It is known that cerebral blood flow declines with age in sedentary adults, although previous studies have involved small sample sizes, making the exact estimate of decline imprecise and the effects of possible moderator variables unknown. Animal studies indicate that aerobic exercise can elevate cerebral blood flow; however, this possibility has not been examined in humans. We examined how regular aerobic exercise affects the age-related decline in blood flow velocity in the middle cerebral artery (MCAv) in healthy humans. Maximal oxygen consumption, body mass index (BMI), blood pressure and MCAv were measured in healthy sedentary (n = 153) and endurance-trained (n = 154) men aged between 18 and 79 years. The relationships between age, training status, BMI and MCAv were examined using analysis of covariance methods. Mean ± s.e.m. estimates of regression coefficients and 95% confidence intervals (95% CI) were calculated. The age-related decline in MCAv was −0.76 ± 0.04 cm s −1 year −1 (95% CI = −0.69 to −0.83, r 2 = 0.66, P < 0.0005) and was independent of training status (P = 0.65). Nevertheless, MCAv was consistently elevated by 9.1 ± 3.3 cm s −1 (CI = 2.7-15.6, P = 0.006) in endurance-trained men throughout the age range. This ∼17% difference between trained and sedentary men amounted to an approximate 10 year reduction in MCAv 'age' and was robust to between-group differences in BMI and blood pressure. Regular aerobic-endurance exercise is associated with higher MCAv in men aged 18-79 years. The persistence of this finding in older endurance-trained men may therefore help explain why there is a lower risk of cerebrovascular disease in this population.

Abstract-Cerebral autoregulation (CA) is a critical process for the maintenance of cerebral blood flow and oxygenation.Assessment of CA is frequently used for experimental research and in the diagnosis, monitoring, or prognosis of cerebrovascular disease; however, despite the extensive use and reference to static CA, a valid quantification of "normal" CA has not been clearly identified. While controlling for the influence of arterial PCO 2 , we provide the first clear examination of static CA in healthy humans over a wide range of blood pressure. In 11 healthy humans, beat-to-beat blood pressure (radial arterial), middle cerebral artery blood velocity (MCAv; transcranial Doppler ultrasound), end-tidal PCO 2 , and cerebral oxygenation (near infrared spectroscopy) were recorded continuously during pharmacological-induced changes in mean blood pressure. In a randomized order, steady-state decreases and increases in mean blood pressure (8 to 14 levels; range: Ϸ40 to Ϸ125 mm Hg) were achieved using intravenous infusions of sodium nitroprusside or phenylephrine, respectively. MCAv mean was altered by 0.82Ϯ0.35% per millimeter of mercury change in mean blood pressure (R 2 ϭ0.82). Changes in cortical oxygenation index were inversely related to changes in mean blood pressure (slopeϭϪ0.18%/mm Hg; R 2 ϭ0.60) and MCAv mean (slopeϭϪ0.26%/cm ⅐ s Ϫ1; R 2 ϭ0.54). There was a progressive increase in MCAv pulsatility with hypotension. These findings indicate that cerebral blood flow closely follows pharmacological-induced changes in blood pressure in otherwise healthy humans. Thus, a finite slope of the plateau region does not necessarily imply a defective CA. Moreover, with progressive hypotension and hypertension there are differential changes in cerebral oxygenation and MCAv mean . (Hypertension. 2010;55:698-705.)

Chronic reductions in cerebral blood flow (CBF) and cerebrovascular reactivity to CO 2 are risk factors for cerebrovascular disease. Higher aerobic fitness is associated with higher CBF at any age; however, whether CBF or reactivity can be elevated following an exercise training intervention in healthy individuals is unknown. The aim of this study was to assess the effect of exercise training on CBF and cerebrovascular reactivity at rest and during exercise in young and older individuals. Ten young (23±5 years; body mass index ) previously sedentary individuals breathed 5 % CO 2 for 3 min at rest and during steady-state cycling exercise (30 and 70 % heart rate range (HRR)) prior to and following a 12-week aerobic exercise intervention. Effects of training on middle cerebral artery blood velocity (MCAv) at rest were unclear in both age groups. The absolute MCAv response to exercise was greater in the young (9 and 9 cm s −1 (30 and 70 % HRR, respectively) vs. 5 and 4 cm s −1 (older), P<0.05) and was similar following training. Cerebrovascular reactivity was elevated following the 12-week training at rest (2.87±0.76 vs. 2.54± 1.12 cm s −1 mm Hg −1 , P00.01) and during exercise, irrespective of age. The finding of a training-induced elevation in cerebrovascular reactivity provides further support for exercise as a preventative tool in cerebrovascular and neurological disease with ageing.

