Exercise breaks prevent attenuation in cerebrovascular function following an acute bout of uninterrupted sitting in healthy children.

The purpose of this study was to examine the effect of an acute bout of prolonged sitting with and without exercise breaks on cerebrovascular function in 7- to 13-year-old children. Forty-two children and adolescents were recruited to a crossover trial, with 15 girls (mean age 10.1 ± 2.5 years) and 16 boys (mean age 10.5 ± 1.3 years) completing the two trial conditions: SIT, uninterrupted sitting for 3 h and CYCLE, 3 h of sitting interrupted hourly with a 10-min moderate intensity exercise break. Cerebrovascular function was measured Pre and Post SIT and CYCLE from blood flow ( Q ̇ ${\dot{Q}}$ ), diameter, and shear rate of the internal carotid artery (ICA) at rest and in response to CO2 . Blood velocity in the middle (MCA) and posterior (PCA) cerebral arteries was assessed at rest, during a neurovascular coupling task (NVC) and in response to CO2 . We demonstrate that SIT but not CYCLE reduced ICA cerebrovascular reactivity to CO2 (%Δ ICA Q ̇ ${\dot{Q}}$ /Δ end-tidal CO2 : SIT: Pre 5.0 ± 2.4%/mmHg to Post 3.3 ± 2.8%/mmHg vs. CYCLE: Pre 4.4 ± 2.3%/mmHg to Post 5.3 ± 3.4%/mmHg, P = 0.05) and slowed the MCA blood velocity onset response time to hypercapnia (SIT: Pre 57.2 ± 32.6 s to Post 76.6 ± 55.2 s, vs. CYCLE: Pre 64.1 ± 40.4 s to Post 52.3 ± 28.8 s, P = 0.05). There were no changes in NVC. Importantly, breaking up prolonged sitting with hourly exercise breaks prevented the reductions in cerebrovascular reactivity to CO2 and the slowed intracranial blood velocity onset response time to hypercapnia apparent with uninterrupted sitting in children. NEW FINDINGS: What is the central question of this study? What are the effects of interrupting prolonged sitting on cerebrovascular function in children? What is the main finding and its importance? Prolonged sitting results in declines in cerebrovascular reactivity, a valuable index of cerebrovascular health. Breaking up prolonged sitting with hourly 10 min exercise breaks prevented these changes. These initial findings suggest excessive sedentary behaviour does impact cerebrovascular function in childhood, but taking exercise breaks prevents declines.

Hemoglobin and cerebral hypoxic vasodilation in humans: Evidence for nitric oxide-dependent and S-nitrosothiol mediated signal transduction.

Cerebral hypoxic vasodilation is poorly understood in humans, which undermines the development of therapeutics to optimize cerebral oxygen delivery. Across four investigations (total n = 195) we investigated the role of nitric oxide (NO) and hemoglobin-based S-nitrosothiol (RSNO) and nitrite (NO2-) signaling in the regulation of cerebral hypoxic vasodilation. We conducted hemodilution (n = 10) and NO synthase inhibition experiments (n = 11) as well as hemoglobin oxygen desaturation protocols, wherein we measured cerebral blood flow (CBF), intra-arterial blood pressure, and in subsets of participants trans-cerebral release/uptake of RSNO and NO2-. Higher CBF during hypoxia was associated with greater trans-cerebral RSNO release but not NO2-, while NO synthase inhibition reduced cerebral hypoxic vasodilation. Hemodilution increased the magnitude of cerebral hypoxic vasodilation following acute hemodilution, while in 134 participants tested under normal conditions, hypoxic cerebral vasodilation was inversely correlated to arterial hemoglobin concentration. These studies were replicated in a sample of polycythemic high-altitude native Andeans suffering from excessive erythrocytosis (n = 40), where cerebral hypoxic vasodilation was inversely correlated to hemoglobin concentration, and improved with hemodilution (n = 6). Collectively, our data indicate that cerebral hypoxic vasodilation is partially NO-dependent, associated with trans-cerebral RSNO release, and place hemoglobin-based NO signaling as a central mechanism of cerebral hypoxic vasodilation in humans.

Cerebral O2 and CO2 transport in isovolumic haemodilution: Compensation of cerebral delivery of O2 and maintenance of cerebrovascular reactivity to CO2.

