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Cerebrovascular haemodynamics are sensitive to multiple physiological stimuli that require synergistic response to maintain adequate perfusion. Understanding haemodynamic changes within cerebral arteries is important to inform how the brain regulates perfusion, however methods for direct measurement of cerebral haemodynamics in these environments is challenging. The aim of this study was to assess velocity waveform metrics obtained using transcranial Doppler (TCD) with flow conserving subject-specific three-dimensional (3D) simulations relying on computational fluid dynamics (CFD). Twelve healthy participants underwent head and neck imaging with 3 Tesla magnetic resonance angiography. Velocity waveforms in the middle cerebral (MCA) artery were measured with transcranial Doppler ultrasound (TCD) while diameter and velocity was measured using duplex ultrasound in the internal carotid (ICA) and vertebral (VA) arteries to calculate incoming cerebral flow at rest, during hypercapnia and exercise. CFD simulations were developed for each condition, with velocity waveform metrics extracted in the same insonation region as TCD. Exposure to stimuli induced significant changes in cardiorespiratory measures across all participants. Absolute measured TCD velocities were significantly higher than those calculated from CFD (all P 0.05). However, relative changes in velocity from resting levels exhibited significant positive correlations when the distinct techniques were compared (r range 0.577–0.770, all P

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

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

It is generally considered that regular exercise maintains brain health and reduces the risk of cerebrovascular diseases such as stroke and dementia. Since the benefits of different "types" of exercise are unclear, we sought to compare the impacts of endurance and resistance training on cerebrovascular function. In a randomized and crossover design, 68 young healthy adults were recruited to participate in 3 mo of resistance and endurance training. Cerebral hemodynamics through the internal carotid, vertebral, middle and posterior cerebral arteries were measured using Duplex ultrasound and transcranial Doppler at rest and during acute exercise, dynamic autoregulation, and cerebrovascular reactivity (to hypercapnia). Following resistance, but not endurance training, middle cerebral artery velocity and pulsatility index significantly decreased (

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.

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

INTRODUCTION: To examine the hypothesis that exercise training induces adaptation in cerebrovascular function, we recruited 63 older adults (62 ± 7 yr, 46 females) to undertake 24 wk of either land walking or water walking, or participate in a nonexercise control group. This is the first multi-interventional study to perform a comprehensive assessment of cerebrovascular function in response to longer term (6-month) training interventions, including water-based exercise, in older healthy individuals. METHODS: Intracranial blood flow velocities (middle cerebral artery (MCAv) and posterior cerebral artery) were assessed at rest and in response to neurovascular coupling, hypercapnic reactivity, and cerebral autoregulation. RESULTS: We observed no change in resting MCAv in response to either training intervention (pre vs post, mean (95% confidence interval), land walking: 65 (59-70) to 63 (57-68) cm·s-1, P = 0.33; water walking: 63 (58-69) to 61 (55-67) cm·s-1, P = 0.92) compared with controls and no change in neurovascular coupling (land walking: P = 0.18, water walking: P = 0.17). There was a significant but modest improvement in autoregulatory normalized gain after the intervention in the water-walking compared with the land-walking group (P = 0.03). Hypercapnic MCAv reactivity was not different based on exercise group (land: P = 087, water: P = 0.83); however, when data were pooled from the exercise groups, increases in fitness were correlated with decreases in hypercapnic reactivity (r2 = 0.25, P = 0.003). CONCLUSIONS: Although exercise was not associated with systematic changes across multiple domains of cerebrovascular function, our data indicate that exercise may induce modest changes in autoregulation and CO2 reactivity. These findings should encourage further studies of the longer-term implications of exercise training on cerebrovascular health.

Reduced middle cerebral artery blood velocity (MCAv) and flow pulsatility are contributors to age-related cerebrovascular disease pathogenesis. It is unknown whether the rate of changes in MCAv and flow pulsatility support the hypothesis of sex-specific trajectories with aging. Therefore, we sought to characterize the rate of changes in MCAv and flow pulsatility across the adult lifespan in females and males as well as within specified age ranges. Participant characteristics, mean arterial pressure, end-tidal carbon dioxide, unilateral MCAv, and flow pulsatility index (PI) were determined from study records compiled from three institutional sites. A total of 524 participants [18–90 yr; females 57 (17) yr, n = 319; males 50 (21) yr, n = 205] were included in the analysis. MCAv was significantly higher in females within the second (P < 0.001), fifth (P = 0.01), and sixth (P < 0.01) decades of life. Flow PI was significantly lower in females within the second decade of life (P < 0.01). Rate of MCAv decline was significantly greater in females than males (−0.39 vs. −0.26 cm s(−1)·yr, P = 0.04). Rate of flow PI rise was significantly greater in females than males (0.006 vs. 0.003 flow PI, P = 0.01). Rate of MCAv change was significantly greater in females than males in the sixth decade of life (−1.44 vs. 0.13 cm s(−1)·yr, P = 0.04). These findings indicate that sex significantly contributes to age-related differences in both MCAv and flow PI. Therefore, further investigation into cerebrovascular function within and between sexes is warranted to improve our understanding of the reported sex differences in cerebrovascular disease prevalence. NEW & NOTEWORTHY We present the largest dataset (n = 524) pooled from three institutions to study how age and sex affect middle cerebral artery blood velocity (MCAv) and flow pulsatility index (PI) across the adult lifespan. We report the rate of MCAv decline and flow PI rise is significantly greater in females compared with in males. These data suggest that sex-specific trajectories with aging and therapeutic interventions to promote healthy brain aging should consider these findings.

