balance (via trans-cerebral [HCO3−] exchange).

KEY POINTS: High-altitude (HA) hypoxia has the potential to alter the structural-functional integrity of the neurovascular unit (NVU) in humans. For the first time, we examined to what extent chronic and lifelong hypoxia impacts multimodal biomarkers reflecting NVU structure-function in lowlanders and native Andean highlanders. Despite lowlanders presenting with a reduction in systemic oxidative-nitrosative stress and maintained cerebral bioenergetic and cerebrovascular function during chronic hypoxia, there was evidence for increased axonal injury and cognitive impairment. Compared to lowlanders at sea-level, highlanders exhibited elevated vascular NO bioavailability, improved dynamic regulatory capacity and cerebrovascular reactivity, comparable cerebral substrate delivery, neurovascular coupling and maintained cognition. Unlike lowlanders following chronic-HA, highlanders presented with lower concentrations of S100B, neurofilament-light chain and total-tau. These findings highlight novel integrated adaptations towards the regulation of the NVU in highlanders that may represent a neuroprotective phenotype underpinning successful adaptation to the lifelong stress of HA hypoxia.ABSTRACT: High-altitude (HA) hypoxia may alter the structural-functional integrity of the neurovascular unit (NVU). Herein, we compared male lowlanders (n = 9) at sea-level (SL) and after 14-days acclimatization to 4,300 m (chronic HA) in Cerro de Pasco (CdP), Peru (HA), against sex, age and body mass index-matched healthy highlanders (n = 9) native to CdP (lifelong-HA). Serum proteins were examined to reflect NVU integrity and venous blood assayed for free radicals and nitric oxide (NO). Regional cerebral blood flow (CBF) was examined in conjunction with cerebral substrate delivery, dynamic cerebral autoregulation (dCA), cerebrovascular reactivity to carbon dioxide (CVRCO2 ) and neurovascular coupling (NVC). Psychomotor tests were employed to examine cognitive function. Compared to lowlanders at SL, highlanders exhibited elevated plasma and red blood cell NO bioavailability (P = 0.005, d = 1.549 and P = 0.003, d = 1.681), improved anterior and posterior dCA (low frequency Gain: P = 0.029, d = -1.292 and P = 0.017, d = -1.255 respectively), elevated anterior CVRCO2 (P = 0.113, d = -0.852) and preserved cerebral substrate delivery and NVC (all P = >0.100). In highlanders, S100B, neurofilament light-chain and T-tau were consistently lower (P = 0.018, d = -1.244, P = 0.037, d = -1.075 and P = 0.100) to lowlanders following chronic-HA. These findings highlight novel integrated adaptations towards regulation of the NVU in highlanders that may represent a neuroprotective phenotype underpinning successful adaptation to the lifelong stress of HA hypoxia. Abstract figure legend We determined how the hypoxia of high-altitude across the temporal continuum of chronic through to lifelong exposure impacts the neurovascular unit (NVU) phenotype and to what extent this is subject to altered redox homeostasis. Basal multimodal biomarkers reflecting NVU structure-function were determined in lowlanders at sea-level (lifelong normoxia) and after 2 weeks acclimatization to 4,300 m (chronic hypoxia) in Cerro de Pasco, Peru (CdP) and compared to age/sex-matched highlanders native to CdP (lifelong hypoxia). Compared to acclimatized lowlanders, highlanders were characterized by elevated systemic nitric oxide (NO) bioavailability, improved dynamic cerebral autoregulation (dCA) and cerebrovascular reactivity to carbon dioxide (CVRCO2 ) and lower concentrations of S100B, neurofilament-light chain (NF-L) and total tau (T-Tau) in the face of preserved cerebral bioenergetics and cognition. Collectively, our novel findings tentatively suggest that these integrated adaptations may collectively reflect a neuroprotective phenotype to cope with the lifelong stress of high-altitude hypoxia. MCA, middle cerebral artery; PCA, posterior cerebral artery; ICA, internal carotid artery; VA, vertebral artery.

New findings What is the central question of this study? During a steady-state cerebrovascular CO2 reactivity test, do different data extraction time points change the outcome for cerebrovascular CO2 reactivity? What is the main finding and its importance? Once steady-state end-tidal pressure of CO2 and haemodynamics were achieved, cerebral blood flow was stable, and so cerebrovascular CO2 reactivity values remained unchanged regardless of data extraction length (30 vs. 60 s) and time point (at 2-5 min). Abstract This study assessed cerebrovascular CO2 reactivity (CVR) and examined data extraction time points and durations with the hypotheses that: (1) there would be no difference in CVR values when calculated with cerebral blood flow (CBF) measures at different time points following the attainment of physiological steady-state, (2) once steady-state was achieved there would be no difference in CVR values derived from 60 to 30 s extracted means, and (3) that changes in V E would not be associated with any changes in CVR. We conducted a single step iso-oxic hypercapnic CVR test using dynamic end-tidal forcing (end-tidal P C O 2 , +9.4 ± 0.7 mmHg), and transcranial Doppler and Duplex ultrasound of middle cerebral artery (MCA) and internal carotid artery (ICA), respectively. From the second minute of hypercapnia onwards, physiological steady-state was apparent, with no subsequent changes in end-tidal P C O 2 , P O 2 or mean arterial pressure. Therefore, CVR measured in the ICA and MCA was stable following the second minute of hypercapnia onwards. Data extraction durations of 30 or 60 s did not give statistically different CVR values. No differences in CVR were detected following the second minute of hypercapnia after accounting for mean arterial pressure via calculated conductance or covariation of mean arterial pressure. These findings demonstrate that, provided the P C O 2 stimulus remains in a steady-state, data extracted from any minute of a CVR test during physiological steady-state conditions produce equivalent CVR values; any change in the CVR value would represent a failure of CVR mechanisms, a change in the magnitude of the stimulus, or measurement error.

