Cerebrovascular Conductance Index Research Articles

The analysis of cardio-respiratory signals and cerebral autoregulation based on CO2 reactivity with healthy subjects and Parkinson's patients.

Current paper focus on Parkinson's patients with autonomic dysfunction and how their interactions between cerebral autoregulation and ventilatory control are affected. The experimental data of dynamic CA assessment from the ANS Laboratory of CCGH was accessed for further processing and analysis. The subjects were classified into the groups of healthy and with Parkinson's disease. Based on the accessed ventilation and CBF data, the percentage changes in ventilation and CBF responses to PETCO2 were examined. To minimize effects of changes in ABP on cerebral vasomotor reactivity (CVMR) estimation, cerebrovascular conductance index (CVCi) was calculated, and CBFV-PETCO2 and CVCi-PETCO2 relationships were quantified by nonlinear logistic regression. The interaction between ventilation responses and CBF autoregulation will be modeled and parameters will be validated.

Arterial stiffness is associated with age-related differences in cerebrovascular conductance

To determine if arterial stiffness is associated with age-related differences in cerebrovascular conductance and reactivity, twenty-eight apparently healthy sedentary young (25±1years; n=15) and older (67±1years; n=13) adults were studied. Brachial-ankle pulse wave velocity (baPWV) was measured as an index of arterial stiffness. Cerebrovascular reactivity was determined by measuring changes in mean blood velocity in the middle cerebral artery under normocapnic, hypocapnic and hypercapnic conditions. Mean baPWV was greater (p<0.05) in older compared with young adults. At baseline, mean cerebral blood flow velocity and cerebrovascular conductance index were lower (p<0.05) in older compared with young adults under normocapnic, hypocapnic and hypercapnic conditions. There were no significant group differences in cerebrovascular reactivity when they were adjusted for stimuli (i.e., end-tidal CO2 concentrations) in most perturbation conditions except for the normocapnia to hypercapnia condition. baPWV was negatively associated with cerebrovascular conductance index at all conditions (all p<0.05). We concluded that arterial stiffness was associated with age-related differences in cerebrovascular conductance and that there were no apparent age-associated differences in cerebrovascular reactivity.

Correlations between endothelial function in the systemic and cerebral circulation and insulin resistance in type 2 diabetes mellitus.

Insulin resistance is associated with endothelial dysfunction in type 2 diabetes mellitus, which can lead to impaired vascular reactivities of both systemic and cerebral circulations. Appropriate 'correction' of vascular reactivity results for non-endothelium-dependent systemic effects avoids misinterpretation of endothelial function. Therefore, we 'corrected' vascular reactivity results and explored the potential correlations between systemic vascular reactivity, cerebrovascular reactivity and insulin resistance. In 34 patients, 'systemic vascular reactivity' was assessed by quantifying reactive hyperaemia. Cerebrovascular reactivity was assessed by quantifying changes in cerebral blood flow velocity during hypercapnia. To minimize the influence of non-endothelium-dependent systemic effects on vascular reactivity results, 'corrected systemic vascular reactivity' was calculated by normalizing systemic vascular reactivity using the measurements from the contralateral side; and cerebrovascular reactivity results were corrected by calculating percentage and absolute changes in cerebrovascular conductance index ('percent cerebrovascular conductance index' and 'delta cerebrovascular conductance index', respectively). Insulin resistance was estimated by homeostatic model assessment. Correlation between conventional cerebrovascular reactivity and systemic vascular reactivity was not significant. But correlations between 'corrected systemic vascular reactivity' and 'percent cerebrovascular conductance index' (r = 0.51; p = 0.002) and 'corrected systemic vascular reactivity' and 'delta cerebrovascular conductance index' (r = 0.50; p = 0.003) were significant. Among all vascular reactivity parameters, only 'delta cerebrovascular conductance index' was significantly correlated with homeostatic model assessment of insulin resistance (r = -0.38; p = 0.029). In conclusion, endothelial function in the systemic and cerebral circulations is moderately correlated, provided that vascular reactivity estimates are corrected for non-endothelium-dependent influences.

The analysis of cardio-respiratory signals and cerebral autoregulation based on CO2 reactivity with healthy subjects and Parkinson's patients.