This study investigated the influence of acute reductions in arterial O2 content (CaO2) via isovolumic haemodilution on global cerebral blood flow (gCBF) and cerebrovascular CO2 reactivity (CVR) in 11 healthy males (age; 28 ± 7 years: body mass index; 23 ± 2 kg/m2). Radial artery and internal jugular vein catheters provided measurement of blood pressure and gases, quantification of cerebral metabolism, cerebral CO2 washout, and trans-cerebral nitrite exchange (ozone based chemiluminescence). Prior to and following haemodilution, the partial pressure of arterial CO2 (PaCO2) was elevated with dynamic end-tidal forcing while gCBF was measured with duplex ultrasound. CVR was determined as the slope of the gCBF response and PaCO2. Replacement of ∼20% of blood volume with an equal volume of 5% human serum albumin (Alburex® 5%) reduced haemoglobin (13.8 ± 0.8 vs. 11.3 ± 0.6 g/dL; P < 0.001) and CaO2 (18.9 ± 1.0 vs 15.0 ± 0.8 mL/dL P < 0.001), elevated gCBF (+18 ± 11%; P = 0.002), preserved cerebral oxygen delivery (P = 0.49), and elevated CO2 washout (+11%; P = 0.01). The net cerebral uptake of nitrite (11.6 ± 14.0 nmol/min; P = 0.027) at baseline was abolished following haemodilution (-3.6 ± 17.9 nmol/min; P = 0.54), perhaps underpinning the conservation of CVR (61.7 ± 19.0 vs. 69.0 ± 19.2 mL/min/mmHg; P = 0.23). These findings demonstrate that the cerebrovascular responses to acute anaemia in healthy humans are sufficient to support the maintenance of CVR.

Dynamic onset response of the internal carotid artery to hypercapnia is blunted in children compared with adults.

Intracranial blood velocity reactivity to a steady-state hypercapnic stimulus has been shown to be similar in children and adults, but the onset response to hypercapnia is slower in the child. Given the vasodilatory effect of hypercapnia on the cerebrovasculature, assessment of vessel diameter, and blood flow are vital to fully elucidate whether the temporal hypercapnic response differs in children versus adults. Assessment of internal carotid artery (ICA) vessel diameter (ICAd), blood velocity (ICAv), volumetric blood flow (QICA ), and shear rate (ICASR ) in response to a 4 min hypercapnic challenge was completed in children (n = 14, 8 girls; 9.8 ± 0.7 years) and adults (n = 17, 7 females; 24.7 ± 1.8 years). The dynamic onset responses of partial pressure of end-tidal CO2 (PET CO2 ), QICA , ICAv, and ICASR to hypercapnia were modeled, and mean response time (MRT) was computed. Following 4 min of hypercapnia, ICA reactivity and ICAd were comparable between the groups. Despite a similar MRT in PET CO2 in children and adults, children had slower QICA (children 108 ± 60 s vs. adults 66 ± 37 s; p = 0.023), ICAv (children 120 ± 52 s vs. adults 52 ± 31 s; p = 0.001), and ICASR (children 90 ± 27 s vs. adults 47 ± 36 s; p = 0.001) MRTs compared with adults. This is the first study to show slower hypercapnic hyperemic kinetic responses of the ICA in children. The mechanisms determining these differences and the need to consider the duration of hypercapnic exposure when assessing CVR in children should be considered in future studies.

The influence of sex and maturation on carotid and vertebral artery hemodynamics and associations with free-living (in)activity in 6-17-year-olds.