KEY POINTS We investigated the influence of arterial PCO2 ( PaCO2 ) with and without acute experimental metabolic alkalosis on neurovascular coupling (NVC). We assessed stepwise iso-oxic alterations in PaCO2 prior to and following intravenous NaHCO3 to acutely elevate arterial pH and [HCO3- ]. The NVC response was not altered following NaHCO3 between stepwise PaCO2 stages; therefore, NVC is acutely mediated by PaCO2 rather than the prevailing arterial [H+ ]/pH. The NVC response was attenuated by 27-38% with -10 mmHg PaCO2 and the absolute peak change was reduced by -19% with +10 mmHg PaCO2 irrespective of acutely elevated arterial pH/[HCO3- ]. The NVC kinetics (i.e. time to peak) were markedly slower with hypercapnia versus hypocapnia (24 ± 5 vs. 7 ± 5 s, respectively) likely indicating an influence of resting cerebrovascular tone on NVC responsiveness. ABSTRACT Elevations in cerebral metabolism necessitate appropriate coordinated and localized increases in cerebral blood flow (i.e. neurovascular coupling; NVC). Recent pre-clinical work indicates that arterial PCO2 ( PaCO2 ) mediates NVC independently of arterial/extracellular pH; this has yet to be experimentally tested in humans. The goal of this study was to investigate the hypotheses that: (1) the NVC response would be unaffected by acute experimentally elevated arterial pH; rather, PaCO2 would regulate any changes in NVC; and (2) stepwise respiratory alkalosis and acidosis would each progressively reduce the NVC response. Ten healthy males completed a standardized visual stimulus-evoked NVC test during matched stepwise iso-oxic alterations in PaCO2 (hypocapnia: -5, -10 mmHg; hypercapnia: +5, +10 mmHg) prior to and following intravenous NaHCO3 (8.4%, 50 mEq/50 ml) that elevated arterial pH (7.406 ± 0.019 vs. 7.457 ± 0.029; P 0.05) irrespective of the higher pH (P = 0.002) at each matched stage of PaCO2 (P = 0.417). The absolute peak change was reduced by -19 ± 41% with +10 mmHg PaCO2 irrespective of acutely elevated arterial pH/[HCO3- ] (stage post hoc: P = 0.022). The NVC kinetics (i.e. time to peak) were markedly slower with hypercapnia versus hypocapnia (24 ± 5 vs. 7 ± 5 s, respectively; stage effect: P

KEY POINTS We investigated the influence of arterial PCO2 (PaCO2 ) with and without experimentally altered pH on cerebral blood flow (CBF) regulation at sea level and with acclimatization to 5050 m. At sea level and high altitude, we assessed stepwise alterations in PaCO2 following metabolic acidosis (via 2 days of oral acetazolamide; ACZ) with and without acute restoration of pH (via intravenous sodium bicarbonate; ACZ+HCO3- ). Total resting CBF was unchanged between trials at each altitude even though arterial pH and [HCO3- ] (i.e. buffering capacity) were effectively altered. The cerebrovascular responses to changes in arterial [H+ ]/pH were consistent with the altered relationship between PaCO2 and [H+ ]/pH following ACZ at high altitude (i.e. leftward x-intercept shifts). Absolute cerebral blood velocity (CBV) and the sensitivity of CBV to PaCO2 was unchanged between trials at high altitude, indicating that CBF is acutely regulated by PaCO2 rather than arterial pH. ABSTRACT Alterations in acid-base balance with progressive acclimatization to high altitude have been well-established. However, how respiratory alkalosis and the resultant metabolic compensation interact to regulate cerebral blood flow (CBF) is uncertain. We addressed this via three separate experimental trials at sea level and following partial acclimatization (14 to 20 days) at 5050 m; involving: (1) resting acid-base balance (control); (2) following metabolic acidosis via 2 days of oral acetazolamide at 250 mg every 8 h (ACZ; pH: Δ -0.07 ± 0.04 and base excess: Δ -5.7 ± 1.9 mEq⋅l-1 , trial effects: P < 0.001 and P < 0.001, respectively); and (3) after acute normalization of arterial acidosis via intravenous sodium bicarbonate (ACZ + HCO3- ; pH: Δ -0.01 ± 0.04 and base excess: Δ -1.5 ± 2.1 mEq⋅l-1 , trial effects: P = 1.000 and P = 0.052, respectively). Within each trial, we utilized transcranial Doppler ultrasound to assess the cerebral blood velocity (CBV) response to stepwise alterations in arterial PCO2 (PaCO2 ), i.e. cerebrovascular CO2 reactivity. Resting CBF (via Duplex ultrasound) was unaltered between trials within each altitude, indicating that respiratory compensation (i.e. Δ -3.4 ± 2.3 mmHg PaCO2 , trial effect: P < 0.001) was sufficient to offset any elevations in CBF induced via the ACZ-mediated metabolic acidosis. Between trials at high altitude, we observed consistent leftward shifts in both the PaCO2 -pH and CBV-pH responses across the CO2 reactivity tests with experimentally reduced arterial pH via ACZ. When indexed against PaCO2 - rather than pH - the absolute CBV and sensitivity of CBV-PaCO2 was unchanged between trials at high altitude. Taken together, following acclimatization, CO2 -mediated changes in cerebrovascular tone rather than arterial [H+ ]/pH is integral to CBF regulation at high altitude.