Cerebral blood flow during exercise is impaired in patients with heart failure implanted with left ventricular assist devices (LVADs). Our aim was to determine whether a 3-mo exercise training program could mitigate cerebrovascular dysfunction. Internal carotid artery (ICA) blood flow and intracranial middle (MCA v) and posterior cerebral (PCA v) artery velocities were measured continuously using Doppler ultrasound, alongside cardiorespiratory measures at rest and in response to an incremental cycle ergometer exercise protocol in 12 LVAD participants (5 female, 53.6 ± 11.8 yr; 84.2 ± 15.7 kg; 1.73 ± 0.08) pre- (PreTR) and post- (PostTR) completion of a 3-mo supervised exercise rehabilitation program. At rest, only PCAv was different PostTR (38.1 ± 10.4 cm/s) compared with PreTR (43.0 ± 10.8 cm/s; P < 0.05). PreTR, the reduction in PCAv observed from rest to exercise (5.2 ± 1.8%) was mitigated PostTR ( P < 0.001). Similarly, exercise training enhanced ICA flow during submaximal exercise (~8.6 ± 13.7%), resulting in increased ICA flow PostTR compared with a reduced flow PreTR ( P < 0.001). Although both end-tidal partial pressure of carbon dioxide and mean arterial pressure responses during incremental exercise were greater PostTR than PreTR, only the improved [Formula: see text] was related to the improved ICA flow ( R2 = 0.14; P < 0.05). Our findings suggest that short-term exercise training improves cerebrovascular function during exercise in patients with LVADs. This finding should encourage future studies investigating long-term exercise training and cerebral and peripheral vascular adaptation. NEW & NOTEWORTHY Left ventricular assist devices, now used as destination therapy in end-stage heart failure, enable patients to undertake rehabilitative exercise training. We show, for the first time in humans, that training improves cerebrovascular function during exercise in patients with left ventricular assist devices. This finding may have implications for cerebrovascular health in patients with heart failure.

Few studies have compared transcranial Doppler (TCD) ultrasound with independent techniques such as computational fluid dynamics (CFD) simulations, particularly in response to stimuli. We compared TCD cerebral blood flow velocity in healthy participants with subject-specific CFD simulations to determine differences in techniques. Twelve participants underwent head and neck imaging with 3 Tesla magnetic resonance angiography. Velocity waveforms in the middle cerebral artery (MCA) were measured with TCD while velocity and diameter in the neck arteries were measured with duplex ultrasound at rest, hypercapnia and exercise. Subject-specific CFD simulations were developed for each condition, with velocity waveforms extracted in the same region as TCD. We found that absolute TCD velocities were significantly higher than CFD data, and non-significantly correlated across all conditions (r range 0.030-0.377, all P>0.05). However, relative changes from rest to hypercapnia and exercise generally exhibited significant positive correlations (r range 0.448-0.770), with the strongest correlation being average velocity change from rest to exercise (r=0.770, P

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

Your heart works as a team with your body’s blood vessels. Your heart pumps the blood, while blood vessels help the blood travel all over your body, just as a garden hose helps move water all around your garden. Blood carries oxygen and other nutrients to your muscles and organs and removes carbon dioxide and other wastes. These are very important chores for the blood! Sometimes doctors need to check whether the heart and blood vessels are working properly, or scientists may want to study how blood vessels work as people get older. To do this, a technique called ultrasound is used to take pictures and videos of the blood vessels and the blood moving through them. But how does sound create pictures? This article will explain how ultrasound works and how it can be used to examine blood vessels and the speed of the blood flow.

Cerebrovascular CO

Optical coherence tomography (OCT) is a novel high-resolution imaging technique capable of visualizing in vivo structures at a resolution of ~10 μm. We have developed specialized OCT-based approaches that quantify diameter, speed, and flow rate in human cutaneous microvessels. In this study, we hypothesized that OCT-based microvascular assessments would possess comparable levels of reliability when compared with those derived using conventional laser Doppler flowmetry (LDF).Speckle decorrelation images (OCT) and red blood cell flux (LDF) measures were collected from adjacent forearm skin locations on 2 d (48 h apart), at baseline, and after a 30-min rapid local heating protocol (30°C-44°C) in eight healthy young individuals. OCT postprocessing quantified cutaneous microvascular diameter, speed, flow rate, and density (vessel recruitment) within a region of interest, and data were compared between days.Forearm skin LDF (13 ± 4 to 182 ± 31 AU, P0.05) and OCT-derived diameter (41.8 ± 6.6 vs 64.5 ± 6.9 μm), speed (68.4 ± 9.5 vs 89.0 ± 7.3 μm·s), flow rate (145.0 ± 60.6 vs 485 ± 132 pL·s), and density (9.9% ± 4.9% vs 45.4% ± 5.9%) increased in response to local heating. The average OCT-derived microvascular flow response (pL·s) to heating (234% increase) was lower (P0.05) than the LDF-derived change (AU) (1360% increase). Pearson correlation was significant for between-day local heating responses in terms of OCT flow (r = 0.93, P0.01), but not LDF (P = 0.49). Bland-Altman analysis revealed that between-day baseline OCT-derived flow rates were less variable than LDF-derived flux.Our findings indicate that OCT, which directly visualizes human microvessels, not only allows microvascular quantification of diameter, speed, flow rate, and vessel recruitment but also provides outputs that are highly reproducible. OCT is a promising novel approach that enables a comprehensive assessment of cutaneous microvascular structure and function in humans.

INTRODUCTION In healthy individuals, cerebral blood flow (CBF) increases during exercise, but few studies have compared changes in CBF during exercise in patients with heart failure (HF) to healthy controls (CTRL) or assessed the effects of left ventricular assist devices (LVAD). We hypothesized that subjects implanted with LVAD would exhibit impaired cerebrovascular responses to cycle exercise when compared with age- and sex-matched healthy CTRL subjects but would have enhanced responses relative to subjects with HF. METHODS Internal carotid artery (ICA) blood flow and intracranial middle (MCAv) and posterior cerebral (PCAv) artery velocities were measured continuously using Doppler ultrasound, alongside cardiorespiratory measures at rest and in response to an incremental submaximal cycle ergometer exercise protocol in nine LVAD participants (58 ± 15 yr, 87 ± 16 kg, 172 ± 8 cm, six females), nine age- and sex-matched subjects with HF (58 ± 8 yr, 84 ± 11 kg, 177 ± 6 cm), and nine CTRL (55 ± 14 yr, 74 ± 16 kg, 168 ± 10 cm). RESULTS At rest, ICA hemodynamics (velocity, shear rate, and flow) were greater in CTRL and LVAD than that in HF (P < 0.05). Higher MCAv (+5.52 ± 1.59 cm·s, P = 0.003) and PCAv (+5.82 ± 1.41 cm·s, P = 0.001) were also observed in LVAD subjects than healthy CTRL. During exercise, ICA flow increased at all workloads in CTRL, but not in HF or LVAD groups. MCAv increased from baseline in both HF and CTRL participants (P = 0.0001), but not in LVAD subjects. Nonetheless, CTRL and LVAD showed higher MCAv (P = 0.006) and PCAv (P < 0.0001) values throughout exercise than HF. CONCLUSION Our findings indicate that LVAD subjects exhibit higher CBF at rest and during exercise than matched HF participants but attenuated brain blood flows during exercise when compared with healthy subjects. CBF should be considered when designing exercise training interventions in patients with HF and LVAD.

