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Key points Diabetes is associated with cognitive impairment, but the underlying mechanism remains unclear. Methylglyoxal (MGO), a precursor to advanced glycation endproducts (AGEs), is elevated in diabetes and linked to microvascular dysfunction. In this study, overexpression of the MGO‐detoxifying enzyme glyoxalase 1 (Glo1) was used in a mouse model of diabetes to explore whether MGO accumulation in diabetes causes cognitive impairment. Diabetes was induced with streptozotocin. Fasting blood glucose, cognitive function, cerebral blood flow, neurovascular coupling (NVC), Glo1 activity, MGO and AGEs were assessed. In diabetes, MGO‐derived hydroimidazolone‐1 increased in the cortex, and was decreased in Glo1‐overexpressing mice compared to controls. Visuospatial memory was decreased in diabetes, but not in Glo1/diabetes. NVC response time was slightly increased in diabetes, and normalised in the Glo1‐overexpressing group. No impact of diabetes or Glo1 overexpression on blood–brain barrier integrity or vascular density was observed. Diabetes induced a mild visuospatial memory impairment and slightly reduced NVC response speed and these effects were mitigated by Glo1. This study shows a link between MGO‐related AGE accumulation and cerebrovascular/cognitive functions in diabetes. Modulation of the MGO–Glo1 pathway may be a novel intervention strategy in patients with diabetes who have cerebrovascular complications. Diabetes is associated with an increased risk of stroke, cognitive decline, depression and Alzheimer's disease, but the underlying mechanism remains unclear. Methylglyoxal (MGO), a highly reactive by‐product of glycolysis, plays an important role in the development of diabetes‐associated microvascular dysfunction in the periphery and is detoxified by the enzyme glyoxalase 1. Diabetes reduced visuospatial memory in mice and slowed the neurovascular coupling response speed, which was improved by overexpression of glyoxalase 1. MGO formation and MGO‐derived advanced glycation endproduct (AGE) accumulation in the brain of diabetic mice are associated with a slight reduction in neurovascular coupling and mild cognitive impairment. The endogenous formation of MGO, and the accumulation of MGO‐derived AGEs, might be a potential target in reducing the risk of vascular cognitive impairment in people with diabetes. [ABSTRACT FROM AUTHOR]

The article delves into the regulation of cerebral blood flow (CBF) under hypoxic conditions, emphasizing the importance of understanding the mechanisms that maintain brain function. It categorizes CBF regulation into autoregulation, neurovascular coupling, endothelium-dependent responses, and reactivity to blood gases. The role of erythrocytes in hypoxic cerebral vasodilation is explored, with studies suggesting a nitric oxide-dependent signaling pathway. The impact of haemoconcentration on acclimatization to hypobaric hypoxia, potential sex differences in global CBF responses, and the influence of haematological factors on haemodynamic adaptations are also discussed. The study by Turner et al. (2024) focuses on sex differences in gas exchange, highlighting distinct responses in cerebral circulations post-haemodilution and the need for further research on varying haemoglobin levels in blood flow regulation. [Extracted from the article]

This article examines the relationship between haemoconcentration and cerebral blood flow (CBF) at high altitudes. The authors compare their own study with a previous study and suggest that the duration of hypoxia and the restoration of plasma volume may have influenced the results. They also discuss the contributions of arterial oxygen saturation and haemoglobin concentration to arterial oxygen content during acclimatization. A letter to the editor raises additional considerations, such as the temperature of infused fluid and potential sex differences in the relationship between hemoglobin and CBF regulation. The author emphasizes the need for careful interpretation of the results and acknowledges the limitations of the study. [Extracted from the article]

This article, published in the Journal of Physiology, explores the impact of passive hyperthermia on human circulation and the underlying mechanisms. The study found that increases in cardiac output during hyperthermia are not solely due to increased heart rate or central mechanisms, but rather involve peripheral hemodynamic changes. The researchers used various protocols and measurements to evaluate blood flow dynamics, cardiac function, and respiratory and metabolic responses. The findings suggest that peripheral mechanisms play a significant role in controlling blood circulation and provide new insights into the study of human circulation. Further research is needed to confirm these results and explore potential treatment options for cardiovascular disease. [Extracted from the article]

The brain is an energetically demanding tissue which, to function adequately, requires constant fine tuning of its supporting blood flow, and hence energy supply. Whilst blood flow was traditionally believed to be regulated only by vascular smooth muscle cells on arteries and arterioles supplying the brain, recent work has suggested a critical role for capillary pericytes, which are also contractile. This concept has evoked some controversy, especially over the relative contributions of arterioles and capillaries to the control of cerebral blood flow. Here we outline why pericytes are in a privileged position to control cerebral blood flow. First we discuss the evidence, and fundamental equations, which describe how the small starting diameter of capillaries, compared to upstream arterioles, confers a potentially greater control by capillary pericytes than by arterioles over total cerebral vascular resistance. Then we suggest that the faster time frame over which low branch order capillary pericytes dilate in response to local energy demands provides a niche role for pericytes to regulate blood flow compared to slower responding arterioles. Finally, we discuss the role of pericytes in capillary stalling, whereby pericyte contraction appears to facilitate a transient stall of circulating blood cells, exacerbating the effect of pericytes upon cerebral blood flow. [ABSTRACT FROM AUTHOR]

Increased peripheral chemoreflex sensitivity is a pathogenic feature of human hypertension (HTN), while both central and peripheral chemoreflex sensitivities are reportedly augmented in animal models of HTN. Herein, we tested the hypothesis that both central and combined central and peripheral chemoreflex sensitivities are augmented in HTN. Fifteen HTN participants (68 ± 5 years; mean ± SD) and 13 normotensives (NT; 65 ± 6 years) performed two modified rebreathing protocols in which the partial pressure of end‐tidal carbon dioxide (PETCO2${P_{{\rm{ETC}}{{\rm{O}}_2}}}$) progressively increased while the partial pressure of end‐tidal oxygen was clamped at either 150 mmHg (isoxic hyperoxia; central chemoreflex activation) or 50 mmHg (isoxic hypoxia; combined central and peripheral chemoreflex activation). Ventilation (V̇E${\dot{V}}_{\rm{E}}$; pneumotachometer) and muscle sympathetic nerve activity (MSNA; microneurography) were recorded, and ventilatory (V̇E${\dot{V}}_{\rm{E}}$vs. PETCO2${P_{{\rm{ETC}}{{\rm{O}}_2}}}$ slope) and sympathetic (MSNA vs. PETCO2${P_{{\rm{ETC}}{{\rm{O}}_2}}}$ slope) chemoreflex sensitivities and recruitment thresholds (breakpoint) were calculated. Global cerebral blood flow (gCBF; duplex Doppler) was measured, and the association with chemoreflex responses was examined. Central ventilatory and sympathetic chemoreflex sensitivities were greater in HTN than NT (2.48 ± 1.33 vs. 1.58 ± 0.42 L min−1 mmHg−1, P = 0.030: 3.32 ± 1.90 vs. 1.77 ± 0.62 a.u. mmHg−1, P = 0.034, respectively), while recruitment thresholds were not different between groups. HTN and NT had similar combined central and peripheral ventilatory and sympathetic chemoreflex sensitivities and recruitment thresholds. A lower gCBF was associated with an earlier recruitment threshold for V̇E${\dot{V}}_{\rm{E}}$ (R2 = 0.666, P < 0.0001) and MSNA (R2 = 0.698, P = 0.004) during isoxic hyperoxic rebreathing. These findings indicate that central ventilatory and sympathetic chemoreflex sensitivities are augmented in human HTN and perhaps suggest that targeting the central chemoreflex may help some forms of HTN. Key points: In human hypertension (HTN) increased peripheral chemoreflex sensitivity has been identified as a pathogenic feature, and in animal models of HTN, both central and peripheral chemoreflex sensitivities are reportedly augmented.In this study, the hypothesis was tested that both central and combined central and peripheral chemoreflex sensitivities are augmented in human HTN.We observed that both central ventilatory and sympathetic chemoreflex sensitivities were augmented in HTN compared to age‐matched normotensive controls, but no difference was found in the combined central and peripheral ventilatory and sympathetic chemoreflex sensitivities.During central chemoreflex activation, the ventilatory and sympathetic recruitment thresholds were lower in those with lower total cerebral blood flow.These results indicate a potential contributory role of the central chemoreceptors in the pathogenesis of human HTN and support the possibility that therapeutic targeting of the central chemoreflex may help some forms of HTN. [ABSTRACT FROM AUTHOR]

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 4300 m (chronic HA) in Cerro de Pasco (CdP), Péru (HA), against sex‐, age‐ and body mass index‐matched healthy highlanders (n = 9) native to CdP (lifelong HA). Venous blood was assayed for serum proteins reflecting NVU integrity, in addition to 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 basal plasma and red blood cell NO bioavailability, improved anterior and posterior dCA, elevated anterior CVRCO2 and preserved cerebral substrate delivery, NVC and cognition. In highlanders, S100B, neurofilament light‐chain (NF‐L) and T‐tau were consistently lower and cognition comparable 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. 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 and function in lowlanders and native Andean highlanders.Despite lowlanders presenting with a reduction in systemic oxidative–nitrosative stress and maintained cerebral bioenergetics 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 and 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 FROM AUTHOR]

This article explores the regulation of cerebral blood flow (CBF) during acclimatization to high altitude. It compares two studies that investigate the relationship between haemoconcentration and CBF during early acclimatization. The first study suggests that haemoglobin concentration and haematocrit contribute to the increase in CBF, while the second study does not support haemoconcentration as a primary regulator of CBF. The article emphasizes the need for further research in this area and suggests considering other factors such as caffeine, exercise, hydration, and sleep deprivation. The article is a citation for a research paper published in The Journal of Physiology, written by J. C. M. and C. O- B., and acknowledges Dr. Michael Tymko for feedback and editing assistance. [Extracted from the article]

Maturational differences exist in cardiopulmonary and cerebrovascular function at sea‐level, but the impact of maturation on acclimatization responses to high altitude is unknown. Ten children (9.8 ± 2.5 years) and 10 adults (34.7 ± 7.1 years) were assessed at sea‐level (BL), 3000 m and twice over 4 days at 3800 m (B1, B4). Measurements included minute ventilation (V̇E${\dot{V}}_{\rm{E}}$), end‐tidal partial pressures of oxygen (PETO2${P}_{{\rm{ETO}}_{\rm{2}}}$) and carbon dioxide, echocardiographic assessment of pulmonary artery systolic pressure (PASP) and stroke volume (SV) and ultrasound assessment of blood flow through the internal carotid and vertebral arteries was performed to calculate global cerebral blood flow (gCBF). At 3000 m, V̇E${\dot{V}}_{\rm{E}}$ was increased from BL by 19.6 ± 19.1% (P = 0.031) in children, but not in adults (P = 0.835); SV was reduced in children (−11 ± 13%, P = 0.020) but not adults (P = 0.827), which was compensated for by a larger increase in heart rate in children (+26 beats min−1vs. +13 beats min−1, P = 0.019). Between B1 and B4, adults increased V̇E${\dot{V}}_{\rm{E}}$ by 38.5 ± 34.7% (P = 0.006), while V̇E${\dot{V}}_{\rm{E}}$ did not increase further in children. The rise in PASP was not different between groups; however, ∆PASP from BL was related to ∆PETO2${P}_{{\rm{ETO}}_{\rm{2}}}$ in adults (R2 = 0.288, P = 0.022), but not children. At BL, gCBF was 43% higher in children than adults (P = 0.017), and this difference was maintained at high altitude, with a similar pattern and magnitude of change in gCBF between groups (P = 0.845). Despite V̇E${\dot{V}}_{\rm{E}}$ increasing in children but not adults at a lower altitude, the pulmonary vascular and cerebrovascular responses to prolonged hypoxia are similar between children and adults. Key points: Children have different ventilatory and metabolic requirements from adults, which may present differently in the pulmonary and cerebral vasculature upon ascent to high altitude.Children (ages 7–14) and adults (ages 23–44) were brought from sea level to high altitude (3000 to 3800 m) and changes in ventilation, pulmonary artery systolic pressure (PASP) and cerebral blood flow (CBF) were assessed over 1 week.Significant increases in ventilation and decreases in left ventricle stroke volume were observed at a lower altitude in children than adults.PASP and CBF increased by a similar relative amount between children and adults at 3800 m.These results help us better understand age‐related differences in compensatory responses to prolonged hypoxia in children, despite similar changes in pulmonary artery pressure and CBF between children and adults. [ABSTRACT FROM AUTHOR]