This study examined cerebrovascular reactivity and ventilation during step changes in CO 2 in humans. We hypothesized that: (1) end-tidal P CO 2 (P ET,CO 2 ) would overestimate arterial P CO 2 (P a,CO 2 ) during step variations in P ET,CO 2 and thus underestimate cerebrovascular CO 2 reactivity; and (2) sinceP CO 2 from the internal jugular vein (P jv,CO 2 ) better represents brain tissueP CO 2 , cerebrovascular CO 2 reactivity would be higher when expressed against P jv,CO 2 than with P a,CO 2 , and would be related to the degree of ventilatory change during hypercapnia. Incremental hypercapnia was achieved through 4 min administrations of 4% and 8% CO 2 . Incremental hypocapnia involved two 4 min steps of hyperventilation to changeP ET,CO 2 , in an equal and opposite direction, to that incurred during hypercapnia. Arterial and internal jugular venous blood was sampled simultaneously at baseline and during each CO 2 step. Cerebrovascular reactivity to CO 2 was expressed as the percentage change in blood flow velocity in the middle cerebral artery (MCAv) per mmHg change in P a,CO 2 and P jv,CO 2 . During hypercapnia, but not hypocapnia, P ET,CO 2 overestimated P a,CO 2 by +2.4 ± 3.4 mmHg and underestimated MCAv-CO 2 reactivity (P < 0.05). The hypercapnic and hypocapnic MCAv-CO 2 reactivity was higher (∼97% and ∼24%, respectively) when expressed with P jv,CO 2 than P a,CO 2 (P < 0.05). The hypercapnic MCAv-P jv,CO 2 reactivity was inversely related to the increase in ventilatory change (R 2 = 0.43; P < 0.05), indicating that a reduced reactivity results in less central CO 2 washout and greater ventilatory stimulus. Differences in the P ET,CO 2 , P a,CO 2 and P jv,CO 2 -MCAv relationships have implications for the true representation and physiological interpretation of cerebrovascular CO 2 reactivity.

Upon ascent to high altitude, cerebral blood flow (CBF) rises substantially before returning to sea-level values. The underlying mechanisms for these changes are unclear. We examined three hypotheses: (1) the balance of arterial blood gases upon arrival at and across 2 weeks of living at 5050 m will closely relate to changes in CBF; (2) CBF reactivity to steady-state changes in CO2 will be reduced following this 2 week acclimatisation period, and (3) reductions in CBF reactivity to CO2 will be reflected in an augmented ventilatory sensitivity to CO2. We measured arterial blood gases, middle cerebral artery blood flow velocity (MCAv, index of CBF) and ventilation () at rest and during steady-state hyperoxic hypercapnia (7% CO2) and voluntary hyperventilation (hypocapnia) at sea level and then again following 2–4, 7–9 and 12–15 days of living at 5050 m. Upon arrival at high altitude, resting MCAv was elevated (up 31 ± 31%; P < 0.01; vs. sea level), but returned to sea-level values within 7–9 days. Elevations in MCAv were strongly correlated (R2= 0.40) with the change in ratio (i.e. the collective tendency of arterial blood gases to cause CBF vasodilatation or constriction). Upon initial arrival and after 2 weeks at high altitude, cerebrovascular reactivity to hypercapnia was reduced (P < 0.05), whereas hypocapnic reactivity was enhanced (P < 0.05 vs. sea level). Ventilatory response to hypercapnia was elevated at days 2–4 (P < 0.05 vs. sea level, 4.01 ± 2.98 vs. 2.09 ± 1.32 l min−1 mmHg−1). These findings indicate that: (1) the balance of arterial blood gases accounts for a large part of the observed variability (∼40%) leading to changes in CBF at high altitude; (2) cerebrovascular reactivity to hypercapnia and hypocapnia is differentially affected by high-altitude exposure and remains distorted during partial acclimatisation, and (3) alterations in cerebrovascular reactivity to CO2 may also affect ventilatory sensitivity.

