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.

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.

Ainslie PN, Barach A, Murrell C, Hamlin M, Hellemans J, Ogoh S. Alterations in cerebral autoregulation and cerebral blood flow velocity during acute hypoxia: rest and exercise. Am J Physiol Heart Circ Physiol 292: H976 -H983, 2007. First published September 29, 2006; doi:10.1152/ajpheart.00639.2006.-We examined the relationship between changes in cardiorespiratory and cerebrovascular function in 14 healthy volunteers with and without hypoxia [arterial O2 saturation (SaO 2 ) ϳ80%] at rest and during 60 -70% maximal oxygen uptake steady-state cycling exercise. During all procedures, ventilation, end-tidal gases, heart rate (HR), arterial blood pressure (BP; Finometer) cardiac output (Modelflow), muscle and cerebral oxygenation (near-infrared spectroscopy), and middle cerebral artery blood flow velocity (MCAV; transcranial Doppler ultrasound) were measured continuously. The effect of hypoxia on dynamic cerebral autoregulation was assessed with transfer function gain and phase shift in mean BP and MCAV. At rest, hypoxia resulted in increases in ventilation, progressive hypocapnia, and general sympathoexcitation (i.e., elevated HR and cardiac output); these responses were more marked during hypoxic exercise (P Ͻ 0.05 vs. rest) and were also reflected in elevation of the slopes of the linear regressions of ventilation, HR, and cardiac output with SaO 2 (P Ͻ 0.05 vs. rest). MCAV was maintained during hypoxic exercise, despite marked hypocapnia (44.1 Ϯ 2.9 to 36.3 Ϯ 4.2 Torr; P Ͻ 0.05). Conversely, hypoxia both at rest and during exercise decreased cerebral oxygenation compared with muscle. The low-frequency phase between MCAV and mean BP was lowered during hypoxic exercise, indicating impairment in cerebral autoregulation. These data indicate that increases in cerebral neurogenic activity and/or sympathoexcitation during hypoxic exercise can potentially outbalance the hypocapniainduced lowering of MCAV. Despite maintaining MCAV, such hypoxic exercise can potentially compromise cerebral autoregulation and oxygenation.hypocapnia; hypoxemia AN IMPORTANT PROTECTIVE FEATURE of the cerebral circulation is the ability to maintain cerebral blood flow (CBF) over a wide range of cerebral perfusion pressures (36). At rest, lowering of arterial PCO 2 (Pa CO 2 ) (hypocapnia) as a result of hyperventilation and elevations in sympathetic activation act to enhance cerebral autoregulation (i.e., by widening the cerebral autoregulation curve and causing a rightward shift, respectively), thus preventing cerebral hyperperfusion (36). During exercise, however, it has been shown that dynamic cerebral autoregulation was impaired by exhaustive exercise despite a hyperventilation-induced reduction in Pa CO 2 and likely exercise-induced elevations in sympathetic activation (35).Acute hypoxia in resting and exercising humans results in an enhanced muscle sympathetic discharge, cardiac output, skeletal muscle blood flow, and increased heart rate with little or no alteration in mean arterial blood pressure (MAP) (15, 38). In the brain, the vasod...

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The reduction in cerebrovascular reactivity to CO 2 and/or endothelial function that occurs in the early hours after waking are potential causes for the increased risk for cardiovascular events at this time point. It is unknown whether cerebral autoregulation is reduced in the morning. We tested the hypothesis that early morning reduction in endothelium-dependent vascular reactivity would be linked to changes in cerebrovascular reactivity to CO 2 and cerebral autoregulation (CA). Overnight changes in a dynamic cerebral autoregulation index (ARI) were determined from continuous recordings of blood flow velocity in the middle cerebral artery (MCAv) and arterial blood pressure (BP) during transiently induced hypotension in 20 individuals. Frontal cortical oxygenation (near infrared spectroscopy) and cerebral haemodynamics were also monitored during hypercapnia and before and during 3 min of active standing. Brachial artery flow-mediated endothelium-dependent vasodilatation (FMD) and endothelium-independent dilatation (NFMD) were also monitored. From evening to morning, there was a significant lowering in ARI (5.3 ± 0.5 versus 4.7 ± 0.6 a.u.; P < 0.05), cerebrovascular reactivity to CO 2 (5.3 ± 0.6 versus 4.6 ± 1.1% mmHg −1 ; P < 0.05) and FMD (7.6 ± 0.9 versus 6.0 ± 1.4%; P < 0.05). The lowered FMD was related to the decrease in cerebrovascular reactivity to CO 2 (r = 0.76; P < 0.05). Transient reductions in morning MCAv and cortical oxyhaemoglobin concentrations were observed upon resuming a supine-to-upright position (P < 0.05 versus evening). The early morning reduction in cerebral autoregulation may facilitate the onset of cerebrovascular accidents; this may be of particular relevance to at-risk groups, especially upon resuming the upright position.