Specifically, these findings are clinically significant because they investigate the potential importance of the magnitude of arrhythmia-induced cerebral hypoperfusion on cognitive decline from ventricular arrhythmias, and not solely on event occurrences (Fig. Keywords: arrhythmia; cerebral blood flow; cognitive function EN arrhythmia cerebral blood flow cognitive function 4255 4258 4 10/04/22 20221001 NES 221001 Ventricular arrhythmias, particularly premature ventricular contractions (PVCs), are highly prevalent in cardiovascular diseases. Thinking from the heart: arrhythmia-induced reduction in cerebral blood flow and the cumulative burden on cognitive function in cardiovascular disease Notably overlooked are whether the magnitude of ventricular arrhythmia-induced CBF reductions can also be predictive of cognitive dysfunction and whether ventricular arrhythmias compromise CBF to the same extent across patient populations. [Extracted from the article]

Humans hyperventilate under heat and cold strain. This hyperventilatory response has detrimental consequences including acid–base dysregulation, dyspnoea, decreased cerebral blood flow and accelerated brain heating. The ventilatory response to hypoxia is exaggerated under whole-body heating and cooling, indicating that altered carotid body function might contribute to thermally mediated hyperventilation. To address whether the carotid body might contribute to heat- and cold-induced hyperventilation, we indirectly measured carotid body tonic activity via hyperoxia, and carotid body sensitivity via hypoxia, under graded heat and cold strain in 13 healthy participants in a repeated-measures design. We hypothesised that carotid body tonic activity and sensitivity would be elevated in a dose-dependent manner under graded heat and cold strain, thereby supporting its role in driving thermally mediated hyperventilation. Carotid body tonic activity was increased in a dose-dependent manner with heating, reaching 175% above baseline (P < 0.0005), and carotid body suppression with hyperoxia removed all of the heat-induced increase in ventilation (P = 0.9297). Core cooling increased carotid body activity by up to 250% (P < 0.0001), but maximal values were reached with mild cooling and thereafter plateaued. Carotid body sensitivity to hypoxia was profoundly increased by up to 180% with heat stress (P = 0.0097), whereas cooling had no detectable effect on hypoxic sensitivity. In summary, cold stress increased carotid body tonic activity and this effect was saturated with mild cooling, whereas heating had clear dose-dependent effects on carotid body tonic activity and sensitivity. These dose-dependent effects with heat strain indicate that the carotid body probably plays a primary role in driving heat-induced hyperventilation. [ABSTRACT FROM AUTHOR]

The foramen ovale is an essential component of the fetal circulation contributing to oxygenation and carbon dioxide elimination that remains patent under certain circumstances in ∼30% of the healthy adult population, without major negative sequelae in most. Adults with a patent foramen ovale (PFO) have a greater tendency to develop symptoms of acute mountain sickness and high‐altitude pulmonary oedema upon ascent to high altitude, and PFO presence is associated with worse cardiopulmonary function in chronic mountain sickness. This increase in altitude illness prevalence may be related to dysregulated cerebral blood flow associated with altered respiratory chemoreflex sensitivity; however, the mechanisms remain to be elucidated. Interestingly, men with a PFO appear to have a shift in thermoregulatory control to higher internal temperatures, both at rest and during exercise, and they have blunted thermal hyperpnoea. The teleological 'reason' for this thermoregulatory shift is unclear, but the shift of ∼0.5°C in core body temperature does not appear to be sufficient to have any significant negative consequences in terms of risk of heat illness. Further work in this area is needed, particularly in women, to evaluate mechanisms of heat storage and dissipation in these individuals compared to people without a PFO. Consequences of a PFO in SCUBA divers include a greater incidence of unprovoked decompression sickness, but whether PFO is beneficial or detrimental to breath hold diving remains unexplored. Whether PFO presence will explain interindividual variability in responses to, and consequences from, other environmental stressors such as spaceflight remain entirely unknown. [ABSTRACT FROM AUTHOR]

Cerebrovascular CO2 reactivity (CVR) is often considered a bioassay of cerebrovascular endothelial function. We recently introduced a test of cerebral shear‐mediated dilatation (cSMD) that may better reflect endothelial function. We aimed to determine the nitric oxide (NO)‐dependency of CVR and cSMD. Eleven volunteers underwent a steady‐state CVR test and transient CO2 test of cSMD during intravenous infusion of the NO synthase inhibitor NG‐monomethyl‐l‐arginine (l‐NMMA) or volume‐matched saline (placebo; single‐blinded and counter‐balanced). We measured cerebral blood flow (CBF; duplex ultrasound), intra‐arterial blood pressure and PaCO2${P_{{\rm{aC}}{{\rm{O}}_{\rm{2}}}}}$. Paired arterial and jugular venous blood sampling allowed for the determination of trans‐cerebral NO2− exchange (ozone‐based chemiluminescence). l‐NMMA reduced arterial NO2− by ∼25% versus saline (74.3 ± 39.9 vs. 98.1 ± 34.2 nM; P = 0.03). The steady‐state CVR (20.1 ± 11.6 nM/min at baseline vs. 3.2 ± 16.7 nM/min at +9 mmHg PaCO2${P_{{\rm{aC}}{{\rm{O}}_{\rm{2}}}}}$; P = 0.017) and transient cSMD tests (3.4 ± 5.9 nM/min at baseline vs. −1.8 ± 8.2 nM/min at 120 s post‐CO2; P = 0.044) shifted trans‐cerebral NO2− exchange towards a greater net release (a negative value indicates release). Although this trans‐cerebral NO2− release was abolished by l‐NMMA, CVR did not differ between the saline and l‐NMMA trials (57.2 ± 14.6 vs. 54.1 ± 12.1 ml/min/mmHg; P = 0.49), nor did l‐NMMA impact peak internal carotid artery dilatation during the steady‐state CVR test (6.2 ± 4.5 vs. 6.2 ± 5.0% dilatation; P = 0.960). However, l‐NMMA reduced cSMD by ∼37% compared to saline (2.91 ± 1.38 vs. 4.65 ± 2.50%; P = 0.009). Our findings indicate that NO is not an obligatory regulator of steady‐state CVR. Further, our novel transient CO2 test of cSMD is largely NO‐dependent and provides an in vivo bioassay of NO‐mediated cerebrovascular function in humans. Key points: Emerging evidence indicates that a transient CO2 stimulus elicits shear‐mediated dilatation of the internal carotid artery, termed cerebral shear‐mediated dilatation.Whether or not cerebrovascular reactivity to a steady‐state CO2 stimulus is NO‐dependent remains unclear in humans.During both a steady‐state cerebrovascular reactivity test and a transient CO2 test of cerebral shear‐mediated dilatation, trans‐cerebral nitrite exchange shifted towards a net release indicating cerebrovascular NO production; this response was not evident following intravenous infusion of the non‐selective NO synthase inhibitor NG‐monomethyl‐l‐arginine.NO synthase blockade did not alter cerebrovascular reactivity in the steady‐state CO2 test; however, cerebral shear‐mediated dilatation following a transient CO2 stimulus was reduced by ∼37% following intravenous infusion of NG‐monomethyl‐l‐arginine.NO is not obligatory for cerebrovascular reactivity to CO2, but is a key contributor to cerebral shear‐mediated dilatation. [ABSTRACT FROM AUTHOR]

Understanding the contribution of the autonomic nervous system to cerebral blood flow (CBF) control is challenging, and interpretations are unclear. The identification of calcium channels and adrenoreceptors within cerebral vessels has led to common misconceptions that the function of these receptors and actions mirror those of the peripheral vasculature. This review outlines the fundamental differences and complex actions of cerebral autonomic activation compared with the peripheral circulation. Anatomical differences, including the closed nature of the cerebrovasculature, and differential adrenoreceptor subtypes, density, distribution and sensitivity, provide evidence that measures on peripheral sympathetic nerve activity cannot be extrapolated to the cerebrovasculature. Cerebral sympathetic nerve activity seems to act opposingly to the peripheral circulation, mediated at least in part by changes in intracranial pressure and cerebral blood volume. Additionally, heterogeneity in cerebral adrenoreceptor distribution highlights region‐specific autonomic regulation of CBF. Compensatory chemo‐ and autoregulatory responses throughout the cerebral circulation, and interactions with parasympathetic nerve activity are unique features to the cerebral circulation. This crosstalk between sympathetic and parasympathetic reflexes acts to ensure adequate perfusion of CBF to rising and falling perfusion pressures, optimizing delivery of oxygen and nutrients to the brain, while attempting to maintain blood volume and intracranial pressure. Herein, we highlight the distinct similarities and differences between autonomic control of cerebral and peripheral blood flow, and the regional specificity of sympathetic and parasympathetic regulation within the cerebrovasculature. Future research directions are outlined with the goal to further our understanding of autonomic control of CBF in humans. [ABSTRACT FROM AUTHOR]

The regulation and defence 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 blood, 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 vs. 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; and 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. [ABSTRACT FROM AUTHOR]