New findings What is the topic of this review? Cerebrovascular reactivity to CO2 is a principle factor in determining ventilatory responses to CO2 through the role reactivity plays in determining cerebral extra- and intra-cellular pH. What advances does it highlight? Recent animal evidence suggests central chemoreceptor vasculature may demonstrate regionally heterogenous cerebrovascular reactivity to CO2 , potentially as a protective mechanism against excessive CO2 washout from the central chemoreceptors, thereby allowing ventilation to reflect the systemic acid-base balance needs (respiratory changes in PaCO2 ) rather than solely the cerebral needs. Ventilation per se does not influence cerebrovascular reactivity independent of changes in PaCO2 . Abstract Alveolar ventilation and cerebral blood flow are both predominantly regulated by arterial blood gases, especially arterial PCO2 , and so are intricately entwined. In this review, the fundamental mechanisms underlying cerebrovascular reactivity and central chemoreceptor control of breathing are covered. We discuss the interaction of cerebral blood flow and its reactivity with the control of ventilation and ventilatory responsiveness to changes in PCO2 , as well as the lack of influence of ventilation itself on cerebrovascular reactivity. We briefly summarize the effects of arterial hypoxaemia on the relationship between ventilatory and cerebrovascular response to both PCO2 and PO2 . We then highlight key methodological considerations regarding the interaction of reactivity and ventilatory sensitivity, including: regional heterogeneity of cerebrovascular reactivity; a pharmacological approach for the reduction of cerebral blood flow; reactivity assessment techniques; the influence of mean arterial blood pressure; and sex-related differences. Finally, we discuss ventilatory and cerebrovascular control in the context of high altitude and congestive heart failure. Future research directions and pertinent questions of interest are highlighted throughout. This article is protected by copyright. All rights reserved.

In this case study, we evaluate the unique physiological profiles of two world-champion breath-hold divers. At close to current world- record depths, the extreme physiological responses to both exercise and asphyxia during progressive elevations in hydrostatic pressure are profound. As such, these professional athletes must be capable of managing such stress, to maintain performing at the forefront human capacity. In both divers, pulmonary function before and after deep dives to 102 m and 117 m in the open sea was assessed using noninvasive pulmonary gas exchange (indexed via the O-2 deficit, which is analogous to the traditional alveolar to arterial oxygen difference), ultrasound B-line scores, airway resistance, and airway reactance. Hydrostatic- induced lung compression was also quantified via spirometry. Both divers successfully performed their dives. Pulmonary gas exchange efficiency was impaired in both divers at 10 min but had mostly restored within a few hours. Mild hemoptysis was transiently evident immediately following the 117- m dive, whereas both divers experienced nitrogen narcosis. Although B-lines were only elevated in one diver postdive, reductions in airway resistance and reactance occurred in both divers, suggesting that the compressive strain on the structural characteristics of the airways can persist for up to 3.5 h. Marked echocardiographic dyssynchrony was evident in one diver after 10 m of descent, which persisted until resolving at similar to 77m during ascent. In summary, despite the enormous hydrostatic and physiological stress to diving beyond 100 m on a single breath, these data provide valuable insight into the extraordinary capacity of those at the pinnacle of apneic performance. NEW & NOTEWORTHY This study shows that world-champion breath-hold divers demonstrate incredible tolerability to extreme levels of hydrostatic-induced lung compression. Immediately following dives to >100 m, there were acute impairments in pulmonary gas exchange efficiency, mild accummulation of extravascular lung fluid, noticable intrathoracic discomfort, and evident nitrogen narcosis, however, within a few hours, these had all mostly resolved.

What is the central question of this study? What are the contributions of shear stress and adrenergic tone to brachial artery vasodilatation during hypercapnia? What is the main finding and its importance? In healthy young adults, shear-mediated vasodilatation does not occur in the brachial artery during hypercapnia, as elevated α₁-adrenergic activity typically maintains vascular tone and offsets distal vasodilatation controlling flow.We aimed to assess the shear stress dependency of brachial artery (BA) responses to hypercapnia, and the α₁-adrenergic restraint of these responses. We hypothesized that elevated shear stress during hypercapnia would cause BA vasodilatation, but where shear stress was prohibited (via arterial compression), the BA would not vasodilate (study 1); and, in the absence of α₁-adrenergic activity, blood flow, shear stress and BA vasodilatation would increase (study 2). In study 1, 14 healthy adults (7/7 male/female, 27 ± 4 years) underwent bilateral BA duplex ultrasound during hypercapnia (partial pressure of end-tidal carbon dioxide, +10.2 ± 0.3 mmHg above baseline, 12 min) via dynamic end-tidal forcing, and shear stress was reduced in one BA using manual compression (compression vs. control arm). Neither diameter nor blood flow was different between baseline and the last minute of hypercapnia (P = 0.423, P = 0.363, respectively) in either arm. The change values from baseline to the last minute, in diameter (%; P = 0.201), flow (ml/min; P = 0.234) and conductance (ml/min/mmHg; P = 0.503) were not different between arms. In study 2, 12 healthy adults (9/3 male/female, 26 ± 4 years) underwent the same design with and without α₁-adrenergic receptor blockade (prazosin; 0.05 mg/kg) in a placebo-controlled, double-blind and randomized design. BA flow, conductance and shear rate increased during hypercapnia in the prazosin control arm (interaction, P 0.001), but in neither arm during placebo. Even in the absence of α₁-adrenergic restraint, downstream vasodilatation in the microvasculature during hypercapnia is insufficient to cause shear-mediated vasodilatation in the BA.