Duplex ultrasound is an evolving technology that allows the assessment of volumetric blood flow in the carotid and vertebral arteries during a range of interventions along the spectrum of health and chronic disease. Duplex ultrasound can provide high-resolution diameter and velocity information in real-time and is noninvasive with minimal risks or contraindications. However, this ultrasound approach is a specialized technique requiring intensive training and stringent control of multiple complex settings; results are highly operator-dependent, and analysis approaches are inconsistent. Importantly, therefore, methodological differences can invalidate comparisons between different imaging modalities and studies; such methodological errors have potential to discredit study findings completely. The task of this review is to provide the first comprehensive, user-friendly technical guideline for the application of duplex ultrasound in measuring extracranial blood flow in human research. An update on recent developments in the use of edge-detection software for offline analysis is highlighted, and suggestions for future directions in this field are provided. These recommendations are presented in an attempt to standardize measurements across research groups and, hence, ultimately to improve the accuracy and reproducibility of measuring extracranial blood flow both within subjects and between groups.

An altered acid-base balance following ascent to high altitude has been well established. Such changes in pH buffering could potentially account for the observed increase in ventilatory CO 2 sensitivity at high altitude. Likewise, if [H + ] is the main determinant of cerebrovascular tone, then an alteration in pH buffering may also enhance the cerebral blood flow (CBF) responsiveness to CO 2 (termed cerebrovascular CO 2 reactivity). However, the effect altered acid-base balance associated with high altitude ascent on cerebrovascular and ventilatory responsiveness to CO 2 remains unclear. We measured ventilation (V E ), middle cerebral artery velocity (MCAv; index of CBF) and arterial blood gases at sea level and following ascent to 5050 m in 17 healthy participants during modified hyperoxic rebreathing. At 5050 m, restingV E , MCAv and pH were higher (P < 0.01), while bicarbonate concentration and partial pressures of arterial O 2 and CO 2 were lower (P < 0.01) compared to sea level. Ascent to 5050 m also increased the hypercapnic MCAv CO 2 reactivity (2.9 ± 1.1 vs. 4.8 ± 1.4% mmHg −1 ; P < 0.01) andV E CO 2 sensitivity (3.6 ± 2.3 vs. 5.1 ± 1.7 l min −1 mmHg −1 ; P < 0.01). Likewise, the hypocapnic MCAv CO 2 reactivity was increased at 5050 m (4.2 ± 1.0 vs. 2.0 ± 0.6% mmHg −1 ; P < 0.01). The hypercapnic MCAv CO 2 reactivity correlated with resting pH at high altitude (R 2 = 0.4; P < 0.01) while the central chemoreflex threshold correlated with bicarbonate concentration (R 2 = 0.7; P < 0.01). These findings indicate that (1) ascent to high altitude increases the ventilatory CO 2 sensitivity and elevates the cerebrovascular responsiveness to hypercapnia and hypocapnia, and (2) alterations in cerebrovascular CO 2 reactivity and central chemoreflex may be partly attributed to an acid-base balance associated with high altitude ascent. Collectively, our findings provide new insights into the influence of high altitude on cerebrovascular function and highlight the potential role of alterations in acid-base balance in the regulation in CBF and ventilatory control. Abbreviations CBF, cerebral blood flow; CVCi, cerebrovascular conductance index; MCAv, middle cerebral artery velocity; MAP, mean arterial blood pressure; SBE, standard basic excess;V E , ventilation.

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