The importance of nitric oxide (NO) in regulating cerebral blood flow (CBF) remains unresolved, due in part to methodological approaches, which lack a comprehensive assessment of both global and regional effects. Importantly, NO synthase (NOS) expression and activity appear greater in some anterior brain regions, suggesting region‐specific NOS influence on CBF. We hypothesized that NO contributes to basal CBF in healthy adults, in a regionally distinct pattern that predominates in the anterior circulation. Fourteen healthy adults (7 females; 24 ± 5 years) underwent two magnetic resonance imaging (MRI) study visits with saline (placebo) or the NOS inhibitor, L‐NMMA, administered in a randomized, single‐blind approach. 4D flow MRI quantified total and regional macrovascular CBF, whereas arterial spin labelling (ASL) MRI quantified total and regional microvascular perfusion. L‐NMMA (or volume‐matched saline) was infused intravenously for 5 min prior to imaging. L‐NMMA reduced CBF (L‐NMMA: 722 ± 100 vs. placebo: 771 ± 121 ml/min, P = 0.01) with similar relative reductions (5–7%) in anterior and posterior cerebral circulations, due in part to the reduced cross‐sectional area of 9 of 11 large cerebral arteries. Global microvascular perfusion (ASL) was reduced by L‐NMMA (L‐NMMA: 42 ± 7 vs. placebo: 47 ± 8 ml/100g/min, P = 0.02), with 7–11% reductions in both hemispheres of the frontal, parietal and temporal lobes, and in the left occipital lobe. We conclude that NO contributes to macrovascular and microvascular regulation including larger artery resting diameter. Contrary to our hypothesis, the influence of NO on cerebral perfusion appears regionally uniform in healthy young adults. Key points: Cerebral blood flow (CBF) is vital for brain health, but the signals that are key to regulating CBF remain unclear.Nitric oxide (NO) is produced in the brain, but its importance in regulating CBF remains controversial since prior studies have not studied all regions of the brain simultaneously.Using modern MRI approaches, a drug that inhibits the enzymes that make NO (L‐NMMA) reduced CBF by up to 11% in different brain regions.NO helps maintain proper CBF in healthy adults. These data will help us understand whether the reductions in CBF that occur during ageing or cardiovascular disease are related to shifts in NO signalling. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Key points: The proposed mechanism for the increased ventilation in response to hyperoxia includes a reduced brain CO2–[H+] washout‐induced central chemoreceptor stimulation that results from a decrease in cerebral perfusion and the weakening of the CO2 affinity for haemoglobin.Nonetheless, hyperoxia also results in excessive brain reactive oxygen species (ROS) formation/accumulation, which hypothetically increases central respiratory drive and causes hyperventilation.We then quantified ventilation, cerebral perfusion/metabolism, arterial/internal jugular vein blood gases and oxidant/antioxidant biomarkers in response to hyperoxia during intravenous infusion of saline or ascorbic acid to determine whether excessive ROS production/accumulation contributes to the hyperoxia‐induced hyperventilation in humans.Ascorbic acid infusion augmented the antioxidant defence levels, blunted ROS production/accumulation and minimized both the reduction in cerebral perfusion and the increase in ventilation observed during saline infusion.Hyperoxic hyperventilation seems to be mediated by central chemoreceptor stimulation provoked by the interaction between an excessive ROS production/accumulation and reduced brain CO2–[H+] washout. The hypothetical mechanism for the increase in ventilation (V̇E) in response to hyperoxia (HX) includes central chemoreceptor stimulation via reduced CO2–[H+] washout. Nonetheless, hyperoxia disturbs redox homeostasis and raises the hypothesis that excessive brain reactive oxygen species (ROS) production/accumulation may increase the sensitivity to CO2 or even solely activate the central chemoreceptors, resulting in hyperventilation. To determine the mechanism behind the HX‐evoked increase in V̇E, 10 healthy men (24 ± 4 years) underwent 10 min trials of HX under saline and ascorbic acid infusion. V̇E, arterial and right internal right jugular vein (ijv) partial pressure for oxygen (PO2) and CO2 (PCO2), pH, oxidant (8‐isoprostane) and antioxidant (ascorbic acid) markers, as well as cerebral blood flow (CBF) (Duplex ultrasonography), were quantified at each hyperoxic trial. HX evoked an increase in arterial partial pressure for oxygen, followed by a hyperventilatory response, a reduction in CBF, an increase in arterial 8‐isoprostane, and unchanged PijvCO2 and ijv pH. Intravenous ascorbic acid infusion augmented the arterial antioxidant marker, blunted the increase in arterial 8‐isoprostane and attenuated both the reduction in CBF and the HX‐induced hyperventilation. Although ascorbic acid infusion resulted in a slight increase in PijvCO2 and a substantial decrease in ijv pH, when compared with the saline bout, HX evoked a similar reduction and a paired increase in the trans‐cerebral exchanges for PCO2 and pH, respectively. These findings indicate that the poikilocapnic hyperoxic hyperventilation is likely mediated via the interaction of the acidic brain interstitial fluid and an increase in central chemoreceptor sensitivity to CO2, which, in turn, seems to be evoked by the excessive ROS production/accumulation. Key points: The proposed mechanism for the increased ventilation in response to hyperoxia includes a reduced brain CO2–[H+] washout‐induced central chemoreceptor stimulation that results from a decrease in cerebral perfusion and the weakening of the CO2 affinity for haemoglobin.Nonetheless, hyperoxia also results in excessive brain reactive oxygen species (ROS) formation/accumulation, which hypothetically increases central respiratory drive and causes hyperventilation.We then quantified ventilation, cerebral perfusion/metabolism, arterial/internal jugular vein blood gases and oxidant/antioxidant biomarkers in response to hyperoxia during intravenous infusion of saline or ascorbic acid to determine whether excessive ROS production/accumulation contributes to the hyperoxia‐induced hyperventilation in humans.Ascorbic acid infusion augmented the antioxidant defence levels, blunted ROS production/accumulation and minimized both the reduction in cerebral perfusion and the increase in ventilation observed during saline infusion.Hyperoxic hyperventilation seems to be mediated by central chemoreceptor stimulation provoked by the interaction between an excessive ROS production/accumulation and reduced brain CO2–[H+] washout. [ABSTRACT FROM AUTHOR]

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. 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 < 0.001) and [HCO3–] (26.2 ± 1.5 vs. 29.3 ± 0.9 mEq/l; P < 0.001). Although the NVC response was collectively attenuated by 27–38% with −10 mmHg PaCO2 (stage post hoc: all P < 0.05), this response was unaltered following NaHCO3 (all 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 < 0.001). Overall, these findings indicate that temporal patterns in NVC are acutely regulated by PaCO2 rather than arterial pH per se in the setting of acute metabolic alkalosis in humans. 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 FROM AUTHOR]

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. 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. 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 FROM AUTHOR]

Key points: The margin of human viability has extended to the extremes of gestational age (<24 weeks) when the lungs are immature and ventilator‐induced lung injury is common.Artificial placenta technology aims to extend gestation ex utero in order to allow the lungs additional time to develop prior to entering an air‐breathing environment.We compared the haemodynamics and cerebral oxygenation of piglets in the immediate period post‐oxygenator (OXY) transition against both paired in utero measures and uniquely against piglets transitioned onto mechanical ventilation (VENT).Post‐transition, OXY piglets became hypotensive with reduced carotid blood flow in comparison with both paired in utero measures and VENT piglets.The addition of a pump to the oxygenator circuit may be required to ensure haemodynamic stability in the immediate post‐transition period. Gestational age at birth is a major predictor of wellbeing; the lower the gestational age, the greater the risk of mortality and morbidity. At the margins of human viability (<24 weeks gestation) immature lungs combined with the need for early ventilatory support means lung injury and respiratory morbidity is common. The abrupt haemodynamic changes consequent on birth may also contribute to preterm‐associated brain injury, including intraventricular haemorrhage. Artificial placenta technology aims to support oxygenation, haemodynamic stability and ongoing fetal development ex utero until mature enough to safely transition to a true ex utero environment. We aimed to characterize the impact of birth transition onto either an oxygenator circuit or positive pressure ventilation on haemodynamic and cerebral oxygenation of the neonatal piglet. At 112 days gestation (term = 115 days), fetal pigs underwent instrumentation surgery and transitioned onto either an oxygenator (OXY, n = 5) or ventilatory support (VENT, n = 8). Blood pressure (BP), carotid blood flow and cerebral oxygenation in VENT piglets rose from in utero levels to be significantly higher than OXY piglets post‐transition. OXY piglet BP, carotid blood flow and carotid oxygen delivery (DO2) decreased from in utero levels post‐transition; however, cerebral regional oxygen saturation (rSO2) was maintained at fetal‐like levels. OXY piglets became hypoxaemic and retained CO2. Whether OXY piglets are able to maintain cerebral rSO2 under these conditions for a prolonged period is yet to be determined. Improvements to OXY piglet oxygenation may lie in maintaining piglet BP at in utero levels and enhancing oxygenator circuit flow. Key points: The margin of human viability has extended to the extremes of gestational age (<24 weeks) when the lungs are immature and ventilator‐induced lung injury is common.Artificial placenta technology aims to extend gestation ex utero in order to allow the lungs additional time to develop prior to entering an air‐breathing environment.We compared the haemodynamics and cerebral oxygenation of piglets in the immediate period post‐oxygenator (OXY) transition against both paired in utero measures and uniquely against piglets transitioned onto mechanical ventilation (VENT).Post‐transition, OXY piglets became hypotensive with reduced carotid blood flow in comparison with both paired in utero measures and VENT piglets.The addition of a pump to the oxygenator circuit may be required to ensure haemodynamic stability in the immediate post‐transition period. [ABSTRACT FROM AUTHOR]

Key points: The human brain is particularly vulnerable to heat stress; this manifests as impaired cognition, orthostatic tolerance, work capacity and eventually, brain death.The brain's limitation in the heat is often ascribed to inadequate cerebral blood flow (CBF), but elevated intracranial pressure is commonly observed in mammalian models of heat stroke and can on its own cause functional impairment.The CBF response to incremental heat strain was dependent on the mode of heating, decreasing by 30% when exposed passively to hot, humid air (sauna), while remaining unchanged or increasing with passive hot‐water immersion (spa) and exercising in a hot environment.Non‐invasive intracranial pressure estimates (nICP) were increased universally by 18% at volitional thermal tolerance across all modes of heat stress, and therefore may play a contributing role in eliciting thermal tolerance.The sauna, more so than the spa or exercise, poses a greater challenge to the brain under mild to severe heating due to lower blood flow but similarly increased nICP. The human brain is particularly vulnerable to heat stress; this manifests as impaired cognitive function, orthostatic tolerance, work capacity, and eventually, brain death. This vulnerability is often ascribed to inadequate cerebral blood flow (CBF); however, elevated intracranial pressure (ICP) is also observed in mammalian models of heat stroke. We investigated the changes in CBF with incremental heat strain under three fundamentally different modes of heating, and assessed whether heating per se increased ICP. Fourteen fit participants (seven female) were heated to thermal tolerance or 40°C core temperature (Tc; oesophageal) via passive hot‐water immersion (spa), passive hot, humid air exposure (sauna), cycling exercise, and cycling exercise with CO2 inhalation to prevent heat‐induced hypocapnia. CBF was measured with duplex ultrasound at each 0.5°C increment in Tc and ICP was estimated non‐invasively (nICP) from optic nerve sheath diameter at thermal tolerance. At thermal tolerance, CBF was decreased by 30% in the sauna (P < 0.001), but was unchanged in the spa or with exercise (P ≥ 0.140). CBF increased by 17% when end‐tidal PCO2 was clamped at eupnoeic pressure (P < 0.001). On the contrary, nICP increased universally by 18% with all modes of heating (P < 0.001). The maximum Tc was achieved with passive heating, and preventing hypocapnia during exercise did not improve exercise or thermal tolerance (P ≥ 0.146). Therefore, the regulation of CBF is dramatically different depending on the mode and dose of heating, whereas nICP responses are not. The sauna, more so than the spa or exercise, poses a greater challenge to the brain under equivalent heat strain. Key points: The human brain is particularly vulnerable to heat stress; this manifests as impaired cognition, orthostatic tolerance, work capacity and eventually, brain death.The brain's limitation in the heat is often ascribed to inadequate cerebral blood flow (CBF), but elevated intracranial pressure is commonly observed in mammalian models of heat stroke and can on its own cause functional impairment.The CBF response to incremental heat strain was dependent on the mode of heating, decreasing by 30% when exposed passively to hot, humid air (sauna), while remaining unchanged or increasing with passive hot‐water immersion (spa) and exercising in a hot environment.Non‐invasive intracranial pressure estimates (nICP) were increased universally by 18% at volitional thermal tolerance across all modes of heat stress, and therefore may play a contributing role in eliciting thermal tolerance.The sauna, more so than the spa or exercise, poses a greater challenge to the brain under mild to severe heating due to lower blood flow but similarly increased nICP. [ABSTRACT FROM AUTHOR]