We hypothesized that 1) acute severe hypoxia, but not hyperoxia, at sea level would impair dynamic cerebral autoregulation (CA); 2) impairment in CA at high altitude (HA) would be partly restored with hyperoxia; and 3) hyperoxia at HA and would have more influence on blood pressure (BP) and less influence on middle cerebral artery blood flow velocity (MCAv). In healthy volunteers, BP and MCAv were measured continuously during normoxia and in acute hypoxia (inspired O2 fraction = 0.12 and 0.10, respectively; n = 10) or hyperoxia (inspired O2 fraction, 1.0; n = 12). Dynamic CA was assessed using transfer-function gain, phase, and coherence between mean BP and MCAv. Arterial blood gases were also obtained. In matched volunteers, the same variables were measured during air breathing and hyperoxia at low altitude (LA; 1,400 m) and after 1-2 days after arrival at HA ( approximately 5,400 m, n = 10). In acute hypoxia and hyperoxia, BP was unchanged whereas it was decreased during hyperoxia at HA (-11 +/- 4%; P < 0.05 vs. LA). MCAv was unchanged during acute hypoxia and at HA; however, acute hyperoxia caused MCAv to fall to a greater extent than at HA (-12 +/- 3 vs. -5 +/- 4%, respectively; P < 0.05). Whereas CA was unchanged in hyperoxia, gain in the low-frequency range was reduced during acute hypoxia, indicating improvement in CA. In contrast, HA was associated with elevations in transfer-function gain in the very low- and low-frequency range, indicating CA impairment; hyperoxia lowered these elevations by approximately 50% (P < 0.05). Findings indicate that hyperoxia at HA can partially improve CA and lower BP, with little effect on MCAv.

We examined potential mechanisms (autonomic function, hypotension, and cerebral hypoperfusion) responsible for orthostatic intolerance following prolonged exercise. Autonomic function and cerebral hemodynamics were monitored in seven athletes pre-, post- (<4 h), and 48 h following a mountain marathon [42.2 km; cumulative gain approximately 1,000 m; approximately 15 degrees C; completion time, 261 +/- 27 (SD) min]. In each condition, middle cerebral artery blood velocity (MCAv), blood pressure (BP), heart rate (HR), and cardiac output (Modelflow) were measured continuously before and during a 6-min stand. Measurements of HR and BP variability and time-domain analysis were used as an index of sympathovagal balance and baroreflex sensitivity (BRS). Cerebral autoregulation was assessed using transfer-function gain and phase shift in BP and MCAv. Hypotension was evident following the marathon during supine rest and on standing despite increased sympathetic and reduced parasympathetic control, and elevations in HR and cardiac output. On standing, following the marathon, there was less elevation in normalized low-frequency HR variability (P < 0.05), indicating attenuated sympathetic activation. MCAv was maintained while supine but reduced during orthostasis postmarathon [-10.4 +/- 9.8% pre- vs. -15.4 +/- 9.9% postmarathon (%change from supine); P < 0.05]; such reductions were related to an attenuation in BRS (r = 0.81; P < 0.05). Cerebral autoregulation was unchanged following the marathon. These findings indicate that following prolonged exercise, hypotension and postural reductions in autonomic function or baroreflex control, or both, rather than a compromise in cerebral autoregulation, may place the brain at risk of hypoperfusion. Such changes may be critical factors in collapse following prolonged exercise.