Key points Preclinical models have demonstrated that nitric oxide is a key component of neurovascular coupling; this has yet to be translated to humans. We conducted two separate protocols utilizing intravenous infusion of a nitric oxide synthase inhibitor and isovolumic haemodilution to assess the influence of nitric oxide on neurovascular coupling in humans. Isovolumic haemodilution did not alter neurovascular coupling. Intravenous infusion of a nitric oxide synthase inhibitor reduced the neurovascular coupling response by ∼30%, indicating that nitric oxide is integral to neurovascular coupling in humans. Abstract Nitric oxide is a vital neurovascular signalling molecule in preclinical models, yet the mechanisms underlying neurovascular coupling (NVC) in humans have yet to be elucidated. To investigate the contribution of nitric oxide to NVC in humans, we utilized a visual stimulus paradigm to elicit an NVC response in the posterior cerebral circulation. Two distinct mechanistic interventions were conducted on young healthy males: (1) NVC was assessed during intravenous infusion of saline (placebo) and the non-selective competitive nitric oxide synthase inhibitor NG -monomethyl-l-arginine (l-NMMA, 5 mg kg-1 bolus & subsequent 50 μg kg-1 min-1 maintenance dose; n = 10). The order of infusion was randomized, counterbalanced and single blinded. A subset of participants in this study (n = 4) underwent a separate intervention with phenylephrine infusion to independently consider the influence of blood pressure changes on NVC (0.1-0.6 μg kg-1 min-1 constant infusion). (2) NVC was assessed prior to and following isovolumic haemodilution, whereby 20% of whole blood was removed and replaced with 5% human serum albumin to reduce haemoglobin concentration (n = 8). For both protocols, arterial and internal jugular venous blood samples were collected at rest and coupled with volumetric measures of cerebral blood flow (duplex ultrasound) to quantify resting cerebral metabolic parameters. l-NMMA elicited a 30% reduction in the peak (P = 0.01), but not average (P = 0.11), NVC response. Neither phenylephrine nor haemodilution influenced NVC. Nitric oxide signalling is integral to NVC in humans, providing a new direction for research into pharmacological treatment of humans with dementia.

New findings What is the central question of this study? What are the characteristics of cerebral blood flow (CBF) regulation following a single SCUBA dive to a depth of 18 m sea water with a 47 min bottom time. What is the main finding and its importance? Acute alterations in CBF regulation at rest, including extra-cranial vasodilatation, reductions in shear patterns and elevations in intra-cranial blood velocity were observed at rest following a single SCUBA dive. These subtle changes in CBF regulation did not translate into any functional changes in cerebrovascular reactivity to hypoxia or hyperoxia, or neurovascular coupling following a single SCUBA dive. Abstract Reductions in vascular function during a SCUBA dive - due to hyperoxia-induced oxidative stress, arterial and venous gas emboli and altered endothelial integrity - may also extend to the cerebrovasculature following return to the surface. This study aimed to characterize cerebral blood flow (CBF) regulation following a single SCUBA dive to a depth of 18 m sea water with a 47 min bottom time. Prior to and following the dive, participants (n = 11) completed (1) resting CBF in the internal carotid (ICA) and vertebral (VA) arteries (duplex ultrasound) and intra-cranial blood velocity (v) of the middle and posterior cerebral arteries (MCAv and PCAv, respectively) (transcranial Doppler ultrasound); (2) cerebrovascular reactivity to acute poikilocapnic hypoxia (i.e. F I O 2 , 0.10) and hyperoxia (i.e. F I O 2 , 1.0); and (3) neurovascular coupling (NVC; regional CBF response to local increases in cerebral metabolism). Global CBF, cerebrovascular reactivity to hypoxia and hyperoxia, and NVC were unaltered following a SCUBA dive (all P > 0.05); however, there were subtle changes in other cerebrovascular metrics post-dive, including reductions in ICA (-13 ± 8%, P = 0.003) and VA (-11 ± 14%, P = 0.021) shear rate, lower ICAv (-10 ± 9%, P = 0.008) and VAv (-9 ± 14%, P = 0.028), increases in ICA diameter (+4 ± 5%, P = 0.017) and elevations in PCAv (+10 ± 19%, P = 0.047). Although we observed subtle alterations in CBF regulation at rest, these changes did not translate into any functional changes in cerebrovascular reactivity to hypoxia or hyperoxia, or NVC. Whether prolonged exposure to hyperoxia and hyperbaria during longer, deeper, colder and/or repetitive SCUBA dives would provoke changes to the cerebrovasculature requires further investigation.

New findings What is the central question of this study? Do differing magnitudes of ventilation influence cerebrovascular CO2 reactivity and the cerebral blood flow response to increases in arterial carbon dioxide? What is the main finding and its importance? While a greater ventilation, through voluntary hyperventilation, is associated with a higher anterior cerebral blood flow during carbon dioxide breathing, this elevated cerebral blood flow is due to a higher blood pressure and not ventilation per se. A greater ventilation, through voluntary hyperventilation, does not influence global or posterior cerebral blood flow during carbon dioxide breathing. Cerebrovascular reactivity to carbon dioxide is not influenced by an individual's ventilatory sensitivity to carbon dioxide. Abstract Recent work demonstrated an influence of ventilation on cerebrovascular reactivity to CO2 ; however, the concomitant influence of changes in mean arterial blood pressure (MAP) on ventilation-induced differences in cerebral blood flow (CBF) has yet to be examined in this context. Healthy participants (n = 15; 25 ± 3 years of age; 179 ± 6 cm height; 74 ± 10 kg weight; 3 female) underwent end-tidal forcing to increase their partial pressure of end-tidal CO2 by +3, +6 and +9 mmHg above baseline in 5-min sequential steps while maintaining iso-oxia. This protocol was then repeated twice, with participants hyperventilating and hypoventilating by ∼30% compared to the first trial. Intra-cranial and extra-cranial CBF were measured using ultrasound. The MAP (finger photo-plethysmography) was higher during the hyperventilation and hypoventilation trials compared to normal ventilation (main effects, P 0.05 for all). Retrospective analysis of a larger data set (n = 53) confirmed these observations and demonstrated no relationships between the ventilatory and global CBF response to hypercapnia (r2 = 0.04; P = 0.14). Therefore, when differences in MAP are accounted for, cerebrovascular CO2 reactivity (assessed via end-tidal forcing) is independent of the magnitude of ventilation.