INTRODUCTION Exercise training has antiatherogenic effects on conduit and resistance artery function and structure in humans and induces angiogenic changes in skeletal muscle. However, training-induced adaptation in cutaneous microvessels is poorly understood, partly because of technological limitations. Optical coherence tomography (OCT) is a novel high-resolution imaging technique capable of visualizing cutaneous microvasculature at a resolution of ~30 μm. We utilized OCT to visualize the effects of training on cutaneous microvessels, alongside assessment of conduit artery flow-mediated dilation (FMD). METHODS We assessed brachial FMD and cutaneous microcirculatory responses at rest and in response to local heating and reactive hyperemia: pretraining and posttraining in eight healthy men compared with age-matched untrained controls (n = 8). Participants in the training group underwent supervised cycling at 80% maximal heart rate three times a week for 8 wk. RESULTS We found a significant interaction (P = 0.04) whereby an increase in FMD was observed after training (post 9.83% ± 3.27% vs pre 6.97% ± 1.77%, P = 0.01), with this posttraining value higher compared with the control group (6.9% ± 2.87%, P = 0.027). FMD was not altered in the controls (P = 0.894). There was a significant interaction for OCT-derived speed (P = 0.038) whereby a significant decrease in the local disk heating response was observed after training (post 98.6 ± 3.9 μm·s-1 vs pre 102 ± 5 μm·s-1, P = 0.012), whereas no changes were observed for OCT-derived speed in the control group (P = 0.877). Other OCT responses (diameter, flow rate, and density) to local heating and reactive hyperemia were unaffected by training. CONCLUSIONS Our findings suggest that vascular adaptation to exercise training is not uniform across all levels of the arterial tree; although exercise training improves larger artery function, this was not accompanied by unequivocal evidence for cutaneous microvascular adaptation in young healthy subjects.

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

NEW FINDINGS What is the central question of this study? Does cerebrovascular pulsatility respond differently to acute increases in arterial stiffness in middle-aged compared with young adults? What is the main finding and its importance? Compared with young adults, middle-aged adults exhibited similar changes in cerebral pulsatile damping despite attenuated changes in carotid diameter and cerebrovascular pulsatility during blood pressure-dependent, but not blood pressure-independent, increases in large artery stiffness. ABSTRACT Acute manipulation of arterial stiffness through interventions that increase sympathetic activity might provoke cerebral pulsatility and damping and reveal whether cerebrovascular haemodynamics respond differently to transient elevations in arterial stiffness in middle-aged compared with young adults. We compared cerebral pulsatility and damping in middle-aged versus young adults during two different sympathetic interventions [cold pressor test (CP) and lower-body negative pressure (LBNP)] that increase arterial stiffness acutely. Cerebrovascular haemodynamics were assessed in 15 middle-aged (54 ± 7 years old; 11 female) and 15 sex-matched young adults (25 ± 4 years old) at rest and during the CP test (4 min, 6.4 ± 0.8°C) and LBNP (6 min, -20 mmHg). Mean blood pressure was measured continuously via finger photoplethysmography. Carotid-femoral pulse wave velocity (cfPWV) and carotid stiffness were measured via tonometry and ultrasound. Blood velocity pulsatility index (PI) was measured at the middle cerebral (MCA) and common carotid artery (CCA) using Doppler, with pulsatile damping calculated as CCA PI divided by MCA PI. Increases in cfPWV were driven by changes in mean pressure during CP but not during LBNP in both groups (P

There is acknowledged variability in the Circle of Willis (CoW) in the general population, yet the structure and function relationship of the cerebrovasculature is poorly understood. We aimed to demonstrate the feasibility of combining high-resolution imaging techniques and computational fluid dynamics (CFD) to describe cerebrovascular structure and function in vivo. We tested our methodology by examining the null hypothesis that monozygotic twins (18–30 yr) would exhibit similar CoW structure and function. Six twin pairs underwent 3T magnetic resonance angiography of the head and neck and B-mode Doppler ultrasound for velocity and diameter recordings in the vertebral and internal carotid arteries under three conditions (rest, hypercapnia, and exercise). Artery diameter, length, tortuosity, and bifurcation angle were assessed in regions of interest of the CoW. We simulated hemodynamics to determine the cardiac-cycle time-averaged wall shear stress (TAWSS), oscillatory shear index (OSI), and relative residence time (RRT). We observed low and insignificant intraclass correlations (ICC) between twins in all regions for diameter (ICC range 0.000–0.657, P > 0.05), two of four regions for length (ICC range 0.355–0.368, P > 0.05), all regions for tortuosity (ICC range 0.270–0.505, P > 0.05), and all bifurcation angles (ICC range 0.000–0.547, P > 0.05). Similarly, no significant correlations were apparent for cerebral blood flow or CFD-derived measures of TAWSS, OSI, and RRT, at rest or in response to hypercapnia or exercise. Therefore, differences exist in CoW structure and associated shear stress in response to physiological stimulation. These data suggest that the structure, function, and health of cerebrovascular arteries are not primarily genetically dependent. NEW & NOTEWORTHY There is acknowledged variability in the Circle of Willis in the general population, yet the structure and function relationship of the cerebrovasculature is poorly understood. Using a combination of magnetic resonance imaging, high-resolution Doppler ultrasound, and computational fluid dynamic modeling, we show that monozygotic twins exhibit differences in cerebrovascular structure and function when exposed to physiological stimuli. These data suggest that the morphology, function, and health of cerebrovascular arteries are not primarily genetically determined.

The first accounts of measuring cerebral blood flow (CBF) in humans were made by Angelo Mosso in ~1880, who recorded brain pulsations in patients with skull defects. In 1890, Charles Roy and Charles Sherrington determined in animals that brain pulsations—assessed via a similar method used by Mosso—were altered during a variety of stimuli including sensory nerve stimulation, asphyxia, and pharmacological interventions. Between 1880 and 1944, measurements for CBF were typically relied on skull abnormalities in humans. Thereafter, Kety and Schmidt introduced a new methodological approach in 1945 that involved nitrous oxide dilution combined with serial arterial and jugular venous blood sampling. Less than a decade later (1950’s), several research groups employed the Kety-Schmidt technique to assess the effects of exercise on global CBF and metabolism; these studies demonstrated an uncoupling of CBF and metabolism during exercise, which was contrary to early hypotheses. However, there were several limitations to this technique related to low temporal resolution and the inability to measure regional CBF. These limitations were overcome in the 1960’s when transcranial Doppler ultrasound (TCD) was developed as a method to measure beat-by-beat cerebral blood velocity. Between 1990 and 2010, TCD further progressed our understanding of CBF regulation and allowed for insight into other mechanistic factors, independent of local metabolism, involved in regulating CBF during exercise. Recently, it was discovered that TCD may not be accurate under several physiological conditions. Other measures of indexing CBF such as Duplex ultrasound and magnetic resonance imaging, although not without some limitations, may be more applicable for future investigations.