Key points: The cerebral fluid response to exercise, including the arterial and venous cerebral blood flow (CBF) and cerebrospinal fluid (CSF), currently remains unknown.We used time‐resolved phase‐contrast magnetic resonance imaging to assess changes in CBF and CSF flow dynamics during moderate‐intensity rhythmic handgrip (RHG) exercise in young healthy men and women.Our data demonstrated that RHG increases the cerebral arterial inflow and venous outflow while decreasing the pulsatile CSF flow during RHG.Furthermore, changes in blood stroke volume at the measured arteries, veins, and sinuses and CSF stroke volume at the cerebral aqueduct were positively correlated with each other during RHG.Male and female participants exhibited distinct blood pressure responses to RHG, but their cerebral fluid responses were similar.These results collectively suggest that RHG influences both CBF and CSF flow dynamics in a way that is consistent with the Monro–Kellie hypothesis to maintain intracranial volume‐pressure homeostasis in young healthy adults. Cerebral blood flow (CBF) increases during exercise, but its impact on cerebrospinal fluid (CSF) flow remains unknown. This study investigated CBF and CSF flow dynamics during moderate‐intensity rhythmic handgrip (RHG) exercise in young healthy men and women. Twenty‐six participants (12 women) underwent the RHG and resting control conditions in random order. Participants performed 3 sets of RHG, during which cine phase‐contrast magnetic resonance imaging (PC‐MRI) was performed to measure blood stroke volume (SV) and flow rate in the internal carotid (ICA) and vertebral (VA) arteries, the internal jugular vein (IJV), the superior sagittal (SSS) and straight sinuses (SRS), and CSF SV and flow rate in the cerebral aqueduct of Sylvius. Blood pressure, end‐tidal CO2 (EtCO2), heart rate (HR), and respiratory rate were simultaneously measured during cine PC‐MRI scans. Compared with control conditions, RHG showed significant elevations of HR, mean arterial pressure, and respiratory rate with a mild reduction of EtCO2 (all P < 0.05). RHG decreased blood SV in the measured arteries, veins, and sinuses and CSF SV in the aqueduct (all P < 0.05). Conversely, RHG increased blood flow in the ICA, VA, and IJV (all P < 0.05). At the aqueduct, RHG decreased the absolute CSF flow rate (P = 0.0307), which was calculated as a sum of the caudal and cranial CSF flow rates. Change in the ICA SV was positively correlated with changes in the IJV, SSS, SRS, and aqueductal SV during RHG (all P < 0.05). These findings demonstrate a close coupling between the CBF and CSF flow dynamics during RHG in young healthy adults. Key points: The cerebral fluid response to exercise, including the arterial and venous cerebral blood flow (CBF) and cerebrospinal fluid (CSF), currently remains unknown.We used time‐resolved phase‐contrast magnetic resonance imaging to assess changes in CBF and CSF flow dynamics during moderate‐intensity rhythmic handgrip (RHG) exercise in young healthy men and women.Our data demonstrated that RHG increases the cerebral arterial inflow and venous outflow while decreasing the pulsatile CSF flow during RHG.Furthermore, changes in blood stroke volume at the measured arteries, veins, and sinuses and CSF stroke volume at the cerebral aqueduct were positively correlated with each other during RHG.Male and female participants exhibited distinct blood pressure responses to RHG, but their cerebral fluid responses were similar.These results collectively suggest that RHG influences both CBF and CSF flow dynamics in a way that is consistent with the Monro–Kellie hypothesis to maintain intracranial volume‐pressure homeostasis in young healthy adults. [ABSTRACT FROM AUTHOR]

Key points: We investigated the influence of arterial PCO2 (PaCO2) 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 PaCO2 (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 PaCO2, indicating that CBF is acutely regulated by PaCO2 rather than arterial pH.The cerebrovascular responses to changes in arterial H+/pH were altered in keeping with the altered relationship between PaCO2 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 PaCO2 levels. Cerebral blood flow (CBF) regulation is dependent on the integrative relationship between arterial PCO2 (PaCO2), pH and cerebrovascular tone; however, pre‐clinical studies indicate that intrinsic sensitivity to pH, independent of changes in PaCO2 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 PaCO2 (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 < 0.001) and [HCO3–] (26.1 ± 1.4 vs. 29.3 ± 0.9 mEq L–1; P < 0.001). Absolute CBF was not different at each stage of CO2 reactivity (P = 0.629) following NaHCO3–, irrespective of a higher pH (P < 0.001) at each matched stage of PaCO2 (P = 0.927). Neither hypocapnic (3.44 ± 0.92 vs. 3.44 ± 1.05% per mmHg PaCO2; P = 0.499), nor hypercapnic (7.45 ± 1.85 vs. 6.37 ± 2.23% per mmHg PaCO2; P = 0.151) reactivity to PaCO2 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 PaCO2 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 PaCO2. These data indicate that in the setting of acute metabolic alkalosis, CBF is regulated by PaCO2 rather than arterial pH. Key points: We investigated the influence of arterial PCO2 (PaCO2) 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 PaCO2 (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 PaCO2, indicating that CBF is acutely regulated by PaCO2 rather than arterial pH.The cerebrovascular responses to changes in arterial H+/pH were altered in keeping with the altered relationship between PaCO2 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 PaCO2 levels. [ABSTRACT FROM AUTHOR]

Key points: Cognitive function depends on adequate cerebrovascular perfusion and control. However, it is unknown whether acutely‐reduced cerebral blood flow (CBF) impairs cognition in healthy adults.In the present study, we used a placebo‐controlled, single‐blinded, randomized cross‐over design to test the hypothesis that acutely‐reduced CBF (using a pharmacological aid; indomethacin) would impair cognition in young and older healthy adults.At baseline, older adults had lower cognitive performance and CBF, but similar cerebrovascular reactivity to CO2 and dynamic cerebral autoregulation compared to young adults.In both young and older adults, cognitive performance on a mental switching task was slightly (7%) reduced after indomethacin, but not significantly associated with reductions in CBF (∼31%).These results indicate that cognitive performance is broadly resilient against a ∼31% reduction in CBF per se in healthy young and older adults. Cognitive function depends on adequate cerebrovascular perfusion and control. However, it is unknown whether acutely‐reduced cerebral blood flow (CBF) impairs cognition in healthy adults. Using a placebo‐controlled, single‐blinded, randomized cross‐over design, we tested the hypothesis that acutely‐reduced CBF (using indomethacin [1.2 mg kg–1 oral dose]) would impair cognition in young (n = 13; 25 ± 4 years) and older (n = 12; 58 ± 6 years) healthy adults. CBF and cerebrovascular control were measured using middle cerebral artery blood velocity (MCAvmean) and its reactivity to hypercapnia (CVRHYPER) and hypocapnia (CVRHYPO), respectively. Cognitive function was assessed using a computerized battery including response time tasks. Baseline comparisons revealed that older adults had 14% lower MCAvmean and 15% lower cognitive performance (all P ≤ 0.048), but not lower CVRHYPER/HYPO (P ≥ 0.26). Linear and rank‐based mixed models revealed that indomethacin decreased MCAvmean by 31% (95% confidence interval = –35 to –26), CVRHYPER by 68% [interquartile range (IQR) = –94 to –44] and CVRHYPO by 50% (IQR = –83 to –33) (treatment‐effect; all P < 0.01), regardless of age. Baseline CVRHYPER/HYPO values were strongly associated with their indomethacin‐induced reductions (r = 0.70 to 0.89, P < 0.01). Mental switching performance was impaired 7% (IQR = 0–19) after indomethacin (P = 0.04), but not significantly associated with reductions in MCAvmean (Young: rho = –0.31, P = 0.30; Older: rho = 0.06, P = 0.86). In conclusion, indomethacin reduced MCAvmean and impaired cognition slightly; however, no clear association was evident in younger or older adults. Older adults had poorer cognition and lower MCAvmean, but similar CVRHYPER/HYPO. Key points: Cognitive function depends on adequate cerebrovascular perfusion and control. However, it is unknown whether acutely‐reduced cerebral blood flow (CBF) impairs cognition in healthy adults.In the present study, we used a placebo‐controlled, single‐blinded, randomized cross‐over design to test the hypothesis that acutely‐reduced CBF (using a pharmacological aid; indomethacin) would impair cognition in young and older healthy adults.At baseline, older adults had lower cognitive performance and CBF, but similar cerebrovascular reactivity to CO2 and dynamic cerebral autoregulation compared to young adults.In both young and older adults, cognitive performance on a mental switching task was slightly (7%) reduced after indomethacin, but not significantly associated with reductions in CBF (∼31%).These results indicate that cognitive performance is broadly resilient against a ∼31% reduction in CBF per se in healthy young and older adults. [ABSTRACT FROM AUTHOR]

Key points: During long‐duration spaceflights, some astronauts develop structural ocular changes including optic disc oedema that resemble signs of intracranial hypertension.In the present study, intracranial pressure was estimated non‐invasively (nICP) using a model‐based analysis of cerebral blood velocity and arterial blood pressure waveforms in 11 astronauts before and after long‐duration spaceflights.Our results show that group‐averaged estimates of nICP decreased significantly in nine astronauts without optic disc oedema, suggesting that the cephalad fluid shift during long‐duration spaceflight rarely increased postflight intracranial pressure.The results of the two astronauts with optic disc oedema suggest that both increases and decreases in nICP are observed post‐flight in astronauts with ocular alterations, arguing against a primary causal relationship between elevated ICP and spaceflight associated optical changes.Cerebral blood velocity increased independently of nICP and spaceflight‐associated ocular alterations. This increase may be caused by the reduced haemoglobin concentration after long‐duration spaceflight. Persistently elevated intracranial pressure (ICP) above upright values is a suspected cause of optic disc oedema in astronauts. However, no systematic studies have evaluated changes in ICP from preflight. Therefore, ICP was estimated non‐invasively before and after spaceflight to test whether ICP would increase after long‐duration spaceflight. Cerebral blood velocity in the middle cerebral artery (MCAv) was obtained by transcranial Doppler sonography and arterial pressure in the radial artery was obtained by tonometry, in the supine and sitting positions before and after 4−12 months of spaceflight in 11 astronauts (10 males and 1 female, 46 ± 7 years old at launch). Non‐invasive ICP (nICP) was computed using a validated model‐based estimation method. Mean MCAv increased significantly after spaceflight (ANOVA, P = 0.007). Haemoglobin decreased significantly after spaceflight (14.6 ± 0.8 to 13.3 ± 0.7 g/dL, P < 0.001). A repeated measures correlation analysis indicated a negative correlation between haemoglobin and mean MCAv (r = −0.589, regression coefficient = −4.68). The nICP did not change significantly after spaceflight in the 11 astronauts. However, nICP decreased significantly by 15% in nine astronauts without optic disc oedema (P < 0.005). Only one astronaut increased nICP to relatively high levels after spaceflight. Contrary to our hypothesis, nICP did not increase after long‐duration spaceflight in the vast majority (>90%) of astronauts, suggesting that the cephalad fluid shift during spaceflight does not systematically or consistently elevate postflight ICP in astronauts. Independently of nICP and ocular alterations, the present results of mean MCAv suggest that long‐duration spaceflight may increase cerebral blood flow, possibly due to reduced haemoglobin concentration. Key points: During long‐duration spaceflights, some astronauts develop structural ocular changes including optic disc oedema that resemble signs of intracranial hypertension.In the present study, intracranial pressure was estimated non‐invasively (nICP) using a model‐based analysis of cerebral blood velocity and arterial blood pressure waveforms in 11 astronauts before and after long‐duration spaceflights.Our results show that group‐averaged estimates of nICP decreased significantly in nine astronauts without optic disc oedema, suggesting that the cephalad fluid shift during long‐duration spaceflight rarely increased postflight intracranial pressure.The results of the two astronauts with optic disc oedema suggest that both increases and decreases in nICP are observed post‐flight in astronauts with ocular alterations, arguing against a primary causal relationship between elevated ICP and spaceflight associated optical changes.Cerebral blood velocity increased independently of nICP and spaceflight‐associated ocular alterations. This increase may be caused by the reduced haemoglobin concentration after long‐duration spaceflight. [ABSTRACT FROM AUTHOR]