Current paper focus on Parkinson's patients with autonomic dysfunction and how their interactions between cerebral autoregulation and ventilatory control are affected. The experimental data of dynamic CA assessment from the ANS Laboratory of CCGH was accessed for further processing and analysis. The subjects were classified into the groups of healthy and with Parkinson's disease. Based on the accessed ventilation and CBF data, the percentage changes in ventilation and CBF responses to PETCO2 were examined. To minimize effects of changes in ABP on cerebral vasomotor reactivity (CVMR) estimation, cerebrovascular conductance index (CVCi) was calculated, and CBFV-PETCO2 and CVCi-PETCO2 relationships were quantified by nonlinear logistic regression. The interaction between ventilation responses and CBF autoregulation will be modeled and parameters will be validated.

Hypoxic Cerebral Vasodilation in Healthy and Metabolic Syndrome Adults: Distinct Interactions between Cyclooxygenase and Reactive Oxygen Species Signaling

Excess reactive oxygen species (ROS) limit hypoxia‐mediated cerebral vasodilation in animal models of metabolic syndrome (MetSyn). Cyclooxygenase (COX) may be a source of ROS, but data are lacking in humans. We hypothesized ROS limit hypoxic cerebral vasodilation in human MetSyn, but COX is not the source. We measured middle cerebral artery velocity (MCAv) with transcranial Doppler ultrasound in 12 MetSyn adults (34±2 yr) and 12 healthy adults (28±1 yr) during baseline and steady‐state hypoxia (SPo2=80%). Intravenous ascorbic acid suppressed ROS during the first steady‐state hypoxia. Oral indomethacin was administered to inhibit COX prior to a second hypoxia trial to investigate the combined roles of ROS and COX during hypoxia. MCAv was normalized for MABP as cerebrovascular conductance index [CVCi = (MCAv ÷ MABP) * 100], and a change in CVCi from baseline (ΔCVCi) indicated hypoxic dilation. ΔCVCi was ~50% lower in adults with MetSyn during control hypoxia (p&lt;0.05). Ascorbic acid infusion increased ΔCVCi in MetSyn adults (p&lt;0.05), but not healthy adults. Combined ascorbic acid and indomethacin increased ΔCVCi in MetSyn adults (p&lt;0.05) similar to ascorbic acid alone. Surprisingly in healthy adults, combined ascorbic acid and indomethacin reduced ΔCVCi by ~75% (p&lt;0.05). This contrasts previous data in healthy adults that indicated no effect of indomethacin alone. In summary, healthy adults express a ROS‐COX redundancy, whereby ROS suppression increased reliance on COX products to achieve hypoxic cerebral vasodilation. MetSyn disrupts this complementary role of ROS, such that COX‐derived ROS restrain hypoxic cerebral vasodilation.

Cerebral vasomotor reactivity: steady-state versus transient changes in carbon dioxide tension.

New FindingsWhat is the central question of this study?The relationship between changes in cerebral blood flow and arterial carbon dioxide tension is used to assess cerebrovascular function. Hypercapnia is generally evoked by two methods, i.e. steady-state and transient increases in carbon dioxide tension. In some cases, the hypercapnia is immediately preceded by a period of hypocapnia. It is unknown whether the cerebrovascular response differs between these methods and whether a period of hypocapnia blunts the subsequent response to hypercapnia.What is the main finding and its importance?The cerebrovascular response is similar between steady-state and transient hypercapnia. However, hyperventilation-induced hypocapnia attenuates the cerebral vasodilatory responses during a subsequent period of rebreathing-induced hypercapnia.Cerebral vasomotor reactivity (CVMR) to changes in arterial carbon dioxide tension () is assessed during steady-state or transient changes in . This study tested the following two hypotheses: (i) that CVMR during steady-state changes differs from that during transient changes in ; and (ii) that CVMR during rebreathing-induced hypercapnia would be blunted when preceded by a period of hyperventilation. For each hypothesis, end-tidal carbon dioxide tension () middle cerebral artery blood velocity (CBFV), cerebrovascular conductance index (CVCI; CBFV/mean arterial pressure) and CVMR (slope of the linear regression between changes in CBFV and CVCI versus ) were assessed in eight individuals. To address the first hypothesis, measurements were made during the following two conditions (randomized): (i) steady-state increases in of 5 and 10 Torr above baseline; and (ii) rebreathing-induced transient breath-by-breath increases in . The linear regression for CBFV versus (P = 0.65) and CVCI versus (P = 0.44) was similar between methods; however, individual variability in CBFV or CVCI responses existed among subjects. To address the second hypothesis, the same measurements were made during the following two conditions (randomized): (i) immediately following a brief period of hypocapnia induced by hyperventilation for 1 min followed by rebreathing; and (ii) during rebreathing only. The slope of the linear regression for CBFV versus (P < 0.01) and CVCI versus (P < 0.01) was reduced during hyperventilation plus rebreathing relative to rebreathing only. These results indicate that cerebral vasomotor reactivity to changes in is similar regardless of the employed methodology to induce changes in and that hyperventilation-induced hypocapnia attenuates the cerebral vasodilatory responses during a subsequent period of rebreathing-induced hypercapnia.