Cerebral hypoxic vasodilation is poorly understood in humans, which undermines the development of therapeutics to optimize cerebral oxygen delivery. Across four investigations (total n = 195) we investigated the role of nitric oxide (NO) and hemoglobin-based S-nitrosothiol (RSNO) and nitrite ([Formula: see text]) signaling in the regulation of cerebral hypoxic vasodilation. We conducted hemodilution (n = 10) and NO synthase inhibition experiments (n = 11) as well as hemoglobin oxygen desaturation protocols, wherein we measured cerebral blood flow (CBF), intra-arterial blood pressure, and in subsets of participants trans-cerebral release/uptake of RSNO and [Formula: see text]. Higher CBF during hypoxia was associated with greater trans-cerebral RSNO release but not [Formula: see text], while NO synthase inhibition reduced cerebral hypoxic vasodilation. Hemodilution increased the magnitude of cerebral hypoxic vasodilation following acute hemodilution, while in 134 participants tested under normal conditions, hypoxic cerebral vasodilation was inversely correlated to arterial hemoglobin concentration. These studies were replicated in a sample of polycythemic high-altitude native Andeans suffering from excessive erythrocytosis (n = 40), where cerebral hypoxic vasodilation was inversely correlated to hemoglobin concentration, and improved with hemodilution (n = 6). Collectively, our data indicate that cerebral hypoxic vasodilation is partially NO-dependent, associated with trans-cerebral RSNO release, and place hemoglobin-based NO signaling as a central mechanism of cerebral hypoxic vasodilation in humans.

This study investigated trans-cerebral internal jugular venous-arterial bicarbonate ([HCO

Cerebrovascular CO

Study design Experimental study. Objectives Compromised cerebrovascular function likely contributes to elevated neurological risk in spinal cord injury (SCI). Passive heating offers many cardiovascular and neurological health benefits ; therefore, we aimed to determine the effects of an acute bout of heating on cerebrovascular function in chronic SCI. Methods Persons with cervical SCI (n = 15) and uninjured controls (CON ; n = 15) completed 60 min of lower limb hot water immersion (40 degrees C). Assessments of middle cerebral (MCA) and posterior cerebral artery (PCA) velocities, pulsatilities, and neurovascular coupling (NVC) were performed using transcranial Doppler ultrasound. Duplex ultrasonography was used to index cerebral blood flow via the internal carotid artery (ICA), and carotid-femoral pulse-wave velocity (PWV) was measured using tonometry. The NVC response was quantified as the peak hyperemic value during 30-s cycles of visual stimulation. Results Mean arterial pressure changed differentially with heating [mean (standard deviation) ; SCI: +6(14) mmHg, CON: -8(12) mmHg ; P = 0 .01]. There were no differences in any intracranial artery measures (all P > 0.05), except for small (similar to 10%) increases in MCA conductance in CON after heating vs. SCI (interaction P = 0.006). Resting ICA flow was greater in SCI vs. CON (P = 0.03) but did not change with heating in either group (interaction P = 0.34). There were also no between-group differences in the NVC response (Delta PCA conductance) pre- [SCI: 29(19)% vs. CON: 30(9)%] or post-heating [SCI 30(9)% vs. 25(9)% ; interaction P = 0.22]. Conclusions Mild acute heating does not impair or improve cerebrovascular function in SCI or CON. Thus, further study of the effects of chronic heating interventions are warranted.

What is the central question of this study? During a steady-state cerebrovascular COThis study assessed cerebrovascular CO

The regulation and defense of intracellular pH is essential for homeostasis. Indeed, alterations in cerebrovascular acid-base balance directly affect cerebral blood flow (CBF) which has implications for human health and disease. For example, changes in CBF regulation during acid-base disturbances are evident in conditions such as chronic obstructive pulmonary disease and diabetic ketoacidosis. The classic experimental studies from the past 75+ years are utilized to describe the integrative relationships between CBF, carbon dioxide tension (PCO2 ), bicarbonate (HCO3 - ), and pH. These factors interact to influence 1) the time course of acid-base compensatory changes and the respective cerebrovascular responses (due to rapid exchange kinetics between arterial, extracellular fluid, and intracellular brain tissue). We propose that alterations in arterial [HCO3 - ] during acute respiratory acidosis/alkalosis contribute to cerebrovascular acid-base regulation; and 2) the regulation of CBF by direct changes in arterial versus extravascular/ interstitial PCO2 and pH - the latter recognized as the proximal compartment which alters vascular smooth muscle cell regulation of CBF. Taken together, these results substantiate two key ideas: first, that the regulation of CBF is affected by the severity of metabolic/respiratory disturbances, including the extent of partial/full acid-base compensation. Second, that the regulation of CBF is independent of arterial pH and that diffusion of CO2 across the blood-brain barrier is integral to altering perivascular extracellular pH. Overall, by realizing the integrative relationships between CBF, PCO2 , HCO3 - , and pH, experimental studies may provide insights to improve CBF regulation in clinical practice with treatment of systemic acid-base disorders. This article is protected by copyright. All rights reserved.