Key points: Dynamic cerebral autoregulation (CA) is often expressed by the mean arterial blood pressure (MAP)–cerebral blood flow (CBF) relationship, with little attention given to the dynamic relationship between MAP and cerebrovascular resistance (CVR).In CBF velocity (CBFV) recordings with transcranial Doppler, evidence demonstrates that CVR should be replaced by a combination of a resistance–area product (RAP) with a critical closing pressure (CrCP) parameter, the blood pressure value where CBFV reaches zero due to vessels collapsing.Transfer function analysis of the MAP–CBFV relationship can be extended to the MAP–RAP and MAP–CrCP relationships, to assess their contribution to the dynamic CA response.During normocapnia, both RAP and CrCP make a significant contribution to explaining the MAP–CBFV relationship.Hypercapnia, a surrogate state of depressed CA, leads to marked changes in dynamic CA, that are entirely explained by the CrCP response, without further contribution from RAP in comparison with normocapnia. Dynamic cerebral autoregulation (CA) is manifested by changes in the diameter of intra‐cerebral vessels, which control cerebrovascular resistance (CVR). We investigated the contribution of critical closing pressure (CrCP), an important determinant of CVR, to explain the cerebral blood flow (CBF) response to a sudden change in mean arterial blood pressure (MAP). In 76 healthy subjects (age range 21–70 years, 36 women), recordings of MAP (Finometer), CBF velocity (CBFV; transcranial Doppler ultrasound), end‐tidal CO2 (capnography) and heart rate (ECG) were performed for 5 min at rest (normocapnia) and during hypercapnia induced by breathing 5% CO2 in air. CrCP and the resistance–area product (RAP) were obtained for each cardiac cycle and their dynamic response to a step change in MAP was calculated by means of transfer function analysis. The recovery of the CBFV response, following a step change in MAP, was mainly due to the contribution of RAP during both breathing conditions. However, CrCP made a highly significant contribution during normocapnia (P < 0.0001) and was the sole determinant of changes in the CBFV response, resulting from hypercapnia, which led to a reduction in the autoregulation index from 5.70 ± 1.58 (normocapnia) to 4.14 ± 2.05 (hypercapnia; P < 0.0001). In conclusion, CrCP makes a very significant contribution to the dynamic CBFV response to changes in MAP and plays a major role in explaining the deterioration of dynamic CA induced by hypercapnia. Further studies are needed to assess the relevance of CrCP contribution in physiological and clinical studies. Key points: Dynamic cerebral autoregulation (CA) is often expressed by the mean arterial blood pressure (MAP)–cerebral blood flow (CBF) relationship, with little attention given to the dynamic relationship between MAP and cerebrovascular resistance (CVR).In CBF velocity (CBFV) recordings with transcranial Doppler, evidence demonstrates that CVR should be replaced by a combination of a resistance–area product (RAP) with a critical closing pressure (CrCP) parameter, the blood pressure value where CBFV reaches zero due to vessels collapsing.Transfer function analysis of the MAP–CBFV relationship can be extended to the MAP–RAP and MAP–CrCP relationships, to assess their contribution to the dynamic CA response.During normocapnia, both RAP and CrCP make a significant contribution to explaining the MAP–CBFV relationship.Hypercapnia, a surrogate state of depressed CA, leads to marked changes in dynamic CA, that are entirely explained by the CrCP response, without further contribution from RAP in comparison with normocapnia. [ABSTRACT FROM AUTHOR]

Key points: Dynamic cerebral autoregulation (CA) is often expressed by the mean arterial blood pressure (MAP)–cerebral blood flow (CBF) relationship, with little attention given to the dynamic relationship between MAP and cerebrovascular resistance (CVR).In CBF velocity (CBFV) recordings with transcranial Doppler, evidence demonstrates that CVR should be replaced by a combination of a resistance–area product (RAP) with a critical closing pressure (CrCP) parameter, the blood pressure value where CBFV reaches zero due to vessels collapsing.Transfer function analysis of the MAP–CBFV relationship can be extended to the MAP–RAP and MAP–CrCP relationships, to assess their contribution to the dynamic CA response.During normocapnia, both RAP and CrCP make a significant contribution to explaining the MAP–CBFV relationship.Hypercapnia, a surrogate state of depressed CA, leads to marked changes in dynamic CA, that are entirely explained by the CrCP response, without further contribution from RAP in comparison with normocapnia. Dynamic cerebral autoregulation (CA) is manifested by changes in the diameter of intra‐cerebral vessels, which control cerebrovascular resistance (CVR). We investigated the contribution of critical closing pressure (CrCP), an important determinant of CVR, to explain the cerebral blood flow (CBF) response to a sudden change in mean arterial blood pressure (MAP). In 76 healthy subjects (age range 21–70 years, 36 women), recordings of MAP (Finometer), CBF velocity (CBFV; transcranial Doppler ultrasound), end‐tidal CO2 (capnography) and heart rate (ECG) were performed for 5 min at rest (normocapnia) and during hypercapnia induced by breathing 5% CO2 in air. CrCP and the resistance–area product (RAP) were obtained for each cardiac cycle and their dynamic response to a step change in MAP was calculated by means of transfer function analysis. The recovery of the CBFV response, following a step change in MAP, was mainly due to the contribution of RAP during both breathing conditions. However, CrCP made a highly significant contribution during normocapnia (P < 0.0001) and was the sole determinant of changes in the CBFV response, resulting from hypercapnia, which led to a reduction in the autoregulation index from 5.70 ± 1.58 (normocapnia) to 4.14 ± 2.05 (hypercapnia; P < 0.0001). In conclusion, CrCP makes a very significant contribution to the dynamic CBFV response to changes in MAP and plays a major role in explaining the deterioration of dynamic CA induced by hypercapnia. Further studies are needed to assess the relevance of CrCP contribution in physiological and clinical studies. Key points: Dynamic cerebral autoregulation (CA) is often expressed by the mean arterial blood pressure (MAP)–cerebral blood flow (CBF) relationship, with little attention given to the dynamic relationship between MAP and cerebrovascular resistance (CVR).In CBF velocity (CBFV) recordings with transcranial Doppler, evidence demonstrates that CVR should be replaced by a combination of a resistance–area product (RAP) with a critical closing pressure (CrCP) parameter, the blood pressure value where CBFV reaches zero due to vessels collapsing.Transfer function analysis of the MAP–CBFV relationship can be extended to the MAP–RAP and MAP–CrCP relationships, to assess their contribution to the dynamic CA response.During normocapnia, both RAP and CrCP make a significant contribution to explaining the MAP–CBFV relationship.Hypercapnia, a surrogate state of depressed CA, leads to marked changes in dynamic CA, that are entirely explained by the CrCP response, without further contribution from RAP in comparison with normocapnia. [ABSTRACT FROM AUTHOR]

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. 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. 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 FROM AUTHOR]

Key points: A fall in oxygen supply releases a remedial response that is otherwise prevented when the oxygen supply is sufficient; for example, the remedial function of HIF‐1α is released when oxygen levels fall.Concept: the physiological responses initiated when oxygen supply is compromised operate in a fail‐safe manner. This concept is applied to two cases: the control of cerebral blood flow, and the detection of hypoxia by the carotid body.The fail‐safe oxygen supply concept was tested with simple computer simulations to demonstrate its function and verify the ability to reproduce measured data.The computer model reproduced published observations, suggesting that the fail‐safe concept can be considered as a principle that provides novel insight into the physiology of oxygen supply in these cases. An engineered fail‐safe system automatically prevents or mitigates the consequences of a system failure. This operational concept can be applied both to the delivery of oxygen to the brain during hypoxia and anaemia, and to the carotid body response to hypoxia and hypercapnia. I aimed to develop simple mathematical models of these fail‐safe processes and examine their ability to replicate experimental observations. The intent is to demonstrate the validity of applying the fail‐safe concept, not to reveal the details of the physiology involved. The model calculations are based on a single compartment of the relevant tissue in each case that is challenged with a decrease in oxygen supply. The model equation parameters were adjusted to reproduce experimental observations. The fail‐safe model of cerebral blood flow control yielded results similar in form to published experimental observations of the cerebral blood flow responses to hypoxia and anaemia. The fail‐safe model of carotid body glomus cell control of intracellular hydrogen ion concentration also yielded results similar in form to observations of carotid sinus nerve responses to hypoxia and hypercapnia. The ability of these simple models to simulate experimental observations demonstrates the applicability of the fail‐safe concept to oxygen delivery. I suggest that a fail‐safe view of oxygen delivery provides novel physiological insight. Key points: A fall in oxygen supply releases a remedial response that is otherwise prevented when the oxygen supply is sufficient; for example, the remedial function of HIF‐1α is released when oxygen levels fall.Concept: the physiological responses initiated when oxygen supply is compromised operate in a fail‐safe manner. This concept is applied to two cases: the control of cerebral blood flow, and the detection of hypoxia by the carotid body.The fail‐safe oxygen supply concept was tested with simple computer simulations to demonstrate its function and verify the ability to reproduce measured data.The computer model reproduced published observations, suggesting that the fail‐safe concept can be considered as a principle that provides novel insight into the physiology of oxygen supply in these cases. [ABSTRACT FROM AUTHOR]

Key points: ATP‐sensitive K+ (KATP) channels mediate hypoxia‐induced cerebral vasodilatation and hyperperfusion in animals.We tested whether KATP channels blockade affects the increase in human cerebral blood flow (CBF) and the maintenance of oxygen delivery (CDO2) during hypoxia.Hypoxia‐induced increases in the anterior circulation and total cerebral perfusion were attenuated under KATP channels blockade affecting the relative changes of brain oxygen delivery.Therefore, in humans, KATP channels activation modulates the vascular tone in the anterior circulation of the brain, contributing to CBF and CDO2 responses to hypoxia. ATP‐sensitive K+ (KATP) channels mediate hypoxia‐induced cerebral vasodilatation and hyperperfusion in animals. We tested whether KATP channels blockade affects the increase in cerebral blood flow (CBF) and the maintenance of oxygen delivery (CDO2) during hypoxia in humans. Nine healthy men were exposed to 5‐min trials of normoxia and isocapnic hypoxia (IHX, 10% O2) before (BGB) and 3 h after glibenclamide ingestion (AGB). Mean arterial pressure (MAP), arterial saturation (SaO2), partial pressure of oxygen (PaO2) and carbon dioxide (PaCO2), internal carotid artery blood flow (ICABF), vertebral artery blood flow (VABF), total (t)CBF (Doppler ultrasound) and CDO2 were quantified during the trials. IHX provoked similar reductions in SaO2 and PaO2, while MAP was not affected by oxygen desaturation or KATP blockade. A smaller increase in ICABF (ΔBGB: 36 ± 23 vs. ΔAGB 11 ± 18%, p = 0.019) but not in VABF (∆BGB 26 ± 21 vs. ∆AGB 27 ± 27%, p = 0.893) was observed during the hypoxic trial under KATP channels blockade. Thus, IHX‐induced increases in tCBF (∆BGB 32 ± 19 vs. ∆AGB 14 ± 13%, p = 0.012) and CDO2 relative changes (∆BGB 7 ± 13 vs. ∆AGB −6 ± 14%, p = 0.048) were attenuated during the AGB hypoxic trial. In a separate protocol, 6 healthy men (5 from protocol 1) underwent a 5‐min exposure to normoxia and IHX before and 3 h after placebo (5 mg of cornstarch) ingestion. IHX reduced SaO2 and PaO2, but placebo did not affect the ICABF, VABF, tCBF, or CDO2 responses. Therefore, in humans, KATP channels activation modulates vascular tone in the anterior rather than the posterior circulation of the brain, contributing to tCBF and CDO2 responses to hypoxia. Key points: ATP‐sensitive K+ (KATP) channels mediate hypoxia‐induced cerebral vasodilatation and hyperperfusion in animals.We tested whether KATP channels blockade affects the increase in human cerebral blood flow (CBF) and the maintenance of oxygen delivery (CDO2) during hypoxia.Hypoxia‐induced increases in the anterior circulation and total cerebral perfusion were attenuated under KATP channels blockade affecting the relative changes of brain oxygen delivery.Therefore, in humans, KATP channels activation modulates the vascular tone in the anterior circulation of the brain, contributing to CBF and CDO2 responses to hypoxia. [ABSTRACT FROM AUTHOR]