We explored the influence of sex and maturation on resting cervical artery hemodynamics (common carotid artery, CCA; internal carotid artery, ICA; and vertebral artery, VA), free-living physical activity, and sedentary behavior in children 6-17 yr of age. In addition, we investigated the relationship between physical activity, sedentary behavior, and cervical artery hemodynamics. Seventy-eight children and adolescents, girls (n = 42; mean age, 11.4 ± 2.5 yr) and boys (n = 36; mean age, 11.0 ± 2.6 yr), completed anthropometric measures, duplex ultrasound assessment of the cervical arteries, and wore an activPAL accelerometer to assess physical activity (indexed by steps/day) and sedentary behavior for 7 days. The ICA and VA diameters were similar between prepubertal and pubertal groups, as was volumetric blood flow (Q); however, the CCA diameter was significantly larger in the pubertal group (P < 0.05). Boys were found to have larger diameters in all cervical arteries than girls, as well as higher QCCA, QICA, and global cerebral blood flow (P < 0.05). The pubertal group was more sedentary (100 min/day more; P < 0.05) and took 3,500 fewer steps/day than the prepubertal group (P < 0.05). Shear rate (SR) and Q of the cervical arteries showed no relationship to physical activity or prolonged bouts of sedentary behavior; however, a significant negative relationship was apparent between total sedentary time and internal carotid artery shear rate (ICASR) after covarying for steps/day and maturation (P < 0.05). These findings provide novel insight into the potential influence sedentary behavior may have on cerebrovascular blood flow in healthy girls and boys.NEW & NOTEWORTHY Cerebral blood flow is known to change with age; however, assessing these age-related changes is complex and requires consideration of pubertal status. This, to our knowledge, is the first study to investigate the influence of sex and maturation on resting cervical artery hemodynamics and subsequently explore associations with physical activity and sedentary behavior in healthy children and adolescents. Our findings suggest that habitual sedentary behavior may influence cervical artery hemodynamics in youth, independent of physical activity, maturation, and sex.

Mental Health Literacy in Zurich: A First Measurement Attempt Using the General HLS-EU-Q47.

Background: Mental health literacy (MHL) promises to be an important factor for public health by enabling people to take responsibility for their own mental health. To date, there is no measurement tool that allows the assessment of a comprehensive understanding of MHL as part of health literacy (HL). Nonetheless, the widely used Health Literacy Survey European Questionnaire 47 (HLS-EU-Q47) includes items assessing at least some MHL-aspects in the context of HL. The present study aimed at investigating how these MHL-aspects are related to HL, health behavior and health outcome and how they differ between sociodemographic groups. Methods: Data from the Health Literacy Survey Zurich 2018, collected by an adapted version of the HLS-EU-Q47, served to investigate these relationships. Results: MHL-aspects were related to HL, health behavior and health outcome. Nearly half of all respondents (45%; N = 904) showed low MHL levels, particularly those with higher age and higher financial deprivation. Conclusions: Relations of MHL-aspects with HL, health behavior, and health outcome indicate their potential importance for future interventions in public health, addressing mental health and MHL. A specific MHL tool is needed to comprehensively investigate these relations, which could be developed by extending the present measurement approach.

Influence of iron manipulation on hypoxic pulmonary vasoconstriction and pulmonary reactivity during ascent and acclimatization to 5050 m.

KEY POINTS: Iron acts as a cofactor in the stabilization of the hypoxic-inducible factor family, and plays an influential role in the modulation of hypoxic pulmonary vasoconstriction. It is uncertain whether iron regulation is altered in lowlanders during either (1) ascent to high altitude, or (2) following partial acclimatization, when compared to high-altitude adapted Sherpa. During ascent to 5050 m, the rise in pulmonary artery systolic pressure (PASP) was blunted in Sherpa, compared to lowlanders; however, upon arrival to 5050 m, PASP levels were comparable in both groups, but the reduction in iron bioavailability was more prevalent in lowlanders compared to Sherpa. Following partial acclimatization to 5050 m, there were differential influences of iron status manipulation (via iron infusion or chelation) at rest and during exercise between lowlanders and Sherpa on the pulmonary vasculature. ABSTRACT: To examine the adaptational role of iron bioavailability on the pulmonary vascular responses to acute and chronic hypobaric hypoxia, the haematological and cardiopulmonary profile of lowlanders and Sherpa were determined during: (1) a 9-day ascent to 5050 m (20 lowlanders; 12 Sherpa), and (2) following partial acclimatization (11 ± 4 days) to 5050 m (18 lowlanders; 20 Sherpa), where both groups received an i.v. infusion of either iron (iron (iii)-hydroxide sucrose) or an iron chelator (desferrioxamine). During ascent, there were reductions in iron status in both lowlanders and Sherpa; however, Sherpa appeared to demonstrate a more efficient capacity to mobilize stored iron, compared to lowlanders, when expressed as a Δhepcidin per unit change in either body iron or the soluble transferrin receptor index, between 3400-5050 m (P = 0.016 and P = 0.029, respectively). The rise in pulmonary artery systolic pressure (PASP) was blunted in Sherpa, compared to lowlanders during ascent; however, PASP was comparable in both groups upon arrival to 5050 m. Following partial acclimatization, despite Sherpa demonstrating a blunted hypoxic ventilatory response and greater resting hypoxaemia, they had similar hypoxic pulmonary vasoconstriction when compared to lowlanders at rest. Iron-infusion attenuated PASP in both groups at rest (P = 0.005), while chelation did not exaggerate PASP in either group at rest or during exaggerated hypoxaemia ( PIO2  = 67 mmHg). During exercise at 25% peak wattage, PASP was only consistently elevated in Sherpa, which persisted following both iron infusion or chelation. These findings provide new evidence on the complex interplay of iron regulation on pulmonary vascular regulation during acclimatization and adaptation to high altitude.