Adults with obesity are at increased risk of neurocognitive impairments, partly as a result of reduced cerebral blood flow and brain-derived neurotrophic factor (BDNF). Ketone supplements containing β-hydroxybutyrate (β-OHB) are a purported therapeutic strategy for improving brain health in at-risk populations. We tested the hypothesis that short-term β-OHB supplementation will elevate cerebral blood flow and BDNF, as well as improve cognition in adults with obesity. In a placebo-controlled double-blind, cross-over design, 14 adults with obesity (10 females; aged 56 ± 12 years; body mass index = 33.8 ± 6.9 kg m-2 ) consumed 30 mL (12 g) of β-OHB or placebo thrice-daily for 14 days. Blood flow (Q) and cerebrovascular conductance (CVC) were measured in the common carotid (CCA), internal carotid (ICA) and vertebral (VA) arteries by duplex ultrasound. BDNF was measured by an enzyme-linked immunosorbent assay. Cognition was assessed by the digit-symbol substitution (DSST), Stroop and task-switching tests. Following 14 days of ketone supplementation, we observed significant improvements in cerebrovascular outcomes including QCCA (+12%), QVA (+11%), VACVC (+12%) and VA shear rate (+10%). DSST performance significantly improved following ketone supplementation (+2.7 correct responses) and improved DSST performance was positively associated improvements in cerebrovascular outcomes including QCCA , CCACVC , QVA and VACVC . By contrast to one hypothesis, β-OHB did not impact fasting serum and plasma BDNF. β-OHB supplementation improved cognition in adults with obesity, which may be partly facilitated by improvements in cerebral blood flow. β-OHB supplementation was well-tolerated and appears to be safe for cerebrovascular health, suggesting potential therapeutic benefits of β-OHB in a population at risk of neurocognitive impairment. KEY POINTS: People with obesity are at increased risk of neurocognitive dysfunction, partly as a result of -induced reductions in cerebral blood flow (CBF) and brain-derived neurotrophic factor (BDNF). Ketone supplements containing β-hydroxybutyrate (β-OHB) reduce postprandial hyperglycaemia, which may increase CBF and BDNF, thereby protecting against obesity-related cognitive dysfunction. We show for the first time that 14 days of thrice-daily β-OHB supplementation improves aspects of cognition and increases cerebrovascular flow, conductance and shear rate in the extracranial arteries of adults with obesity. Our preliminary data indicate a significant positive relationship between elevated CBF and improved cognition following β-OHB supplementation. This trial provides a foundation for the potential non-pharmacological therapeutic application of β-OHB supplementation in patient groups at risk of hyperglycaemic cerebrovascular disease and cognitive dysfunction.

We investigated the influence of arterialElevations in cerebral metabolism necessitate appropriate coordinated and localized increases in cerebral blood flow (i.e. neurovascular coupling; NVC). Recent pre-clinical work indicates that arterial

We investigated the influence of arterial PCOAlterations in acid-base balance with progressive acclimatization to high altitude have been well-established. However, how respiratory alkalosis and the resultant metabolic compensation interact to regulate cerebral blood flow (CBF) is uncertain. We addressed this via three separate experimental trials at sea level and following partial acclimatization (14 to 20 days) at 5050 m; involving: (1) resting acid-base balance (control); (2) following metabolic acidosis via 2 days of oral acetazolamide at 250 mg every 8 h (ACZ; pH: Δ -0.07 ± 0.04 and base excess: Δ -5.7 ± 1.9 mEq⋅l

New Findings What is the central question of this study? How does deep breath-hold diving impact cardiopulmonary function, both acutely and over the subsequent 2.5 hours post-dive? What is the main finding and its importance? Breath-hold diving, to depths below residual volume, is associated with acute impairments in pulmonary gas exchange, which typically resolve within 2.5 hours. These data provide new insight into the behaviour of the lungs and pulmonary vasculature following deep diving. Breath-hold diving involves highly integrative and extreme physiological responses to both exercise and asphyxia during progressive elevations in hydrostatic pressure. Over two diving training camps (Study 1 and 2), 25 breath-hold divers (recreational to world- champion) performed 66 dives to 57 +/- 20 m (range: 18-117 m). Using the deepest dive from each diver, temporal changes in cardiopulmonary function were assessed using non-invasive pulmonary gas exchange (indexed via the O-2 deficit), ultrasound B-line scores, lung compliance and pulmonary haemodynamics at baseline and following the dive. Hydrostatically induced lung compression was quantified in Study 2, using spirometry and lung volume measurement, enabling each dive to be categorized by its residual volume (RV)-equivalent depth. From both studies, pulmonary gas exchange inefficiency - defined as an increase in O-2 deficit - was related to the depth of the dive (r(2 )= 0.345 ; P < 0.001), with dives associated with lung squeeze symptoms exhibiting the greatest deficits. In Study 1, although B-lines doubled from baseline (P = 0.027), cardiac output and pulmonary artery systolic pressure were unchanged post-dive. In Study 2, dives with lung compression to

Healthy males (n = 10; age: 24 ± 4 years; body mass index: 24 ± 2 kg·m−2) completed 2 randomized conditions separated by ≥48 h involving 6–8.5 h of sitting with (“stair snacks”) and without (sedentary) hourly staircase sprint interval exercise (∼14–20 s each). Resting blood flow and shear rates were measured in the femoral artery, internal carotid artery, and vertebral artery (Duplex ultrasound). Flow-mediated dilation (FMD) was quantified as an index of peripheral endothelial function in the femoral artery. Neurovascular coupling (NVC; regional blood flow response to local increases in cerebral metabolism) was assessed in the posterior cerebral artery (transcranial Doppler ultrasound). Femoral artery hemodynamics were higher following the active trial with no change in the sedentary trial, including blood flow (+32 ± 23% vs. −10 ± 28%; P = 0.015 and P = 0.253, respectively), vascular conductance (+32 ± 27% vs. −15 ± 26%; P = 0.012 and P = 0.098, respectively), and mean shear rate (+17 ± 8% vs. −8 ± 28%; P = 0.004 and P = 0.310, respectively). The change in FMD was not different within or between conditions (P = 0.184). Global cerebral blood flow (CBF), conductance, shear patterns, and NVC were not different within or between conditions (all P > 0.05). Overall, exercise “stair snacks” improve femoral artery blood flow and shear patterns but not peripheral (e.g., FMD) or cerebral (e.g., CBF and NVC) vascular function following prolonged sitting. The study was registered at ClinicalTrials.gov (NCT03374436). Novelty: Breaking up 8.5 h of sitting with hourly staircase sprinting exercise “snacks” improves resting femoral artery shear patterns but not FMD. Cerebral blood flow and neurovascular coupling were unaltered following 6 h of sitting with and without hourly exercise breaks.