Key points: Rapid alterations of gravitational stress during high‐performance aircraft push–pull manoeuvres induce dramatic shifts in volume and pressure within the circulation system, which may result in loss of consciousness due to the rapid and significant reduction in cerebral perfusion. There are still no specific and effective countermeasures so far.We found that lower body negative pressure (LBNP), applied prior to and during −Gz and released at the subsequent transition to +Gz, could effectively counteract gravitational haemodynamic stress induced by a simulated push–pull manoeuvre and improve cerebral diastolic perfusion in human subjects.We developed a LBNP strategy that effectively protects cerebral perfusion at rapid −Gz to +Gz transitions via improving cerebral blood flow and blood pressure during push–pull manoeuvres and highlight the importance of the timing of the intervention.Our findings provide a systemic link of integrated responses between the peripheral and cerebral haemodynamic changes during push–pull manoeuvres. The acute negative (−Gz) to positive (+Gz) gravity stress during high‐performance aircraft push–pull manoeuvres dramatically reduces transient cerebral perfusion, which may lead to loss of vision or even consciousness. The aim of this study was to explore a specific and effective counteractive strategy. Twenty‐three healthy young male volunteers (age 21 ± 1 year) were subjected to tilting‐simulated push–pull manoeuvres. Lower body negative pressure (LBNP) of −40 mmHg was applied prior to and during −Gz stress (−0.50 or −0.87 Gz) and released at the subsequent transition to +1.00 Gz stress. Beat‐to‐beat cerebral and systemic haemodynamics were continuously recorded during the simulated push–pull manoeuvre in LBNP bouts and corresponding control bouts. During the rapid gravitational transition from −Gz to +Gz, the mean cerebral blood flow velocity decreased significantly in control bouts, while it increased in LBNP bouts (control vs. LBNP bouts, −6.6 ± 4.6 vs. 5.1 ± 6.8 cm s−1 for −0.50 Gz, and −7.4 ± 4.8 vs. 3.4 ± 4.6 cm s−1 for −0.87 Gz, P < 0.01), which was attributed mainly to the elevation of diastolic flow. The LBNP bouts showed much smaller reduction of mean arterial blood pressure at the brain level than control bouts (control bouts vs. LBNP bouts, −38 ± 12 vs. −23 ± 10 mmHg for −0.50 to +1.00 Gz, and −62 ± 16 vs. −43 ± 11 mmHg for −0.87 to +1.00 Gz, P < 0.01). LBNP applied at −Gz and released at subsequent +Gz had biphasic counteractive effects against the gravitational responses to the push–pull manoeuvre. These data demonstrate that this LBNP strategy could effectively protect cerebral perfusion with dominant improvement of diastolic flow during push–pull manoeuvres. Key points: Rapid alterations of gravitational stress during high‐performance aircraft push–pull manoeuvres induce dramatic shifts in volume and pressure within the circulation system, which may result in loss of consciousness due to the rapid and significant reduction in cerebral perfusion. There are still no specific and effective countermeasures so far.We found that lower body negative pressure (LBNP), applied prior to and during −Gz and released at the subsequent transition to +Gz, could effectively counteract gravitational haemodynamic stress induced by a simulated push–pull manoeuvre and improve cerebral diastolic perfusion in human subjects.We developed a LBNP strategy that effectively protects cerebral perfusion at rapid −Gz to +Gz transitions via improving cerebral blood flow and blood pressure during push–pull manoeuvres and highlight the importance of the timing of the intervention.Our findings provide a systemic link of integrated responses between the peripheral and cerebral haemodynamic changes during push–pull manoeuvres. [ABSTRACT FROM AUTHOR]

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 investigatedThe present study assessed CBF regulation and neurovascular coupling during submaximal cycling exercise and temperature‐matched passive heat stress during isocapnia (i.e. end‐tidal PCO2 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 PCO2 and blood pressureExternal carotid artery blood flow increased by ∼43% during both exercise and passive heat stress, with no change in internal carotid artery blood flowNeurovascular 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 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 PCO2 and metabolism. The present study aimed to isolate the role of Tc from PCO2 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 PCO2 and PO2 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 PCO2 (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 < 0.001; 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 PCO2 and blood pressure. 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 investigatedThe present study assessed CBF regulation and neurovascular coupling during submaximal cycling exercise and temperature‐matched passive heat stress during isocapnia (i.e. end‐tidal PCO2 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 PCO2 and blood pressureExternal carotid artery blood flow increased by ∼43% during both exercise and passive heat stress, with no change in internal carotid artery blood flowNeurovascular 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 FROM AUTHOR]

Key points: It was unknown whether respiratory alkalosis impacts the global cerebral metabolic response as well as the cerebral pro‐oxidation and inflammatory response in passive hyperthermia.This study demonstrated that the cerebral metabolic rate was increased by ∼20% with passive hyperthermia of up to +2°C oesophageal temperature, and this response was unaffected by respiratory alkalosis.Additionally, the increase in cerebral metabolism did not significantly impact the net cerebral release of oxidative and inflammatory markers.These data indicate that passive heating of up to +2°C core temperature in healthy young men is not enough to confer a major oxidative and inflammatory burden on the brain, but it does markedly increase the cerebral metabolic rate, independently of PaCO2. There is limited information concerning the impact of arterial PCO2/pH on heat‐induced alteration in cerebral metabolism, as well as on the cerebral oxidative/inflammatory burden of hyperthermia. Accordingly, we sought to address two hypotheses: (1) passive hyperthermia will increase the cerebral metabolic rate of oxygen (CMRO2) consistent with a combined influence of Q10 and respiratory alkalosis; and (2) the net cerebral release of pro‐oxidative and pro‐inflammatory markers will be elevated in hyperthermia, particularly in poikilocapnic hyperthermia. Healthy young men (n = 6) underwent passive heating until an oesophageal temperature of 2°C above resting was reached. At 0.5°C increments in core temperature, CMRO2 was calculated from the product of cerebral blood flow (ultrasound) and the radial artery–jugular venous oxygen content difference (cannulation). Net cerebral glucose/lactate exchange, and biomarkers of oxidative and inflammatory stress were also measured. At +2.0°C oesophageal temperature, arterial PCO2 was restored to normothermic values using end‐tidal forcing. The primary findings were: (1) while CMRO2 was increased (P < 0.05) by ∼20% with hyperthermia of +1.5–2.0°C, this was not influenced by respiratory alkalosis, and (2) although biomarkers of pro‐oxidation and pro‐inflammation were systemically elevated in hyperthermia (P < 0.05), there were no differences in the trans‐cerebral exchange kinetics. These novel data indicate that passive heating of up to +2°C core temperature in healthy young men is not enough to confer a major oxidative and inflammatory burden on the brain, despite it markedly increasing CMRO2, irrespective of arterial pH. Key points: It was unknown whether respiratory alkalosis impacts the global cerebral metabolic response as well as the cerebral pro‐oxidation and inflammatory response in passive hyperthermia.This study demonstrated that the cerebral metabolic rate was increased by ∼20% with passive hyperthermia of up to +2°C oesophageal temperature, and this response was unaffected by respiratory alkalosis.Additionally, the increase in cerebral metabolism did not significantly impact the net cerebral release of oxidative and inflammatory markers.These data indicate that passive heating of up to +2°C core temperature in healthy young men is not enough to confer a major oxidative and inflammatory burden on the brain, but it does markedly increase the cerebral metabolic rate, independently of PaCO2. [ABSTRACT FROM AUTHOR]

Key points: The control of cerebral blood flow in hypoxia, anaemia and hypocapnia is reviewed with an emphasis on the links between cerebral blood flow and possible stimuli.A mathematical model is developed to examine the changes in the partial pressure of oxygen in brain tissue associated with changes in cerebral blood flow regulation produced by carbon dioxide, anaemia and hypoxia.The model demonstrates that hypoxia, anaemia and hypocapnia, alone or in combination, produce varying degrees of cerebral hypoxia, an effect exacerbated when blood flow regulation is impaired.The suitability of brain hypoxia as a common regulator of cerebral blood flow in hypoxia and anaemia was explored, although we failed to find support for this hypothesis. Rather, cerebral blood flow appears to be related to arterial oxygen concentration in both anaemia and hypoxia. A mathematical model is developed to examine the changes in the partial pressure of oxygen in brain tissue associated with changes in cerebral blood flow regulation produced by carbon dioxide, anaemia and hypoxia. The model simulation assesses the physiological plausibility of some currently hypothesized cerebral blood flow control mechanisms in hypoxia and anaemia, and also examines the impact of anaemia and hypoxia on brain hypoxia. In addition, carbon dioxide is examined for its impact on brain hypoxia in the context of concomitant changes associated with anaemia and hypoxia. The model calculations are based on a single compartment of brain tissue with constant metabolism and perfusion pressure, as well as previously developed equations describing oxygen and carbon dioxide carriage in blood. Experimental data are used to develop the control equations for cerebral blood flow regulation. The interactive model illustrates that there are clear interactions of anaemia, hypoxia and carbon dioxide in the determination of cerebral blood flow and brain tissue oxygen tension. In both anaemia and hypoxia, cerebral blood flow increases to maintain oxygen delivery, with brain hypoxia increasing when cerebral blood flow control mechanisms are impaired. Hypocapnia superimposes its effects, increasing brain hypoxia. Hypoxia, anaemia and hypocapnia, alone or in combination, produce varying degrees of cerebral hypoxia, and this effect is exacerbated when blood flow regulation is degraded by conditions that negatively impact cerebrovascular control. Differences in brain hypoxia in anaemia and hypoxia suggest that brain oxygen tension is not a plausible sensor for cerebral blood flow control. Key points: The control of cerebral blood flow in hypoxia, anaemia and hypocapnia is reviewed with an emphasis on the links between cerebral blood flow and possible stimuli.A mathematical model is developed to examine the changes in the partial pressure of oxygen in brain tissue associated with changes in cerebral blood flow regulation produced by carbon dioxide, anaemia and hypoxia.The model demonstrates that hypoxia, anaemia and hypocapnia, alone or in combination, produce varying degrees of cerebral hypoxia, an effect exacerbated when blood flow regulation is impaired.The suitability of brain hypoxia as a common regulator of cerebral blood flow in hypoxia and anaemia was explored, although we failed to find support for this hypothesis. Rather, cerebral blood flow appears to be related to arterial oxygen concentration in both anaemia and hypoxia. [ABSTRACT FROM AUTHOR]

Key points: Thermal and hypoxic stress commonly coexist in environmental, occupational and clinical settings, yet how the brain tolerates these multi‐stressor environments is unknownCore cooling by 1.0°C reduced cerebral blood flow (CBF) by 20–30% and cerebral oxygen delivery (CDO2) by 12–19% at sea level and high altitude, whereas core heating by 1.5°C did not reliably reduce CBF or CDO2Oxygen content in arterial blood was fully restored with acclimatisation to 4330 m, but concurrent cold stress reduced CBF and CDO2Gross indices of cognition were not impaired by any combination of thermal and hypoxic stress despite large reductions in CDO2Chronic hypoxia renders the brain susceptible to large reductions in oxygen delivery with concurrent cold stress, which might make monitoring core temperature more important in this context Real‐world settings are composed of multiple environmental stressors, yet the majority of research in environmental physiology investigates these stressors in isolation. The brain is central in both behavioural and physiological responses to threatening stimuli and, given its tight metabolic and haemodynamic requirements, is particularly susceptible to environmental stress. We measured cerebral blood flow (CBF, duplex ultrasound), cerebral oxygen delivery (CDO2), oesophageal temperature, and arterial blood gases during exposure to three commonly experienced environmental stressors – heat, cold and hypoxia – in isolation, and in combination. Twelve healthy male subjects (27 ± 11 years) underwent core cooling by 1.0°C and core heating by 1.5°C in randomised order at sea level; acute hypoxia (PET,O2 = 50 mm Hg) was imposed at baseline and at each thermal extreme. Core cooling and heating protocols were repeated after 16 ± 4 days residing at 4330 m to investigate any interactions with high altitude acclimatisation. Cold stress decreased CBF by 20–30% and CDO2 by 12–19% (both P < 0.01) irrespective of altitude, whereas heating did not reliably change either CBF or CDO2 (both P > 0.08). The increases in CBF with acute hypoxia during thermal stress were appropriate to maintain CDO2 at normothermic, normoxic values. Reaction time was faster and slower by 6–9% with heating and cooling, respectively (both P < 0.01), but central (brain) processes were not impaired by any combination of environmental stressors. These findings highlight the powerful influence of core cooling in reducing CDO2. Despite these large reductions in CDO2 with cold stress, gross indices of cognition remained stable. Key points: Thermal and hypoxic stress commonly coexist in environmental, occupational and clinical settings, yet how the brain tolerates these multi‐stressor environments is unknownCore cooling by 1.0°C reduced cerebral blood flow (CBF) by 20–30% and cerebral oxygen delivery (CDO2) by 12–19% at sea level and high altitude, whereas core heating by 1.5°C did not reliably reduce CBF or CDO2Oxygen content in arterial blood was fully restored with acclimatisation to 4330 m, but concurrent cold stress reduced CBF and CDO2Gross indices of cognition were not impaired by any combination of thermal and hypoxic stress despite large reductions in CDO2Chronic hypoxia renders the brain susceptible to large reductions in oxygen delivery with concurrent cold stress, which might make monitoring core temperature more important in this context [ABSTRACT FROM AUTHOR]