Earlier studies have indicated an important role for cerebral blood flow in the pathophysiology of central sleep apnea (CSA) at high altitude, but were not decisive. To test the hypothesis that pharmacologically altering cerebral blood flow (CBF) without altering arterial blood gas (ABGs) values would alter the severity of CSA at high altitude, we studied 11 healthy volunteers (8M, 3F; 31 ± 7 yr) in a randomized placebo-controlled single-blind study at 5,050 m in Nepal. CBF was increased by intravenous (iv) acetazolamide (Az; 10 mg/kg) plus intravenous dobutamine (Dob) infusion (2–5 μg·kg−1·min−1) and reduced by oral indomethacin (Indo; 100 mg). ABG samples were collected and ventilatory responses to hypercapnia (HCVR) and hypoxia (HVR) were measured by rebreathing and steady-state techniques before and after drug/placebo. Duplex ultrasound of blood flow in the internal carotid and vertebral arteries was used to measure global CBF. The initial 3–4 h of sleep were recorded by full polysomnography. Intravenous Az + Dob increased global CBF by 37 ± 15% compared with placebo ( P < 0.001), whereas it was reduced by 21 ± 8% by oral Indo ( P < 0.001). ABGs and HVR were unchanged in both interventions. HCVR was reduced by 28% ± 43% ( P = 0.1) during intravenous Az ± Dob administration and was elevated by 23% ± 30% ( P = 0.05) by Indo. During intravenous Az + Dob, the CSA index fell from 140 ± 45 (control night) to 48 ± 37 events/h of sleep ( P < 0.001). Oral Indo had no significant effect on CSA. We conclude that increasing cerebral blood flow reduced the severity of CSA at high altitude; the likely mechanism is via a reduction in the background stimulation of central chemoreceptors.NEW & NOTEWORTHY This work is significant because it shows convincingly for the first time in healthy volunteers that increasing cerebral blood flow will reduce the severity of central sleep apnea in a high-altitude model, without the potentially confounding effects of altering partial pressure of arterial carbon dioxide or the ventilatory response to hypoxia. The proposed mechanism of action is that of increasing the removal of locally produced CO2from the central chemoreceptors, causing the reduction in hypercapnic ventilatory response, hence reducing loop gain.

New Findings What is the topic of this review? The manuscript collectively combines the experimental observations from >100 publications focusing on the regulation of cerebral blood flow and metabolism during exercise from 1945 to the present day. What advances does it highlight? This article highlights the importance of traditional and historical assessments of cerebral blood flow and metabolism during exercise, as well as traditional and new insights into the complex factors involved in the integrative regulation of brain blood flow and metabolism during exercise. The overarching theme is the importance of quantifying cerebral blood flow and metabolism during exercise using techniques that consider multiple volumetric cerebral haemodynamics (i.e. velocity, diameter, shear and flow). Cerebral function in humans is crucially dependent upon continuous oxygen delivery, metabolic nutrients and active regulation of cerebral blood flow (CBF). As a consequence, cerebrovascular function is precisely titrated by multiple physiological mechanisms, characterized by complex integration, synergism and protective redundancy. At rest, adequate CBF is regulated through reflexive responses in the following order of regulatory importance: fluctuating arterial blood gases (in particularly, partial pressure of carbon dioxide), cerebral metabolism, arterial blood pressure, neurogenic activity and cardiac output. Unfortunately, the magnitude that these integrative and synergistic relationships contribute to governing the CBF during exercise remains unclear. Despite some evidence indicating that CBF regulation during exercise is dependent on the changes of blood pressure, neurogenic activity and cardiac output, their role as a primary governor of the CBF response to exercise remains controversial. In contrast, the balance between the partial pressure of carbon dioxide and cerebral metabolism continues to gain empirical support as the primary contributor to the intensity-dependent changes in CBF observed during submaximal, moderate and maximal exercise. The goal of this review is to summarize the fundamental physiology and mechanisms involved in regulation of CBF and metabolism during exercise. The clinical implications of a better understanding of CBF during exercise and new research directions are also outlined.

Evidence for shear stress as a regulator of carotid artery dilation in response to increased arterial CO2 was recently demonstrated in humans during sustained elevations in CO2 (hypercapnia); however, the relative contributions of CO2 and shear stress to this response remains unclear. We examined the hypothesis that, after a 30-s transient increase in arterial CO2 tension and consequent increase in internal carotid artery shear stress, internal carotid artery diameter would increase, indicating shear-mediated dilation, in the absence of concurrent hypercapnia. In 27 healthy participants, partial pressures of end-tidal O2 and CO2, ventilation (pneumotachography), blood pressure (finger photoplethysmography), heart rate (electrocardiogram), internal carotid artery flow, diameter, and shear stress (high-resolution duplex ultrasound), and middle cerebral artery blood velocity (transcranial Doppler) were measured during 4-min steady-state and transient 30-s hypercapnic tests (both +9 mmHg CO2). Internal carotid artery dilation was lower in the transient compared with steady-state hypercapnia (3.3 ± 1.9 vs. 5.3 ± 2.9%, respectively, P < 0.03). Increases in internal carotid artery shear stress preceded increases in diameter in both transient (time: 16.8 ± 13.2 vs. 59.4 ± 60.3 s, P < 0.01) and steady-state (time: 18.2 ± 14.2 vs. 110.3 ± 79.6 s, P < 0.01) tests. Internal carotid artery dilation was positively correlated with shear rate area under the curve in the transient ( r2 = 0.44, P < 0.01) but not steady-state ( r2 = 0.02, P = 0.53) trial. Collectively, these results suggest that hypercapnia induces shear-mediated dilation of the internal carotid artery in humans. This study further promotes the application and development of hypercapnia as a clinical strategy for the assessment of cerebrovascular vasodilatory function and health in humans. NEW & NOTEWORTHY Shear stress dilates the internal carotid artery in humans. This vasodilatory response occurs independent of other physiological factors, as demonstrated by our transient CO2 test, and is strongly correlated to shear area under the curve. Assessing carotid shear-mediated dilation may provide a future avenue for assessing cerebrovascular health and the risk of cerebrovascular events.