Self-Assessment Tool to Promote Organizational Health Literacy in Primary Care Settings in Switzerland.

Dealing with health information and taking care of one's own health are key aspects of health literacy and a difficulty for nearly half of the population in Europe. Limited health literacy often results in poorer health outcomes. Health literacy is a fundamental health determinant, and its improvement provides great potential for addressing public health challenges. Health care organizations play an important role in improving population's health literacy. Health literate health care organizations facilitate access, understanding and use of health information and decrease the demands and complexities of the health care system. Few efforts have been taken so far to promote organizational health literacy, especially in German-speaking countries. This project aimed at developing a self-assessment tool, which enables primary care organizations to assess and improve their level of health literacy. The self-assessment tool was developed and evaluated with general practitioners and community care organizations in Switzerland. Here the participative development process, outcomes and the three modules of the self-assessment tool are presented: (1) manual with detailed introduction and instruction, (2) checklist for self-assessment of organizational health literacy and (3) handbook with measures for improvement. The aim of this tool is that organizations are able to identify the need for action, plan and implement improvement measures.

Nitric oxide is fundamental to neurovascular coupling in humans.

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

Acute reductions in haematocrit increase flow-mediated dilatation independent of resting nitric oxide bioavailability in humans.

KEY POINTS: Changes in haematocrit influence nitric oxide signalling through alterations in shear stress stimuli and haemoglobin scavenging of nitric oxide; these two regulatory factors have not been assessed simultaneously Isovolumic haemodilution led to a marked increase in brachial artery flow-mediated dilatation in humans The increase in flow-mediated dilatation occurred in the face of an unaltered shear stress stimulus for vasodilatation and reduced resting steady-state nitric oxide levels in the blood Collectively, our data point towards haemoglobin scavenging of nitric oxide as a key regulatory factor of brachial flow-mediated dilatation and highlight the importance of the simultaneous consideration of nitric oxide production and inactivation when investigating vascular function in humans ABSTRACT: Haemoglobin (Hb) may impact the transduction of endothelium-dependent and nitric oxide (NO)-mediated vasodilator activity, given its contribution to shear stress stimuli and diverse biochemical reactions with NO. We hypothesized that an acute reduction in [Hb] and haematocrit (Hct) would increase brachial artery flow-mediated dilatation (FMD). In 11 healthy males (28 ± 7 years; 23 ± 2 kg m-2 ), FMD (Duplex ultrasound), arterial blood gases, Hct and [Hb], blood viscosity, and NO metabolites (ozone-based chemiluminescence) were measured before and after isovolumic haemodilution, where ∼20% of whole blood was removed and replaced with 5% human serum albumin. Haemodilution reduced Hct by 18 ± 2% (P < 0.001) and whole blood viscosity by 22 ± 5% (P < 0.001). Plasma nitrite (P = 0.01), S-nitrosothiols (P = 0.03) and total red blood cell NO (P = 0.001) were collectively reduced by ∼15-40%. Brachial artery FMD increased by ∼160% from 3.8 ± 2.1 to 9.7 ± 4.5% (P = 0.004). Statistical covariation for the shear stress stimulus did not alter FMD, indicating that the increase in FMD was not directly related to alterations in whole blood viscosity and the shear stimulus. Collectively, these findings indicate that haemoglobin scavenging of NO appears to be an important factor in the regulation of FMD under normal conditions through constraint of endothelium-dependent NO-mediated vasodilatation in healthy humans.