Key points: Dynamic cerebral autoregulation (CA) is expressed by the temporal pattern of cerebral blood flow (CBF) recovery following a sudden change in arterial blood pressure (BP).Transfer function analysis of BP as input and CBF velocity as output can express dynamic CA through its amplitude (or gain) and phase frequency responses.The upper frequency limit (FupLim) at which dynamic CA can operate is of considerable physiological interest and can also provide additional information about worsening CA due to disease processes.In healthy subjects FupLim was strongly dependent on arterial PCO2 changes induced by four different breathing manoeuvres.The considerable intersubject variability in FupLim suggests that fixed frequency bands should not be adopted for averaging values of gain and phase in studies of dynamic CA. Dynamic cerebral autoregulation (CA) can be expressed in the frequency domain by the amplitude and phase frequency responses calculated by transfer function analysis of arterial blood pressure (BP) and cerebral blood flow velocity (CBFV). We studied the effects of arterial PCO2 (PaCO2) on the upper frequency limit (FupLim) of these responses and its intersubject variability. Twenty‐four healthy subjects (11 female, age 36.0 ± 13.4 years) were recruited. Recordings of CBFV (transcranial Doppler ultrasound), BP (Finometer) and end‐tidal CO2 (PETCO2, capnography) were performed during 5 min at rest (normocapnia) and during four breathing manoeuvres: 5% and 8% CO2 in air and hyperventilation targeting reductions of 5 and 10 mmHg compared to normocapnia. FupLim was determined by the break point of the autoregulation index (ARI) curve as a function of frequency when the phase response was gradually set to zero. The five breathing conditions led to highly significant differences in PETCO2 (p < 0.0001), CBFV (P < 0.0001), ARI (p < 0.0001) and FupLim (p < 0.0001). FupLim ranged from 0.167 ± 0.036 Hz at the lowest values of hypocapnia (28.1 ± 1.9 mmHg) to 0.094 ± 0.040 Hz at the highest level of hypercapnia (41.7 ± 5.4 mmHg), showing a correlation of r = −0.53 (p < 0.001) with PETCO2. These findings reinforce the key role of PaCO2 in CBF regulation. The considerable intersubject variability of FupLim suggests that fixed frequency bands should not be adopted for averaging values of gain and phase in dynamic CA studies, and that the higher frequency band (0.20–0.40 Hz), in particular, does not contain relevant information about dynamic CA. Further investigations are needed to assess the information value of FupLim as a marker of dynamic CA efficiency in physiological and clinical studies. Key points: Dynamic cerebral autoregulation (CA) is expressed by the temporal pattern of cerebral blood flow (CBF) recovery following a sudden change in arterial blood pressure (BP).Transfer function analysis of BP as input and CBF velocity as output can express dynamic CA through its amplitude (or gain) and phase frequency responses.The upper frequency limit (FupLim) at which dynamic CA can operate is of considerable physiological interest and can also provide additional information about worsening CA due to disease processes.In healthy subjects FupLim was strongly dependent on arterial PCO2 changes induced by four different breathing manoeuvres.The considerable intersubject variability in FupLim suggests that fixed frequency bands should not be adopted for averaging values of gain and phase in studies of dynamic CA. [ABSTRACT FROM AUTHOR]

Key points: Sherpa have lived in the Nepal Himalaya for 25–40 thousand years and display positive physiological adaptations to hypoxia.Sherpa have previously been demonstrated to suffer less negative cerebral side effects of ascent to extreme altitude, yet little is known as to whether or not they display differential regulation of oxygen delivery to the brain compared to lowland natives.We demonstrate that Sherpa have lower brain blood flow during ascent to and acclimatization at high altitude compared to lowlanders and that this difference in flow is not attributable to factors such as mean arterial pressure, blood viscosity and pH.The observed lower cerebral oxygen delivery in Sherpa likely represents a positive adaptation that may indicate a cerebral hypometabolic conservation of energy at altitude and/or decreased risk of other cerebral consequences such as vasogenic oedema. Debilitating side effects of hypoxia manifest within the central nervous system; however, high‐altitude natives of the Tibetan plateau, the Sherpa, experience negligible cerebral effects compared to lowland natives at extreme altitude. Phenotypical optimization of the oxygen cascade has been demonstrated in the systemic circulation of Tibetans and Sherpa, likely underscoring their adapted capacity to thrive at altitude. Yet, little is known as to how the cerebral circulation of Sherpa may be adapted. To examine potential differences in cerebral oxygen delivery in Sherpa compared to lowlanders we measured arterial blood gases and global cerebral blood flow (duplex ultrasound) during a 9 day ascent to 5050 m. Although cerebral oxygen delivery was maintained during ascent in lowlanders, it was significantly reduced in the Sherpa at 3400 m (−30.3 ± 21.6%; P < 0.01) and 4371 m (−14.2 ± 10.7%; P = 0.03). Furthermore, linear mixed effects modelling indicated that independent of differences in mean arterial pressure, pH and blood viscosity, race accounts for an approximately 100 mL min−1 (∼17–34%) lower cerebral blood flow in Sherpa compared to lowlanders across ascent to altitude (P = 0.046). To ascertain the role of chronic hypoxia independent of the ascent, Sherpa who had not recently descended were also examined at 5050 m. In these Sherpa, cerebral oxygen delivery was also lower compared to lowlanders (∼22% lower; P < 0.01). We highlight new information about the influence of race and genetic adaptation in the regulation of cerebral oxygen delivery. The lower cerebral oxygen delivery in the Sherpa potentially represents a positive adaptation considering Sherpa endure less deleterious cerebral consequences than lowlanders at altitude. Key points: Sherpa have lived in the Nepal Himalaya for 25–40 thousand years and display positive physiological adaptations to hypoxia.Sherpa have previously been demonstrated to suffer less negative cerebral side effects of ascent to extreme altitude, yet little is known as to whether or not they display differential regulation of oxygen delivery to the brain compared to lowland natives.We demonstrate that Sherpa have lower brain blood flow during ascent to and acclimatization at high altitude compared to lowlanders and that this difference in flow is not attributable to factors such as mean arterial pressure, blood viscosity and pH.The observed lower cerebral oxygen delivery in Sherpa likely represents a positive adaptation that may indicate a cerebral hypometabolic conservation of energy at altitude and/or decreased risk of other cerebral consequences such as vasogenic oedema. [ABSTRACT FROM AUTHOR]

Key points: Cerebral autoregulation is most effective in buffering against pressure fluctuations slower than 0.03 Hz (∼30 s). This suggests that frequency bands for characterizing cerebral autoregulation should be redefinedLow cross‐spectral coherence below 0.03 Hz highlights the limitations of transfer function approachesHaemodynamic changes induced by lower body pressure could not fully explain the differences in autoregulation estimated from spontaneous vs. augmented fluctuations, and thus, observations of spontaneous fluctuations should not be relied on whenever possible. There is currently little empirical basis for time scales that are considered to be most significant in cerebrovascular counter‐regulation of changes in arterial pressure. Although it is well established that cerebral autoregulation behaves as a 'high‐pass' filter, recommended frequency bands have been largely arbitrarily determined. To test effectiveness of cerebral autoregulation, we refined oscillatory lower body pressure (LBP) to augment resting pressure fluctuations below 0.1 Hz by a factor of two in 13 young male volunteers, and thoroughly characterized the time and frequency responses of cerebral autoregulation. We observed that despite a threefold increase in arterial pressure power <0.03 Hz with oscillatory LBP, there was no change in cerebral blood flow power, indicating near perfect counter‐regulation. By contrast, in the range 0.03–0.10 Hz, both cerebral blood flow and arterial pressure power more than doubled. Our data demonstrate that cerebral autoregulation is most effective in buffering against pressure fluctuations slower than 0.03 Hz (∼30 s). This suggests that frequency bands of interest should be redefined and recording length should be increased considerably to account for this. Furthermore, low cross‐spectral coherence below 0.03 Hz, even when pressure fluctuations were augmented, highlights the uncertainty in transfer function approaches and the need to either report precision or use non‐linear approaches. Finally, haemodynamic changes induced by LBP could not fully explain the differences in autoregulation estimated from spontaneous vs. augmented fluctuations, and thus, observations of spontaneous fluctuations should not be relied on whenever possible. Key points: Cerebral autoregulation is most effective in buffering against pressure fluctuations slower than 0.03 Hz (∼30 s). This suggests that frequency bands for characterizing cerebral autoregulation should be redefinedLow cross‐spectral coherence below 0.03 Hz highlights the limitations of transfer function approachesHaemodynamic changes induced by lower body pressure could not fully explain the differences in autoregulation estimated from spontaneous vs. augmented fluctuations, and thus, observations of spontaneous fluctuations should not be relied on whenever possible. [ABSTRACT FROM AUTHOR]

Key points: Sleep disordered breathing (SDB) affects 4–11% of children and is associated with adverse neurocognitive, behavioural and cardiovascular outcomes, including reduced autonomic control.The relationship between heart rate variability (HRV; a measure of autonomic control) and age found in non‐snoring control children was absent during sleep in children with SDB.Age significantly predicted increasing cerebral oxygenation during wake in non‐snoring control children, whereas during sleep, HRV significantly predicted decreasing cerebral oxygenation.Cerebral oxygenation was not associated with either age or HRV in children with SDB during both wake and sleep.SDB significantly disrupts the normal maturation of autonomic control and the positive association between autonomic control and cerebral oxygenation found in non‐snoring children, and we speculate that the dampened autonomic control exhibited by children with SDB may have an attenuating effect on cerebral autoregulation via the moderating influence of HRV on cerebral blood flow. The repetitive episodes of hypoxia that are features of sleep disordered breathing (SDB) in children are associated with alterations in autonomic control of heart rate in an age‐dependent manner. We aimed to relate heart rate variability (HRV) parameters to age and measures of cerebral oxygenation in children (3–12 years old) with SDB and non‐snoring controls. Children (SDB, n = 117; controls, n = 42; 3–12 years) underwent overnight polysomnography. Total (TP), low‐ (LF) and high‐frequency (HF) power, tissue oxygenation index (TOI) and fractional tissue oxygen extraction (FTOE) were analysed during wake and sleep. Pearson's correlations determined the association between age and HRV parameters, and multiple linear regressions between HRV, age and cerebral oxygenation parameters. During wake, age had a positive association with LF power, reflecting increased parasympathetic and sympathetic activity with increasing age for both control and SDB groups. This association was also evident during sleep in controls, but was absent in children with SDB. In controls, during wake TOI had a positive, and FTOE a negative association with age. During sleep, TP, LF and HF power were significant, negative determinants of TOI and positive determinants of FTOE. These associations were not seen in children with SDB during wake or sleep. SDB disrupts the normal maturation of the autonomic control of heart rate and the association between HRV and cerebral oxygenation exhibited by non‐snoring control children of primary school age. These results highlight the impact SDB has on cardiovascular control and the potential impact on adverse cardiovascular outcomes. Key points: Sleep disordered breathing (SDB) affects 4–11% of children and is associated with adverse neurocognitive, behavioural and cardiovascular outcomes, including reduced autonomic control.The relationship between heart rate variability (HRV; a measure of autonomic control) and age found in non‐snoring control children was absent during sleep in children with SDB.Age significantly predicted increasing cerebral oxygenation during wake in non‐snoring control children, whereas during sleep, HRV significantly predicted decreasing cerebral oxygenation.Cerebral oxygenation was not associated with either age or HRV in children with SDB during both wake and sleep.SDB significantly disrupts the normal maturation of autonomic control and the positive association between autonomic control and cerebral oxygenation found in non‐snoring children, and we speculate that the dampened autonomic control exhibited by children with SDB may have an attenuating effect on cerebral autoregulation via the moderating influence of HRV on cerebral blood flow. [ABSTRACT FROM AUTHOR]