The mechanisms underlying reactive hyperemia (RH) responses in microvessels are poorly understood. Previous assessment tools have not been capable of directly visualizing microvessels during physiological stimulation in humans. Optical coherence tomography (OCT) is capable of imaging and quantifying subcutaneous microvessels as small as ~30 µm. In this study we use OCT to visualize and quantify skin microvascular changes in response to RH for the first time in humans. We also assessed the reproducibility of this technique. OCT and laser Doppler flowmetry (LDF) were used simultaneously to scan cutaneous microvessels in 10 young healthy subjects on 2 days. We applied a speckle decorrelation algorithm to assess OCT images and calculated flow rate, speed, diameter, and density parameters. Measures were obtained at rest (baseline) and 30-s following a 5-min cuff inflation (RH). All data were compared between days. The RH stimulus significantly increased ( P < 0.0001) OCT-derived microvascular diameter (37.6 ± 3.4 vs. 44.5 ± 5.2 µm), flow rate (82.4 ± 23.4 vs. 240.1 ± 58.6 pl/s), speed (48 ± 5.7 vs. 101.5 ± 17.1 µm/s), density (5.1 ± 1.7 vs. 14.6 ± 2.6%), and also LDF-derived flux (12.3 ± 5.7 vs. 31.6 ± 9.1 perfusion units). At baseline, OCT-derived diameter ( r = 0.55), flow rate ( r = 0.64), speed ( r = 0.55), and density ( r = 0.75) showed significant between-day correlations ( P < 0.05), as did LDF results ( r = 0.74). In response to RH, OCT-derived diameter ( r = 0.63) and density ( r = 0.64) showed significant correlations ( P < 0.05), whereas flow rate ( r = 0.45), speed ( r = 0.43), and LDF ( r = 0.26) were less reproducible. Our study is novel in that it establishes the feasibility of using OCT to visualize and quantify microvascular structure and function responses to RH in humans. NEW & NOTEWORTHY This study describes the first evidence in humans that optical coherence tomography provides direct visualization and comprehensive quantification of cutaneous microvascular hemodynamics as a response to reactive hyperemia. This imaging technique will greatly improve human cutaneous microvascular assessment in physiological and clinical settings.

Preventing declines in cerebral blood flow is important for maintaining optimal brain health with aging. We compared the effects of a morning bout of moderate-intensity exercise, with and without subsequent light-intensity walking breaks from sitting, on cerebral blood velocity over 8 h in older adults. In a randomized crossover trial, overweight/obese older adults ( n = 12, 70 ± 7 yr; 30.4 ± 4.3 kg/m2), completed three acute conditions (6-day washout); SIT: prolonged sitting (8 h, control); EX+SIT: sitting (1 h), moderate-intensity walking (30 min), followed by uninterrupted sitting (6.5 h); and EX + BR: sitting (1 h), moderate-intensity walking (30 min), followed by sitting (6.5 h) interrupted with 3 min of light-intensity walking every 30 min. Bilateral middle cerebral artery velocities (MCAv) were determined using transcranial Doppler at 13 time points across the day. The temporal pattern and average MCAv over 8 h was determined. The pattern of MCAv over 8 h was a negative linear trend in SIT ( P < 0.001), but a positive quadratic trend in EX + SIT ( P < 0.001) and EX + BR ( P < 0.01). Afternoon time points in SIT were lower than baseline within condition ( P ≤ 0.001 for all). A morning dip in MCAv was observed in EX + SIT and EX + BR ( P < 0.05 relative to baseline), but afternoon time points were not significantly lower than baseline. The average MCAv over 8 h was higher in EX + SIT than SIT ( P = 0.007) or EX + BR ( P = 0.024). Uninterrupted sitting should be avoided, and moderate-intensity exercise should be encouraged for the daily maintenance of cerebral blood flow in older adults. The clinical implications of maintaining adequate cerebral blood flow include the delivery of vital oxygen and nutrients to the brain. NEW & NOTEWORTHY This is the first study to measure the combined effects of an exercise bout with breaks in sitting on cerebral blood velocity in older adults. Using frequent recordings over an 8-h period, we have performed a novel analysis of the pattern of cerebral blood velocity, adjusting for concurrent measures of mean arterial pressure and other potential confounders in a linear mixed effects regression.

Increases in arterial carbon dioxide tension (hypercapnia) elicit potent vasodilation of cerebral arterioles. Recent studies have also reported vasodilation of the internal carotid artery during hypercapnia, but the mechanism(s) mediating this extracranial vasoreactivity are unknown. Hypercapnia increases carotid shear stress, a known stimulus to vasodilation in other conduit arteries. To explore the hypothesis that shear stress contributes to hypercapnic internal carotid dilation in humans, temporal changes in internal and common carotid shear rate and diameter, along with changes in middle cerebral artery velocity, were simultaneously assessed in 18 subjects at rest and during hypercapnia (6% carbon dioxide). Middle cerebral artery velocity increased significantly (69±10–103±17 cm/s; P P P P r =0.68; P

Cerebral blood flow (CBF) is temporally related to exercise-induced changes in partial pressure of end-tidal carbon dioxide (PetCO2); hyperoxia is known to enhance this relationship. We examined the hypothesis that preventing PetCO2 from rising (isocapnia) during submaximal exercise with and without hyperoxia [end-tidal Po2 (PetO2) = 300 mmHg] would attenuate the increases in CBF. Additionally, we aimed to identify the magnitude that breathing, per se, influences the CBF response to normoxic and hyperoxic exercise. In 14 participants, CBF (intra- and extracranial) measurements were measured during exercise [20, 40, 60, and 80% of maximum workload (Wmax)] and during rest while ventilation (V̇e) was volitionally increased to mimic volumes achieved during exercise (isocapnic hyperpnea). While V̇e was uncontrolled during poikilocapnic exercise, during isocapnic exercise and isocapnic hyperpnea, V̇e was increased to prevent PetCO2 from rising above resting values (∼40 mmHg). Although PetCO2 differed by 2 ± 3 mmHg during normoxic poikilocapnic and isocapnic exercise, except for a greater poikilocapnic compared with isocapnic increase in blood velocity in the posterior cerebral artery at 60% Wmax, the between condition increases in intracranial (∼12-15%) and extracranial (15–20%) blood flow were similar at each workload. The poikilocapnic hyperoxic increases in both intra- and extracranial blood-flow (∼17–29%) were greater compared with poikilocapnic normoxia (∼8–20%) at intensities >40% Wmax ( P < 0.01). During both normoxic and hyperoxic conditions, isocapnia normalized both the intracranial and extracranial blood-flow differences. Isocapnic hyperpnea did not alter CBF. Our findings demonstrate a differential effect of PetCO2 on CBF during exercise influenced by the prevailing PetO2.