The influence of age and sex on cerebrovascular reactivity and ventilatory response to hypercapnia in children and adults.

NEW FINDINGS: What is the central question of this study? In this study, we investigated intracranial cerebrovascular and ventilatory reactivity to 6% CO2 in children and adults and explored dynamic ventilatory and cerebrovascular onset responses. What is the main finding and its importance? We showed that cerebrovascular reactivity was similar in children and adults, but the intracranial blood velocity onset response was markedly attenuated in children. Sex differences were apparent, with greater increases in intracranial blood velocity in females and lower ventilatory reactivity in adult females. Our study confirms the importance of investigating dynamic onset responses when assessing the influence of development on cerebrovascular regulation. ABSTRACT: The purpose of this study was to compare the integrated intracranial cerebrovascular reactivity (CVR) and hypercapnic ventilatory response between children and adults and to explore the dynamic response of the middle cerebral artery mean velocity (MCAV ). Children (n = 20; 9.9 ± 0.7 years of age) and adults (n = 21; 24.4 ± 2.0 years of age) completed assessment of CVR over 240 s using a fixed fraction of inspired CO2 (0.06). Baseline MCAV was higher in the adult females compared with the males (P ≤ 0.05). The MCAV was greater in female children compared with male children (P ≤ 0.05) and in female adults compared with male adults (P ≤ 0.05) with hypercapnia. Relative CVR was similar in children and adults (3.71 ± 1.06 versus 4.12 ± 1.32% mmHg-1 ; P = 0.098), with absolute CVR being higher in adult females than males (3.27 ± 0.86 versus 2.53 ± 0.70 cm s-1  mmHg-1 ; P ≤ 0.001). Likewise, the hypercapnic ventilatory response did not differ between the children and adults (1.89 ± 1.00 versus 1.77 ± 1.34 l min-1  mmHg-1 ; P = 0.597), but was lower in adult females than males (1.815 ± 0.37 versus 2.33 ± 1.66 l min-1  mmHg-1 ; P ≤ 0.05). The heart rate response to hypercapnia was greater in children than in adults (P = 0.001). A monoexponential regression model was used to characterize the dynamic onset, consisting of a delay term, amplitude and time constant (τ). The results revealed that MCAV τ was faster in adults than in children (34 ± 18 versus 74 ± 28 s; P = 0.001). Our study provides new insight into the impact of age and sex on CVR and the dynamic response of the MCAV to hypercapnia.

Cerebrovascular reactivity to carbon dioxide is not influenced by variability in the ventilatory sensitivity to carbon dioxide.

NEW FINDINGS: What is the central question of this study? Do differing magnitudes of ventilation influence cerebrovascular CO2 reactivity and the cerebral blood flow response to increases in arterial carbon dioxide? What is the main finding and its importance? While a greater ventilation, through voluntary hyperventilation, is associated with a higher anterior cerebral blood flow during carbon dioxide breathing, this elevated cerebral blood flow is due to a higher blood pressure and not ventilation per se. A greater ventilation, through voluntary hyperventilation, does not influence global or posterior cerebral blood flow during carbon dioxide breathing. Cerebrovascular reactivity to carbon dioxide is not influenced by an individual's ventilatory sensitivity to carbon dioxide. ABSTRACT: Recent work demonstrated an influence of ventilation on cerebrovascular reactivity to CO2 ; however, the concomitant influence of changes in mean arterial blood pressure (MAP) on ventilation-induced differences in cerebral blood flow (CBF) has yet to be examined in this context. Healthy participants (n = 15; 25 ± 3 years of age; 179 ± 6 cm height; 74 ± 10 kg weight; 3 female) underwent end-tidal forcing to increase their partial pressure of end-tidal CO2 by +3, +6 and +9 mmHg above baseline in 5-min sequential steps while maintaining iso-oxia. This protocol was then repeated twice, with participants hyperventilating and hypoventilating by ∼30% compared to the first trial. Intra-cranial and extra-cranial CBF were measured using ultrasound. The MAP (finger photo-plethysmography) was higher during the hyperventilation and hypoventilation trials compared to normal ventilation (main effects, P < 0.05 for both). While internal carotid artery blood flow was higher during the hyperventilation trial compared to normal ventilation (P = 0.01), this was due to a higher MAP, as indicated by analysis of conductance values (P = 0.68) or inclusion of MAP in covariate analysis (P = 0.11). Global CBF (P = 0.11) and vertebral artery blood flow (P = 0.93) were unaffected by the magnitude of ventilation. Further, CO2 reactivity was not affected by the different breathing trials (P > 0.05 for all). Retrospective analysis of a larger data set (n = 53) confirmed these observations and demonstrated no relationships between the ventilatory and global CBF response to hypercapnia (r2  = 0.04; P = 0.14). Therefore, when differences in MAP are accounted for, cerebrovascular CO2 reactivity (assessed via end-tidal forcing) is independent of the magnitude of ventilation.