Key points We investigated the influence of arterial P C O 2 ( P aC O 2 ) with and without acutely elevated arterial pH and bicarbonate ([HCO3 - ]) on cerebral blood flow (CBF) regulation in the internal carotid artery and vertebral artery. We assessed stepwise iso-oxic alterations in P aC O 2 (i.e. cerebrovascular CO2 reactivity) prior to and following i.v. sodium bicarbonate infusion (NaHCO3 - ) to acutely elevate arterial pH and [HCO3 - ]. Total CBF was unchanged irrespective of a higher arterial pH at each matched stage of P aC O 2 , indicating that CBF is acutely regulated by P aC O 2 rather than arterial pH. The cerebrovascular responses to changes in arterial H+ /pH were altered in keeping with the altered relationship between P aC O 2 and H+ /pH following NaHCO3 - infusion (i.e. changes in buffering capacity). Total CBF was ∼7% higher following NaHCO3 - infusion during isocapnic breathing providing initial evidence for a direct vasodilatory influence of HCO3 - independent of P aC O 2 levels. Abstract Cerebral blood flow (CBF) regulation is dependent on the integrative relationship between arterial P C O 2 ( P aC O 2 ), pH and cerebrovascular tone; however, pre-clinical studies indicate that intrinsic sensitivity to pH, independent of changes in P aC O 2 or intravascular bicarbonate ([HCO3 - ]), principally influences cerebrovascular tone. Eleven healthy males completed a standardized cerebrovascular CO2 reactivity (CVR) test utilizing radial artery catheterization and Duplex ultrasound (CBF); consisting of matched stepwise iso-oxic alterations in P aC O 2 (hypocapnia: -5, -10 mmHg; hypercapnia: +5, +10 mmHg) prior to and following i.v. sodium bicarbonate (NaHCO3 - ; 8.4%, 50 mEq 50 mL-1 ) to elevate pH (7.408 ± 0.020 vs. 7.461 ± 0.030; P P aC O 2 (P = 0.927). Neither hypocapnic (3.44 ± 0.92 vs. 3.44 ± 1.05% per mmHg P aC O 2 ; P = 0.499), nor hypercapnic (7.45 ± 1.85 vs. 6.37 ± 2.23% per mmHg P aC O 2 ; P = 0.151) reactivity to P aC O 2 were altered pre- to post-NaHCO3 - . When indexed against arterial [H+ ], the relative hypocapnic CVR was higher (P = 0.019) and hypercapnic CVR was lower (P = 0.025) following NaHCO3 - , respectively. These changes in reactivity to [H+ ] were, however, explained by alterations in buffering between P aC O 2 and arterial H+ /pH consequent to NaHCO3 - . Lastly, CBF was higher (688 ± 105 vs. 732 ± 89 mL min-1 , 7% ± 12%; P = 0.047) following NaHCO3 - during isocapnic breathing providing support for a direct influence of HCO3 - on cerebrovascular tone independent of P aC O 2 . These data indicate that in the setting of acute metabolic alkalosis, CBF is regulated by P aC O 2 rather than arterial pH.

KEY POINTS: Brachial artery (BA) shear-mediated dilation is a widely used assessment of vascular function with links to coronary artery health and cardiovascular risk. Cerebral vascular health is often interrogated using cerebrovascular (middle cerebral artery velocity) reactivity to carbon dioxide. We show that endothelium-dependent diameter (dilator) responses are not significantly related between the internal carotid artery (ICA) and BA; nor are endothelium-independent responses. Additionally, ICA endothelium-dependent responses are not related to MCA velocity or ICA blood flow reactivity responses to carbon dioxide. Therefore, assessment of large extracranial cerebral artery vascular health should be quantified via methods specific to the vessel, not via peripheral endothelial function or cerebrovascular reactivity to carbon dioxide. ABSTRACT: This study compared internal carotid artery (ICA) and brachial artery (BA) endothelium-dependent and -independent vasodilation. We hypothesized that endothelium-dependent and -independent vasodilation of the ICA and BA would be neither similar in magnitude nor correlated between vessels. In 19 healthy adults (23±6 years, 24±3 kg/m2 , 6 female), endothelium-dependent dilation in the ICA was determined via Duplex ultrasound during transiently elevated shear stress caused by increased partial pressure of end-tidal carbon dioxide using dynamic end-tidal forcing (+9mmHg; cerebral flow-mediated dilation, cFMD). BA endothelium-dependent dilation was assessed via standard flow-mediated dilation (FMD). Endothelium-independent dilation in the ICA and BA was assessed concurrently for 10-minutes following administration of 400 µg sublingual glyceryl trinitrate (GTN). Endothelium-dependent vasodilation of the ICA (3.4±2.4%) was lower than (P = 0.013) and not correlated to that of the BA (7.9±3.3%; r2 = 0.00, P = 0.93). Including baseline diameter and shear-rate area under the curve as covariates maintained the difference between cFMD and FMD (3.3±4.2 % vs. 7.8±3.8 %, P = 0.03), while including baseline diameter and baseline shear rate-adjusted area under the curve as covariates abolished it (5.9±3.7 % vs. 5.9.8±3.5 %, P = 0.99). GTN-mediated vasodilation of the ICA (14.3±2.9%) was lower than (P = 0.002) and not correlated to that of the BA (25.5±8.8%; r2 = 0.12, P = 0.19). Adjusting for baseline diameter eliminated the differences in GTN-induced vasodilation (ICA: 20.1±5.8 % vs. BA: 20.4±5.5 %; P = 0.93). Differences in endothelium-dependent responses, and the lack of correlations between arteries, indicates that endothelium-dependent function cannot be assumed to be related across cerebral and peripheral vasculatures in young, healthy humans. This article is protected by copyright. All rights reserved.