The first accounts of measuring cerebral blood flow (CBF) in humans were made by Angelo Mosso in ~1880, who recorded brain pulsations in patients with skull defects. In 1890, Charles Roy and Charles Sherrington determined in animals that brain pulsations-assessed via a similar method used by Mosso-were altered during a variety of stimuli including sensory nerve stimulation, asphyxia, and pharmacological interventions. Between 1880 and 1944, measurements for CBF were typically relied on skull abnormalities in humans. Thereafter, Kety and Schmidt introduced a new methodological approach in 1945 that involved nitrous oxide dilution combined with serial arterial and jugular venous blood sampling. Less than a decade later (1950's), several research groups employed the Kety-Schmidt technique to assess the effects of exercise on global CBF and metabolism; these studies demonstrated an uncoupling of CBF and metabolism during exercise, which was contrary to early hypotheses. However, there were several limitations to this technique related to low temporal resolution and the inability to measure regional CBF. These limitations were overcome in the 1960's when transcranial Doppler ultrasound (TCD) was developed as a method to measure beat-by-beat cerebral blood velocity. Between 1990 and 2010, TCD further progressed our understanding of CBF regulation and allowed for insight into other mechanistic factors, independent of local metabolism, involved in regulating CBF during exercise. Recently, it was discovered that TCD may not be accurate under several physiological conditions. Other measures of indexing CBF such as Duplex ultrasound and magnetic resonance imaging, although not without some limitations, may be more applicable for future investigations.

Purpose: This study investigated whether reported improvements in blood flow distribution, and the possible related effects on thermoregulation during exercise following supplementation with beetroot juice (BR), a rich source of dietary nitrate (NO3 −), are mitigated in the heat. Methods: 12 male endurance-trained cyclists (age 27 ± 6 years, VO2peak 68.6 ± 8.1 ml kg−1 min−1) completed two 60 min submaximal cycling trials at 60% of VO2peak power output. Trials were performed in hot environmental conditions (33.3 ± 0.4 °C, 48.8 ± 3.0% RH) following 3 days of supplementationwith either NO3 −-rich BR (6.5 mmol NO3 − for 2 days and 13 mmol NO3 − on the final day) or NO3 −-depleted placebo (PLA). Salivary NO3 − and nitrite (NO2 −) were measured before and after the supplementation period. During exercise, cutaneous blood flow, blood pressure (MAP), core temperature (Tc), mean skin temperature (Tsk), indices of muscle oxygenation and oxygen (O2) consumption were measured. Results: Salivary NO3 − and NO2 − increased significantly following BR by 680 and 890%, respectively. There were no significant differences observed for cutaneous blood flow, MAP, Tc, Tsk, muscle oxygenation, or O2 consumption between BR and PLA. Conclusion: This investigation shows that the ergogenic effects and health benefits of BR supplementation, such as augmented cutaneous blood flow, reduced MAP, increased muscle oxygenation, and improved aerobic efficiency may be attenuated when exercise is performed in hot conditions.

Excessive sedentary behaviour has serious clinical and public health implications; however, the physiological changes that accompany prolonged sitting in the child are not completely understood. Herein, we examined the acute effect a prolonged period of sitting has upon superficial femoral artery function in 7- to 10-year-old girls and the impact of interrupting prolonged sitting with exercise breaks. Superficial femoral artery endothelium-dependent flow-mediated dilatation, total shear rate, anterograde and retrograde shear rates and oscillatory shear index were assessed before and after two experimental conditions: a 3 h uninterrupted period of sitting (SIT) and a 3 h period of sitting interrupted each hour with 10 min of moderate-intensity exercise (EX). A mixed-model analysis of variance was used to compare between-condition and within-condition main effects, controlling for the within-subject nature of the experiment by including random effects for participant. Superficial femoral artery endothelium-dependent flow-mediated dilatation decreased significantly from pre- to post-SIT (mean difference 2.2% flow-mediated dilatation; 95% confidence interval = 0.60–2.94%, P < 0.001). This relative decline of 33% was abolished in the EX intervention. Shear rates were not significantly different within conditions. Our data demonstrate the effectiveness of short but regular exercise breaks in offsetting the detrimental effects of uninterrupted sitting in young girls.

The effects of partial acclimatization to high altitude (HA; 5,050 m) on cerebral metabolism and cerebrovascular function have not been characterized. We hypothesized (1) increased cerebrovascular reactivity (CVR) at HA; and (2) that CO2 would affect cerebral metabolism more than hypoxia. PaO2 and PaCO2 were manipulated at sea level (SL) to simulate HA exposure, and at HA, SL blood gases were simulated; CVR was assessed at both altitudes. Arterial–jugular venous differences were measured to calculate cerebral metabolic rates and cerebral blood flow (CBF). We observed that (1) partial acclimatization yields a steeper CO2-H+ relation in both arterial and jugular venous blood; yet (2) CVR did not change, despite (3) mean arterial pressure (MAP)-CO2 reactivity being doubled at HA, thus indicating effective cerebral autoregulation. (4) At SL hypoxia increased CBF, and restoration of oxygen at HA reduced CBF, but neither had any effect on cerebral metabolism. Acclimatization resets the cerebrovasculature to chronic hypocapnia.