Influence of dynamic cerebral autoregulation on presyncope in endurance athletes (1184.5)

The impact of dynamic cerebral autoregulation (dCA) on presyncope symptoms (PS) is controversial in endurance athletes. We examined the influence of dCA during transient hypotension on PS in 11 male athletes using 1) the thigh‐cuff method (rate of regulation [RoR]), and 2) the relative reduction in cerebrovascular conductance index (CVCi) during transient hypotension induced by squat‐stand maneuvers at different frequencies (0.025, 0.05 and 0.1 Hz). Prevalence of PS was assessed using a 20‐min glyceryl trinitrate‐provoked head‐up tilt. Correlations were assessed between dCA metrics. Subjects were then divided into two groups according to presence (n=6; PS group) or absence (n=5; non‐PS group) of PS. There were no correlations between dCA metrics and time to PS. dCA metrics were unrelated, except CVCi response to hypotension at 0.05 Hz and 0.1 Hz (B=0.846, p=0.008). ROR was comparable between PS and non‐PS groups. The CVCi response to hypotension was attenuated in the PS group vs. non‐PS group (0.05 Hz: 1.51 ± 0.31 vs. 2.47 ± 0.27 %/%; 0.1 Hz: 1.35 ± 0.36 vs. 2.32 ± 0.41 %/%, all p&lt;0.05). These results suggest that although CVCi was better adapted to coping with transient hypotension in athletes with PS vs. those without PS, this was unrelated to PS. Thus, metrics of dCA assessing the cerebral blood flow response to hypotension cannot be used to predict PS risk in endurance athletes.Grant Funding Source: Supported by a research contract from the Ministère de l'Éductation, du Loisir et du Sport (Québec)

Cerebral blood flow regulation during blood loss compared to lower body negative pressure in humans (1068.9)

Lower body negative pressure (LBNP) is often used to simulate blood loss in humans. However, it is unknown if the effects of actual blood loss (BL) on cerebral blood flow regulation is analogous to simulated blood loss during LBNP. Nine healthy men (32±6 y) were studied at baseline, during 3 levels of LBNP (5 min each at ‐15, ‐30, ‐45 mmHg), and during 3 levels of blood loss (5 min each at 333, 667, 1000 mL). LBNP and BL conditions were randomized. Intra‐arterial mean arterial pressure (MAP) was similar during LBNP compared with BL (p&gt;0.20). Central venous pressure (CVP; 2.8±0.7 vs. 4.0±0.8, 1.2±0.6 vs. 3.5±0.8, 0.2±0.9 vs. 2.1±0.9 mmHg for level 1, 2, and 3; p&lt;0.01) and stroke volume (71±4 vs. 80±3, 60±3 vs. 74±3, 51±2 vs. 68±4 mL for level 1, 2, and 3; p&lt;0.01) were lower during LBNP compared with BL. Despite differences in CVP, middle cerebral artery velocity (MCAv) and cerebrovascular conductance index (CVCi) were similar between LBNP and BL at each level (MCAv at level 3: 62±6 vs. 66±5 cm/s; p=0.37; CVCi at level 3: 0.72±0.05 vs. 0.73±0.05 cm/s/mmHg; p=0.29). Furthermore, the slope of the relationship between MAP and MCAv was not different between LBNP and BL (1.06 vs. 1.07 cm/s/mmHg). Our results suggest that the cerebral hemodynamic responses to LBNP are similar to actual blood loss.Grant Funding Source: Supported by U.S. Army MRMC Combat Casualty Care Research Program Grant # W81XWH‐11‐1‐0823

Middle cerebral artery mean flow velocity changes to non‐pharmacologically induced hypertension and hypotension in humans (1184.6)