Cerebral metabolism, oxidation and inflammation in severe passive hyperthermia with and without respiratory alkalosis.

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: 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.

UBC-Nepal Expedition: Cerebrovascular Responses to Exercise in Sherpa Children Residing at High Altitude.

Understanding the process of successful adaptation to high altitude provides valuable insight into the pathogenesis of conditions associated with impaired oxygen uptake and utilization. Prepubertal children residing at low altitude show a reduced cerebrovascular response to exercise in comparison to adults, and a transient uncoupling of cerebral blood flow to changes in the partial pressure of end-tidal CO2 (PETCO2); however, little is known about the cerebrovascular response to exercise in high-altitude native children. We sought to compare the cerebral hemodynamic response to acute exercise between prepubertal children residing at high and low altitude. Prepubertal children (n = 32; 17 female) of Sherpa descent (Sherpa children [SC]) at high altitude (3800 m, Nepal) and maturational-matched (n = 32; 20 female) children (lowland children [LLC]) residing at low altitude (342 m, Canada). Ventilation, peripheral oxygen saturation (SpO2), PETCO2, and blood velocity in the middle and posterior cerebral arteries (MCAv and PCAv) were continuously measured during a graded cycling exercise test to exhaustion. At baseline (BL), PETCO2 (-19 ± 4 mmHg, p < 0.001), SpO2 (-6.0% ± 2.1%, p < 0.001), MCAv (-12% ± 5%, p = 0.02), and PCAv (-12% ± 6%, p = 0.04) were lower in SC when compared with LLC. Despite this, the relative change in MCAv and PCAv during exercise was similar between the two groups (p = 0.99). Linear regression analysis demonstrated a positive relationship between changes in PETCO2 with MCAv in SC (R2 = 0.13, p > 0.001), but not in LLC (R2 = 0.03, p = 0.10). Our findings demonstrate a similar increase in intra-cranial perfusion during exercise in prepubertal SC, despite differential BL values and changes in PETCO2 and SpO2.

Cerebrovascular Function in the Large Arteries Is Maintained Following Moderate Intensity Exercise.

Exercise has been shown to induce cerebrovascular adaptations. However, the underlying temporal dynamics are poorly understood, and regional variation in the vascular response to exercise has been observed in the large cerebral arteries. Here, we sought to measure the cerebrovascular effects of a single 20-min session of moderate-intensity exercise in the one hour period immediately following exercise cessation. We employed transcranial Doppler (TCD) ultrasonography to measure cerebral blood flow velocity (CBFV) in the middle cerebral artery (MCAv) and posterior cerebral artery (PCAv) before, during, and following exercise. Additionally, we simultaneously measured cerebral blood flow (CBF) in the internal carotid artery (ICA) and vertebral artery (VA) before and up to one hour following exercise cessation using Duplex ultrasound. A hypercapnia challenge was used before and after exercise to examine exercise-induced changes in cerebrovascular reactivity (CVR). We found that MCAv and PCAv were significantly elevated during exercise (p = 4.81 × 10-5 and 2.40 × 10-4, respectively). A general linear model revealed that these changes were largely explained by the partial pressure of end-tidal CO2 and not a direct vascular effect of exercise. After exercise cessation, there was no effect of exercise on CBFV or CVR in the intracranial or extracranial arteries (all p > 0.05). Taken together, these data confirm that CBF is rapidly and uniformly regulated following exercise cessation in healthy young males.

Effect of healthy aging on cerebral blood flow, CO2 reactivity, and neurovascular coupling during exercise.