The mechanistic role of arterial shear stress in the regulation of cerebrovascular responses to physiological stimuli (exercise and hypercapnia) is poorly understood. We hypothesised that, if shear stress is a key regulator of arterial dilation, then matched increases in shear, induced by distinct physiological stimuli, would trigger similar dilation of the large extra-cranial arteries. Participants ( n = 10) participated in three 30-min experimental interventions, each separated by ≥48 h: (1) mild-hypercapnia (FICO2:∼0.045); (2) submaximal cycling (EX; 60%HRreserve); or (3) resting (time-matched control, CTRL). Blood flow, diameter, and shear rate were assessed (via Duplex ultrasound) in the internal carotid and vertebral arteries (ICA, VA) at baseline, during and following the interventions. Hypercapnia and EX produced similar elevations in blood flow and shear rate through the ICA and VA ( p

Background: Cocoa contains polyphenols that are thought to be beneficial for vascular health.Objective: We assessed the impact of chocolate containing distinct concentrations of cocoa on cerebrovascular function and cognition.Methods: Using a counterbalanced within-subject design, we compared the acute impact of consumption of energy-matched chocolate containing 80%, 35%, and 0% single-origin cacao on vascular endothelial function, cognition, and cerebrovascular function in 12 healthy postmenopausal women (mean ± SD age: 57.3 ± 5.3 y). Participants attended a familiarization session, followed by 3 experimental trials, each separated by 1 wk. Outcome measures included cerebral blood flow velocity (CBFv) responses, recorded before and during completion of a computerized cognitive assessment battery (CogState); brachial artery flow-mediated dilation (FMD); and hemodynamic responses (heart rate and blood pressure).Results: When CBFv data before and after chocolate intake were compared between conditions through the use of 2-factor ANOVA, an interaction effect (P = 0.003) and main effects for chocolate (P = 0.043) and time (P = 0.001) were evident. Post hoc analysis revealed that both milk chocolate (MC; 35% cocoa; P = 0.02) and dark chocolate (DC; 80% cocoa; P = 0.003) induced significantly lower cerebral blood flow responses during the cognitive tasks, after normalizing for changes in arterial pressure. DC consumption also increased brachial FMD compared with the baseline value before chocolate consumption (P = 0.002), whereas MC and white chocolate (0% cocoa) caused no change (P-interaction between conditions = 0.034).Conclusions: Consumption of chocolate containing high concentrations of cocoa enhanced vascular endothelial function, which was reflected by improvements in FMD. Cognitive function outcomes did not differ between conditions; however, cerebral blood flow responses during these cognitive tasks were lower in those consuming MC and DC. These findings suggest that chocolate containing high concentrations of cocoa may modify the relation between cerebral metabolism and blood flow responses in postmenopausal women. This trial was registered at www.ANZCTR.orgau as ACTRN12616000990426.

What is the topic of this review? The manuscript collectively combines the experimental observations from100 publications focusing on the regulation of cerebral blood flow and metabolism during exercise from 1945 to the present day. What advances does it highlight? This article highlights the importance of traditional and historical assessments of cerebral blood flow and metabolism during exercise, as well as traditional and new insights into the complex factors involved in the integrative regulation of brain blood flow and metabolism during exercise. The overarching theme is the importance of quantifying cerebral blood flow and metabolism during exercise using techniques that consider multiple volumetric cerebral haemodynamics (i.e. velocity, diameter, shear and flow). Cerebral function in humans is crucially dependent upon continuous oxygen delivery, metabolic nutrients and active regulation of cerebral blood flow (CBF). As a consequence, cerebrovascular function is precisely titrated by multiple physiological mechanisms, characterized by complex integration, synergism and protective redundancy. At rest, adequate CBF is regulated through reflexive responses in the following order of regulatory importance: fluctuating arterial blood gases (in particularly, partial pressure of carbon dioxide), cerebral metabolism, arterial blood pressure, neurogenic activity and cardiac output. Unfortunately, the magnitude that these integrative and synergistic relationships contribute to governing the CBF during exercise remains unclear. Despite some evidence indicating that CBF regulation during exercise is dependent on the changes of blood pressure, neurogenic activity and cardiac output, their role as a primary governor of the CBF response to exercise remains controversial. In contrast, the balance between the partial pressure of carbon dioxide and cerebral metabolism continues to gain empirical support as the primary contributor to the intensity-dependent changes in CBF observed during submaximal, moderate and maximal exercise. The goal of this review is to summarize the fundamental physiology and mechanisms involved in regulation of CBF and metabolism during exercise. The clinical implications of a better understanding of CBF during exercise and new research directions are also outlined.

Characterization of the influence of oxygen availability on brain metabolism is an essential step toward a better understanding of brain energy homoeostasis and has obvious clinical implications. However, how brain metabolism depends on oxygen availability has not been clearly examined in humans. We therefore assessed the influence of oxygen on CBF (cerebral blood flow) and CMRO2 (cerebral metabolic rates for oxygen) and carbohydrates. PaO2 (arterial partial pressure of oxygen) was decreased for 15 min to ~60, ~44 and ~35 mmHg [to target a SaO2 (arterial oxygen saturation) of 90, 80 and 70% respectively], and elevated to ~320 and ~430 mmHg. Isocapnia was maintained during each trial. At the end of each stage, arterial–jugular venous differences and volumetric CBF were measured to directly calculate cerebral metabolic rates. During progressive hypoxaemia, elevations in CBF were correlated with the reductions in both SaO2 (R2=0.54, P

The potential differences in cerebrovascular responses between the anterior and posterior circulations to changes in CO₂ are unclear in humans. Using transcranial Doppler ultrasound, we compared the CO₂ reactivity of the (1) BA and PCA and (2) MCA and PCA during hyperoxic rebreathing in supine position. The reactivity in the BA and PCA was similar in both absolute (1.27 ± 0.5 and 1.27 ± 0.6 cm/s/Torr; P=0.992) and relative (3.98 ± 1.3 and 3.66 ± 1.5%/Torr CO2; P=0.581) measures, suggesting that the PCA is an adequate surrogate measure of reactivity for the BA. The MCA reactivity was greater than the PCA in absolute (2.09 ± 0.7 and 1.22 ± 0.5 cm/s/Torr CO₂; P