Asymmetrical responses of cerebral blood flow in response to elevating vs. falling blood pressure has been reported using cyclic inflation and deflation of thigh cuffs in head injury patients and pharmacologically in healthy volunteers. Whether this phenomenon exists with non‐pharmacologically induced hypertension and hypotension is unknown. In this study, we examined the relative changes in cerebrovascular conductance index (CVCi), defined as percent changes in middle cerebral artery mean flow velocity / percent changes in mean arterial pressure, during transient hypertension vs. hypotension in 10 healthy male volunteers {age [median (range)]: 24 (22‐35 yrs), body weight [mean±SD: 72±12 kg]; maximal oxygen uptake: 55±5 ml/kg/min}. Transient hypertension and hypotension were induced via squat‐stand manoeuvres executed at 0.025, 0.05 and 0.1 Hz. The CVCi responses to hypertension (squat) compared to hypotension (stand) were attenuated at 0.05 Hz (0.57±0.38 vs. 1.84±0.56 %/%) and 0.1 Hz [0.83±0.41 vs. 1.59±0.57 %/%; all p&lt;0.01), but not at 0.025 Hz [0.86±0.30 vs. 1.12±0.31 %/%; p=0.1). These results suggest that the human cerebrovascular function is better adapted to combat non‐pharmacologically and physiologically relevant transient hypertension than transient hypotension.Grant Funding Source: Supported by a research contract from the Ministère de l’Éducation, du Loisir et du Sport (Québec)

Role of cyclooxygenase in sex‐specific cerebrovascular responses to hypoxia (708.2)

Animal data suggest females rely more on cyclooxygenase (COX) than males to achieve increases in cerebral blood flow. Our aim was to determine the contribution of COX to hypoxia‐mediated increases in cerebral blood flow in young, healthy female and male humans. We hypothesized females would exhibit greater hypoxia‐mediated increases in cerebral blood flow due to increased COX signaling. We measured middle cerebral artery velocity (MCAv) with transcranial Doppler ultrasound in young (24±1 yr) females (n=12) and males (n=17). Females were studied during early follicular phase (cycle day 1 ‐ 5) to minimize the effects of female hormones. Inspired air was titrated to lower arterial O2 saturation to 80% for 5 minutes while end‐tidal CO2 was maintained at basal levels. MCAv was normalized for blood pressure as cerebrovascular conductance index (CVCi). Hypoxia was conducted on twice after ingestion of placebo or COX inhibitor (100mg indomethacin). Hypoxia increased CVCi (ΔCVCi) but ΔCVCi was not different between groups (females: 13±2 vs. males: 10±2 cm/s/mmHg, p=0.55). Indomethacin reduced ΔCVCi 4±3 cm/s/mmHg in females and increased ΔCVCi 0.5±2 cm/s/mmHg in males; however, the indomethacin‐mediated change in ΔCVCi was not statistically significant (p=0.15). Our data indicate males and females respond similarly to hypoxia, but COX may play a relatively larger role in females to mediate cerebral vasodilation.Grant Funding Source: AHA PRE7390038 &amp; NIH HL105820

AltitudeOmics: enhanced cerebrovascular reactivity and ventilatory response to CO2 with high-altitude acclimatization and reexposure

The present study is the first to examine the effect of high-altitude acclimatization and reexposure on the responses of cerebral blood flow and ventilation to CO2. We also compared the steady-state estimates of these parameters during acclimatization with the modified rebreathing method. We assessed changes in steady-state responses of middle cerebral artery velocity (MCAv), cerebrovascular conductance index (CVCi), and ventilation (V(E)) to varied levels of CO2 in 21 lowlanders (9 women; 21 ± 1 years of age) at sea level (SL), during initial exposure to 5,260 m (ALT1), after 16 days of acclimatization (ALT16), and upon reexposure to altitude following either 7 (POST7) or 21 days (POST21) at low altitude (1,525 m). In the nonacclimatized state (ALT1), MCAv and V(E) responses to CO2 were elevated compared with those at SL (by 79 ± 75% and 14.8 ± 12.3 l/min, respectively; P = 0.004 and P = 0.011). Acclimatization at ALT16 further elevated both MCAv and Ve responses to CO2 compared with ALT1 (by 89 ± 70% and 48.3 ± 32.0 l/min, respectively; P < 0.001). The acclimatization gained for V(E) responses to CO2 at ALT16 was retained by 38% upon reexposure to altitude at POST7 (P = 0.004 vs. ALT1), whereas no retention was observed for the MCAv responses (P > 0.05). We found good agreement between steady-state and modified rebreathing estimates of MCAv and V(E) responses to CO2 across all three time points (P < 0.001, pooled data). Regardless of the method of assessment, altitude acclimatization elevates both the cerebrovascular and ventilatory responsiveness to CO2. Our data further demonstrate that this enhanced ventilatory CO2 response is partly retained after 7 days at low altitude.