We sought to make the first comparisons of duplex Doppler ultrasonography-derived measures of cerebral blood flow during exercise in young and older individuals and to assess whether healthy aging influences the effect of exercise on neurovascular coupling (NVC) and cerebral vascular reactivity to changes in carbon dioxide (CVRco2). In 10 healthy young (23 ± 2 yr; mean ± SD) and 9 healthy older (66 ± 3 yr) individuals, internal carotid artery (ICA) and vertebral artery (VA) blood flows were concurrently measured, along with middle and posterior cerebral artery mean blood velocity (MCAvmean and PCAvmean). Measures were made at rest and during leg cycling (75 W and 35% maximum aerobic workload). ICA and VA blood flow during dynamic exercise, undertaken at matched absolute (ICA: young 336 ± 95, older 352 ± 155; VA: young 95 ± 43, older 100 ± 30 ml/min) and relative (ICA: young 355 ± 125, older 323 ± 153; VA: young 115 ± 48, older 110 ± 32 ml/min) intensities, were not different between groups ( P > 0.670). The PCAvmean responses to visual stimulation (NVC) were blunted in older versus younger group at rest (16 ± 6% vs. 23 ± 7%, P < 0.026) and exercise; however, these responses were not changed from rest to exercise in either group. The ICA and VA CVRco2 were comparable in both groups and unaltered during exercise. Collectively, our findings suggest that 1) ICA and VA blood flow responses to dynamic exercise are similar in healthy young and older individuals, 2) NVC is blunted in healthy older individuals at rest and exercise but is not different between rest to exercise in either group, and 3) CVRco2 is similar during exercise in healthy young and older groups. NEW & NOTEWORTHY Internal carotid artery and vertebral artery blood flow responses to dynamic exercise are similar in healthy young and older individuals. Neurovascular coupling and cerebrovascular carbon dioxide reactivity, two key mechanisms mediating the cerebral blood flow responses to exercise, are generally unaffected by exercise in both healthy young and older individuals.

Severity-dependent influence of isocapnic hypoxia on reaction time is independent of neurovascular coupling.

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

UBC-Nepal expedition: The use of oral antioxidants does not alter cerebrovascular function at sea level or high altitude.

NEW FINDINGS: What is the central question of the study? Does the use of antioxidants alter cerebrovascular function and blood flow at sea level (344 m) and/or high altitude (5050 m)? What is the main finding and its importance? This is the first study to investigate whether antioxidant administration alters cerebrovascular regulation and blood flow in response to hypercapnia, acute hypoxia and chronic hypoxia in healthy humans. We demonstrate that an acute dose of antioxidants does not alter cerebrovascular function and blood flow at sea level (344 m) or after 12 days at high altitude (5050 m). ABSTRACT: Hypoxia is associated with an increase in systemic and cerebral formation of free radicals and associated reactants that may be linked to impaired cerebral vascular function and neurological sequelae. To what extent oral antioxidant prophylaxis impacts cerebrovascular function in humans throughout the course of acclimatization to the hypoxia of terrestrial high altitude has not been examined. Thus, the purpose of the present study was to examine the influence of orally ingested antioxidants at clinically relevant doses (vitamins C and E and α-lipoic acid) on cerebrovascular regulation at sea level (344 m; n = 12; female n = 2 participants) and at high altitude (5050 m; n = 9; female n = 2) in a randomized, placebo-controlled and double-blinded crossover design. Hypercapnic and hypoxic cerebrovascular reactivity tests of the internal carotid artery (ICA) were conducted at sea level, and global and regional cerebral blood flow (CBF; i.e. ICA and vertebral artery) were assessed 10-12 days after arrival at 5050 m. At sea level, acute administration of antioxidants did not alter cerebral hypoxic cerebrovascular reactivity (pre versus post: 1.5 ± 0.7 versus 1.2 ± 0.8%∆CBF/-%∆SpO2; P = 0.96) or cerebral hypercapnic cerebrovascular reactivity (pre versus post: 5.7 ± 2.0 versus 5.8 ± 1.9%∆CBF/∆mmHg; P = 0.33). Furthermore, global CBF (P = 0.43) and cerebral vascular conductance (ICA P = 0.08; vertebral artery P = 0.32) were unaltered at 5050 m after antioxidant administration. In conclusion, these data show that an oral antioxidant cocktail known to attenuate systemic oxidative stress failed to alter cerebrovascular function at sea level and CBF during acclimatization to high altitude.