Key points: It is unknown whether excessive reactive oxygen species (ROS) production drives the isocapnic hyperoxia (IH)‐induced decline in human cerebral blood flow (CBF) via reduced nitric oxide (NO) bioavailability and leads to disruption of the blood–brain barrier (BBB) or neural‐parenchymal damage.Cerebral metabolic rate for oxygen (CMRO2) and transcerebral exchanges of NO end‐products, oxidants, antioxidants and neural‐parenchymal damage markers were simultaneously quantified under IH with intravenous saline and ascorbic acid infusion.CBF and CMR O2 were reduced during IH, responses that were followed by increased oxidative stress and reduced NO bioavailability when saline was infused. No indication of neural‐parenchymal damage or disruption of the BBB was observed during IH.Antioxidant defences were increased during ascorbic acid infusion, while CBF, CMR O2, oxidant and NO bioavailability markers remained unchanged.ROS play a role in the regulation of CBF and metabolism during IH without evidence of BBB disruption or neural‐parenchymal damage. To test the hypothesis that isocapnic hyperoxia (IH) affects cerebral blood flow (CBF) and metabolism through exaggerated reactive oxygen species (ROS) production, reduced nitric oxide (NO) bioavailability, disturbances in the blood–brain barrier (BBB) and neural‐parenchymal homeostasis, 10 men (24 ± 1 years) were exposed to a 10 min IH trial (100% O2) while receiving intravenous saline and ascorbic acid (AA, 3 g) infusion. Internal carotid artery blood flow (ICABF), vertebral artery blood flow (VABF) and total CBF (tCBF, Doppler ultrasound) were determined. Arterial and right internal jugular venous blood was sampled to quantify the cerebral metabolic rate of oxygen (CMRO2), transcerebral exchanges (TCE) of NO end‐products (plasma nitrite), antioxidants (AA and AA plus dehydroascorbic acid (AA+DA)) and oxidant biomarkers (thiobarbituric acid‐reactive substances (TBARS) and 8‐isoprostane), and an index of BBB disruption and neuronal‐parenchymal damage (neuron‐specific enolase; NSE). IH reduced ICABF, tCBF and CMR O2, while VABF remained unchanged. Arterial 8‐isoprostane and nitrite TCE increased, indicating that CBF decline was related to ROS production and reduced NO bioavailability. AA, AA+DA and NSE TCE did not change during IH. AA infusion did not change the resting haemodynamic and metabolic parameters but raised antioxidant defences, as indicated by increased AA/AA+DA concentrations. Negative AA+DA TCE, unchanged nitrite, reductions in arterial and venous 8‐isoprostane, and TBARS TCE indicated that AA infusion effectively inhibited ROS production and preserved NO bioavailability. Similarly, AA infusion prevented IH‐induced decline in regional and total CBF and re‐established CMR O2. These findings indicate that ROS play a role in CBF regulation and metabolism during IH without evidence of BBB disruption or neural‐parenchymal damage. Key points: It is unknown whether excessive reactive oxygen species (ROS) production drives the isocapnic hyperoxia (IH)‐induced decline in human cerebral blood flow (CBF) via reduced nitric oxide (NO) bioavailability and leads to disruption of the blood–brain barrier (BBB) or neural‐parenchymal damage.Cerebral metabolic rate for oxygen (CMRO2) and transcerebral exchanges of NO end‐products, oxidants, antioxidants and neural‐parenchymal damage markers were simultaneously quantified under IH with intravenous saline and ascorbic acid infusion.CBF and CMR O2 were reduced during IH, responses that were followed by increased oxidative stress and reduced NO bioavailability when saline was infused. No indication of neural‐parenchymal damage or disruption of the BBB was observed during IH.Antioxidant defences were increased during ascorbic acid infusion, while CBF, CMR O2, oxidant and NO bioavailability markers remained unchanged.ROS play a role in the regulation of CBF and metabolism during IH without evidence of BBB disruption or neural‐parenchymal damage. [ABSTRACT FROM AUTHOR]

The article discusses the blood flow pulsatility in patients with continuous flow (CF) left ventricular assist device (LVAD). Topics mention including the level of the microcirculation, impact of CF-LVAD on cerebral artery properties beyond gas exchange and perfusion–cerebral blood flow (CBF) curve unusual point.

Key points: Preterm infants often have poor cardiovascular function that is associated with adverse neurodevelopmental outcomes.Preterm infants may be vulnerable to hypovolaemia due to excessive vasodilatation and leaky capillaries.Following reduction in blood volume, cardiac output and mean arterial pressure were reduced to the same extent in term and preterm piglets.Cerebral blood flow was maintained following blood volume reduction in term but not in preterm piglets.Effective detection and treatment of functional hypovolaemia may reduce the risk of brain injury in preterm infants. Preterm infants often have impaired cardiovascular function that may contribute to poor neurodevelopmental outcomes. The study aimed to determine the effects of reduced blood volume on cardiovascular function, including cerebral blood flow, in preterm and term piglets. In preterm (97/115 days) and term piglets, up to 10% of the estimated blood volume was removed. Removal of blood was stopped if MAP dropped below 20 mmHg. Heart rate, cardiac contractility and relaxation, cardiac output, mean arterial pressure (MAP), and cerebral blood flow were measured at baseline and again after blood volume reduction. The volume of blood removed was less in preterm piglets than in term piglets (5.1 ± 1.8 vs. 7.7 ± 0.9 mL kg−1, mean ± SD, P < 0.001). Cardiac output and MAP decreased to the same extent in term and preterm piglets. Cerebral blood flow decreased in preterm but not term piglets and cerebral vascular conductance increased in term piglets only. Compensatory responses to maintain cerebral blood flow after blood volume reduction are active in term piglets but not in preterm piglets. As a result, even a small reduction in blood volume, or an increase in the capacity of the circulatory system leading to functional hypovolaemia, may lead to a significant reduction in cerebral blood flow and contribute to brain injury in preterm neonates. Key points: Preterm infants often have poor cardiovascular function that is associated with adverse neurodevelopmental outcomes.Preterm infants may be vulnerable to hypovolaemia due to excessive vasodilatation and leaky capillaries.Following reduction in blood volume, cardiac output and mean arterial pressure were reduced to the same extent in term and preterm piglets.Cerebral blood flow was maintained following blood volume reduction in term but not in preterm piglets.Effective detection and treatment of functional hypovolaemia may reduce the risk of brain injury in preterm infants. [ABSTRACT FROM AUTHOR]

Additionally, as reductions in CBF during severe heat strain did not dictate thermal tolerance or affect exercise performance, these results may indicate an increased possibility of cerebral oxidative/pro-inflammatory stress (via reduced convective heat loss) with prolonged sauna/spa heat therapy and hyperthermic exercise prior to achieving subjective tolerance. Keywords: cerebral blood flow; cerebrovascular CO2 reactivity; exercise; heat stress; thermal tolerance EN cerebral blood flow cerebrovascular CO2 reactivity exercise heat stress thermal tolerance 2513 2515 3 05/17/21 20210515 NES 210515 The high relative metabolic rate of brain tissue, paired with an exceptionally restricted capacity for substrate storage (e.g. <10% non-oxidative metabolism), necessitates tight regulation of cerebral oxygen delivery ( HT ht = cerebral blood flow × arterial oxygen content). [Extracted from the article]

Keywords: CBF; cognition; enigma EN CBF cognition enigma 1739 1741 3 03/17/21 20210315 NES 210315 The relationship between cerebral blood flow (CBF) and cognitive function has been widely explored, although the extent to which CBF influences cognition remains inconclusive. Cognition assessment tools There is no universally accepted tool to assess cognition. Several factors that can impact cognition need to be considered in experimental studies that assess cognition. [Extracted from the article]

Keywords: altitude; brain blood flow; cerebral blood flow; cold stress; heat stress; hypoxia Most of these studies have not assessed CBF and CDO SB 2 sb as mechanisms underlying these changes in cognitive function with independent or combined exposures to cold stress and hypoxia. Importantly, they found that exposure to acute hypoxia during cold stress attenuates the hypocapnia-induced cerebral vasoconstriction and that altitude acclimatization exacerbates the reductions in CBF and CDO SB 2 sb during cold stress. Altitude, brain blood flow, cerebral blood flow, cold stress, heat stress, hypoxia. [Extracted from the article]

Key points: Hypoxaemia evokes a repertoire of homeostatic adjustments that maintain oxygen supply to organs and tissues including the brain and skeletal muscles. Because hypertensive patients have impaired endothelial‐dependent vasodilatation and an increased sympathetic response to arterial oxygen desaturation, we investigated whether hypertension impairs isocapnic hypoxia‐induced cerebral and skeletal muscle hyperaemia to an extent that limits oxygen supply. In middle‐aged hypertensive men, vertebral and femoral artery blood flow do not increase in response to isocapnic hypoxia, limiting brain and peripheral hyperaemia and oxygen supply. Increased chemoreflex‐induced sympathetic activation impairs skeletal muscle perfusion and oxygen supply, whereas an attenuation of local vasodilatory signalling in the posterior cerebrovasculature reduced brain hyperperfusion of hypertensive middle‐aged men in response to isocapnic hypoxia. Abstract: The present study investigated whether hypertension impairs isocapnic hypoxia (IH)‐induced cerebral and skeletal muscle hyperaemia to an extent that limits oxygen supply. Oxygen saturation (oxymetry), mean arterial pressure (photoplethysmography) and muscle sympathetic nerve activity (MSNA; microneugraphy), as well as femoral artery (FA), internal carotid artery and vertebral artery (VA) blood flow (BF; Doppler ultrasound), were quantified in nine normotensive (NT) (aged 40 ± 11 years, systolic pressure 119 ± 7 mmHg and diastolic pressure 73 ± 6 mmHg) and nine hypertensive men (HT) (aged 44 ± 12 years, systolic pressure 152 ± 11 mmHg and diastolic pressure 90 ± 9 mmHg) during 5 min of normoxia (21% O2) and IH (10% O2). Total cerebral blood flow (tCBF), brain (CDO2) and leg (LDO2) oxygen delivery were estimated. IH provoked similar oxygen desaturation without changing mean arterial pressure. Internal carotid artery perfusion increased in both groups during IH. However, VA and FA BF only increased in NT. Thus, IH‐induced increase in tCBF was smaller in HT. CDO2 only increased in NT and LDO2 decreased in HT. Furthermore, IH evoked a greater increase in HT MSNA. Changes in MSNA were inversely related to FA BF, LDO2 and end‐tidal oxygen tension. In conclusion, hypertension disturbs regional and total cerebrovascular and peripheral responses to IH and consequently limits oxygen supply to the brain and skeletal muscle. Although increased chemoreflex‐induced sympathetic activation may explain impaired peripheral perfusion, attenuated vasodilatory signalling in the posterior cerebrovasculature appears to be responsible for the small increase in tCBF when HT were exposed to IH. [ABSTRACT FROM AUTHOR]