We investigated 1) the regional distribution of cerebral blood flow (CBF), 2) the influence of end-tidal Pco2 (PetCO2) on CBF, and 3) the potential for an extracranial blood “steal” from the anterior brain region during passive hyperthermia. Nineteen (13 male) volunteers underwent supine passive heating until a steady-state esophageal temperature of 2°C above resting was established. Measurements were obtained 1) during normothermia (Normo), 2) during poikilocapnic hyperthermia (Hyper), and 3) during hyperthermia with PetCO2 and end-tidal Po2 clamped to Normo levels (Hyper-clamp). Blood flow in the internal carotid (Q̇ica), vertebral (Q̇VA), and external carotid (Q̇eca) arteries (Duplex ultrasound), blood velocity of the middle cerebral (MCAv) and posterior cerebral (PCAv) arteries (transcranial Doppler), and cutaneous vascular conductance on the cheek (cheek CVC; Doppler velocimetry) were measured at each stage. During Hyper, PetCO2 was lowered by 7.0 ± 5.2 mmHg, resulting in a reduction in Q̇ica (−18 ± 17%), Q̇va (−31 ± 21%), MCAv (−22 ± 13%), and PCAv (−18 ± 10%) compared with Normo ( P < 0.05). The reduction in Q̇VA was greater than that in Q̇ICA ( P = 0.017), MCAv ( P = 0.047), and PCAv ( P = 0.034). Blood flow/velocity was completely restored in each intracranial vessel (ICA, VA, MCA, and PCA) during Hyper-clamp. Despite a ∼250% increase in Q̇ECA and a subsequent increase in cheek CVC during Hyper compared with Normo, reductions in Q̇ICA were unrelated to changes in Q̇ECA. These data provide three novel findings: 1) hyperthermia attenuates Q̇VA to a greater extent than Q̇ICA, 2) reductions in CBF during hyperthermia are governed primarily by reductions in arterial Pco2, and 3) increased Q̇ECA is unlikely to compromise Q̇ICA during hyperthermia.

Despite the importance of blood flow on brainstem control of respiratory and autonomic function, little is known about regional cerebral blood flow (CBF) during changes in arterial blood gases.We quantified: (1) anterior and posterior CBF and reactivity through a wide range of steady-state changes in the partial pressures of CO2 (PaCO2) and O2 (PaO2) in arterial blood, and (2) determined if the internal carotid artery (ICA) and vertebral artery (VA) change diameter through the same range.We used near-concurrent vascular ultrasound measures of flow through the ICA and VA, and blood velocity in their downstream arteries (the middle (MCA) and posterior (PCA) cerebral arteries). Part A (n =16) examined iso-oxic changes in PaCO2, consisting of three hypocapnic stages (PaCO2 =∼15, ∼20 and ∼30 mmHg) and four hypercapnic stages (PaCO2 =∼50, ∼55, ∼60 and ∼65 mmHg). In Part B (n =10), during isocapnia, PaO2 was decreased to ∼60, ∼44, and ∼35 mmHg and increased to ∼320 mmHg and ∼430 mmHg. Stages lasted ∼15 min. Intra-arterial pressure was measured continuously; arterial blood gases were sampled at the end of each stage. There were three principal findings. (1) Regional reactivity: the VA reactivity to hypocapnia was larger than the ICA, MCA and PCA; hypercapnic reactivity was similar.With profound hypoxia (35 mmHg) the relative increase in VA flow was 50% greater than the other vessels. (2) Neck vessel diameters: changes in diameter (∼25%) of the ICA was positively related to changes in PaCO2 (R2, 0.63±0.26; P

Cerebral blood flow (CBF) is reduced during passive heat stress, with 50% of this reduction associated with hyperventilatory-induced hypocapnia and subsequent cerebral vasoconstriction. It remains unknown, however, what other factors may contribute to the remaining 50%. We tested the hypothesis that the distribution of cardiac output plays an important role in maintaining cerebral perfusion during mild and severe heat stress. Middle cerebral artery and posterior cerebral artery blood flow velocity (MCAv and PCAv; transcranial Doppler) and left ventricular end-diastolic and end-systolic volumes (2-D echocardiography) were measured under conditions of normothermia and mild and severe passive heat stress (core temperature +0.8 ± 0.1°C (Protocol I; n = 10) and 1.8 ± 0.1°C (Protocol II; n = 8) above baseline). Venous return was manipulated by passive tilt table positioning (30 deg head-down tilt (HDT) and 30 deg head-up tilt (HUT)). Measurements were made under poikilocapnic and isocapnic conditions. Protocol I consisted of mild heat stress which resulted in small reductions in end-tidal CO2 (−5.6 ± 3.5%), MCAv/PCAv (−7.3 ± 2.3% and −10.3 ± 2.9%, respectively) and stroke volume (−8.5 ± 4.2%); while end-diastolic volume was significantly reduced (−16.9 ± 4.0%) and cardiac output augmented (17.2 ± 7.4%). During mild heat stress, CBF was related to left ventricular end-diastolic volume (MCAv, r2 = 0.81; PCAv, r2 = 0.83; P < 0.05) and stroke volume (MCAv, r2 = 0.38; PCAv, r2 = 0.43), but not with cardiac output. Protocol II consisted of severe heat stress which resulted in much greater reductions in end-tidal CO2 (−87.5 ± 31.5%) and CBF (MCAv, −36.4 ± 6.1%; PCAv, −30.1 ± 4.8%; P < 0.01 for all variables), while end-diastolic volume and stroke volume decreased to a similar extent as for mild heat stress. Importantly, isocapnia restored MCAv and PCAv back to normothermic baseline. This investigation therefore produced two novel findings: first, that venous return and stroke volume are related to CBF during mild heat stress; and second, that hyperventilatory hypocapnia has a major influence on CBF during severe passive heat stress.

There is considerable utility in the use of transcranial Doppler ultrasound (TCD) to assess cerebrovascular function. The brain is unique in its high energy and oxygen demand but limited capacity for energy storage that necessitates an effective means of regional blood delivery. The relative low cost, ease-of-use, non-invasiveness, and excellent temporal resolution of TCD make it an ideal tool for the examination of cerebrovascular function in both research and clinical settings. TCD is an efficient tool to access blood velocities within the cerebral vessels, cerebral autoregulation, cerebrovascular reactivity to CO2, and neurovascular coupling, in both physiological states and in pathological conditions such as stroke and head trauma. In this review, we provide: (1) an overview of TCD methodology with respect to other techniques; (2) a methodological synopsis of the cerebrovascular exam using TCD; (3) an overview of the physiological mechanisms involved in regulation of the cerebral blood flow; (4) the utility of TCD for assessment of cerebrovascular pathology; and (5) recommendations for the assessment of four critical and complimentary aspects of cerebrovascular function: intra-cranial blood flow velocity, cerebral autoregulation, cerebral reactivity, and neurovascular coupling. The integration of these regulatory mechanisms from an integrated systems perspective is discussed, and future research directions are explored.