Background Exogenous ketones make it possible to reach a state of ketosis that may improve metabolic control in humans. Objectives The main objective of this study was to determine whether the ingestion of a ketone monoester (KE) drink before a 2-h oral-glucose-tolerance test (OGTT) would lower blood glucose concentrations. Secondary objectives were to determine the impact of KE on nonesterified fatty acid (NEFA) concentration and glucoregulatory hormones. Methods We conducted a randomized controlled crossover experiment in 15 individuals with obesity (mean ± SD age: 47 ± 10 y; BMI: 34 ± 5 kg/m2). After an overnight fast, participants consumed a KE drink [(R)-3-hydroxybutyl (R)-3-hydroxybutyrate; 0.45 mL/kg body weight] or taste-matched control drink 30 min before completing a 75-g OGTT. Participants and study personnel performing laboratory analyses were blinded to each condition. Results The KE increased D-β-hydroxybutyrate to a maximum of ∼3.4 mM (P < 0.001) during the OGTT. Compared with the control drink, KE reduced glucose (−11%, P = 0.002), NEFA (−21%, P = 0.009), and glucagon-like peptide 1 (−31%, P = 0.001) areas under the curve (AUCs), whereas glucagon AUC increased (+11%, P = 0.030). No differences in triglyceride, C-peptide, and insulin AUCs were observed after the KE drink. Mean arterial blood pressure decreased and heart rate increased after the KE drink (both P < 0.01). Conclusions A KE drink consumed before an OGTT lowered glucose and NEFA AUCs with no increase in circulating insulin. Our results suggest that a single drink of KE may acutely improve metabolic control in individuals with obesity. Future research is warranted to examine whether KE could be used safely to have longer-term effects on metabolic control. This trial was registered at clinicaltrials.gov as NCT03461068.

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 (Tc ; +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 Tc 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 Tc (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 QICA was unchanged with EX and HS interventions (P = 0.665), consistent with the unchanged end-tidal P C O 2 (P = 0.327); whereas, QVA 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 QVA 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 QECA increased throughout both EX and HS (EX: Δ42 ± 58% vs. HS: Δ53 ± 28%, time effect: 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.

Breath-hold diving is a ubiquitous activity, with recreational, fishing, military and competitive divers. During a dive, immersion and the increasing hydrostatic pressure of descent facilitate card...

With exposure to acute normobaric hypoxia, global cerebral oxygen delivery is maintained via increases in cerebral blood flow (CBF); therefore, regional and localized changes in oxygen tension may explain neurocognitive impairment. Neurovascular coupling (NVC) is the close temporal and regional relationship of CBF to changes in neural activity and may aid in explaining the localized CBF response with cognitive activation. High-altitude related cognitive impairment is likely affected by hypocapnic cerebral vasoconstriction that may influence regional CBF regulation independent of hypoxia. We assessed neurocognition and NVC following 30 min of acute exposure to isocapnic hypoxia (decreased partial pressure of end-tidal oxygen; PETO2) during moderate hypoxia (MOD HX; 55 mm Hg PETO2), and severe hypoxia (SEV HX; 45 mm Hg PETO2) in 10 healthy individuals (25.5 ± 3.3 yrs). Transcranial Doppler ultrasound was used to assess mean posterior and middle cerebral blood velocity (PCAv and MCAv, respectively) and neurocognitive performance was assessed via validated computerized tests. The main finding was that reaction time (i.e., kinesthetic and visual-motor ability via Stroop test) was selectively impaired in SEV HX (−4.6 ± 5.2%, P = 0.04), but not MOD HX, while complex cognitive performance (e.g., psychomotor speed, cognitive flexibility, processing speed, executive function, and motor speed) was unaffected with hypoxia (P > 0.05). Additionally, severity of hypoxia had no effect on NVC (PCAv CON vs. SEV HX relative peak response 13.7 ± 6.4% vs. 16.2 ± 11.5%, P = 0.71, respectively). In summary, severe isocapnic hypoxia impaired reaction time, but not complex cognitive performance or NVC. These findings have implications for recreational and military personnel who may experience acute hypoxia.

Hypoxia-induced neurocognitive impairments have been of clinical interest for centuries. The mechanisms responsible for these neurocognitive impairments at altitude are unclear, but may relate to the uncoupling of local neural activity with appropriate changes in cerebral blood flow (CBF; i.e., functional hyperemia). At both sea level and following 3 and 7days at 3800m (Barcroft Research Lab, White Mountain, CA, USA), transcranial Doppler was used to index CBF during three separate tasks designed to evoke cerebral functional hyperemia in 11 healthy individuals (26.6±5.5yrs, 2 females). The tasks were: 1) Visual stimulation (VS), with measurement of anterior and posterior CBF; 2) Verbal fluency (VF), with measurement of bilateral CBF; and 3) Visuospatial task (VST), with measurement of bilateral CBF. The VS evoked an increase from baseline to percent peak response in both the posterior (15.2±7.7%, P0.01) and anterior (7.6±3.5%, P0.01) cerebral hemispheres; however, the percent peak response was higher in the posterior brain, where visual regions are localized (P=0.01). The left-sided task, VF, resulted in an increase in both the left (12.2±4.0%, P0.01) and right (9.0±4.4%, P0.01) cerebral hemispheres; however, the percent peak response was higher in the left brain, where language centers are located (P0.01). The right-sided task, VST, evoked an increase in both the left (13.9±7.1%, P0.01) and right (16.8±6.7%, P0.01) cerebral hemispheres; however, the percent peak response was higher in the right brain, where visuospatial regions are located (P0.01). Each cerebral functional hyperemia response for all three tasks was unaffected by high altitude exposure (P0.05). Overall, at least at 3800m, neurovascular function is intact with exposure to 3 and 7days of high altitude and likely does not explain the previous reports of neurocognitive impairment.