Cyclooxygenase-derived vasoconstriction restrains hypoxia-mediated cerebral vasodilation in young adults with metabolic syndrome

Poor cerebrovascular function in metabolic syndrome (MetSyn) likely contributes to elevated risk of cerebrovascular disease in this growing clinical population. Younger MetSyn adults without clinical evidence of cerebrovascular disease exhibit preserved hypercapnic vasodilation yet markedly impaired hypoxic vasodilation, but the mechanisms behind reduced hypoxic vasodilation are unknown. Based on data from rats, we tested the hypothesis that younger adults with MetSyn exhibit reduced cerebral hypoxic vasodilation due to loss of vasodilating prostaglandins. Middle cerebral artery velocity (MCAv) was measured with transcranial Doppler ultrasound in adults with MetSyn (n = 13, 33 ± 3 yr) and healthy controls (n = 15, 31 ± 2 yr). Isocapnic hypoxia was induced by titrating inspired oxygen to lower arterial saturation to 90% and 80% for 5 min each. Separately, hypercapnia was induced by increasing end-tidal CO2 10 mmHg above baseline levels. Cyclooxygenase inhibition (100 mg indomethacin) was conducted in a randomized double-blind, placebo controlled design. MCAv was normalized for group differences in blood pressure (healthy: 89 ± 2 mmHg vs. MetSyn: 102 ± 2 mmHg) as cerebrovascular conductance index (CVCi), and used to assess cerebral vasodilation. Hypoxia increased CVCi in both groups; however, vasodilation was ∼55% lower in MetSyn at SpO2 = 80% (P < 0.05). Indomethacin tended to decrease hypoxic vasodilation in healthy controls, and unexpectedly increased dilation in MetSyn (P < 0.05). In contrast to hypoxia, hypercapnia-mediated vasodilation was similar between groups, as was the decrease in vasodilation with indomethacin. These data indicate increased production of vasoconstrictor prostaglandins restrains hypoxic cerebral vasodilation in MetSyn, preventing them from responding appropriately to this important physiological stressor.

Correction for Blood Pressure Improves Correlation between Cerebrovascular Reactivity Assessed by Breath Holding and 6% CO2 Breathing

Changes in cerebral blood flow velocity to hypercapnia are associated with changes in systemic blood pressure (BP). These confounding BP-dependent changes in cerebral blood flow velocity cause misinterpretation of cerebrovascular reactivity (CVR) results. The objective of the study was to determine the relationship between CVR assessed by breath holding and 6% CO2 breathing after correcting for BP-dependent changes in cerebral blood flow velocity. In 33 patients of uncomplicated type 2 diabetes mellitus, CVR was assessed as percentage changes in cerebral blood flow velocity and cerebrovascular conductance index. Percentage change in cerebral blood flow velocity during breath holding was positively correlated with that of during 6% CO2 breathing (r = .35; P = .0448). CVR during breath holding and 6% CO2 breathing were better correlated when expressed as percentage changes in cerebrovascular conductance index (r = .49; P = .0040). Similarly, breath-holding test results expressed as percentage changes in cerebral blood flow velocity correctly identified only 37.5% of the poor reactors to 6% CO2 breathing. However, when the breath-holding test results were expressed as percentage changes in cerebrovascular conductance index, 62.5% of the poor reactors to 6% CO2 breathing were correctly identified indicating a better agreement between the test results obtained by the 2 methods. Cerebrovascular response to breath holding is better correlated with that of 6% CO2 breathing when changes in cerebral blood flow velocity were corrected for associated changes in BP.

Sex differences in age‐related changes in cerebral vasodilator responses

Cerebral vasodilator responses to hypercapnia decrease with aging, and recent data suggests sex differences in cerebrovascular regulation exist. Yet, it is unknown how sex and age interact in response to the stress of cyclooxygenase inhibition. We examined cerebral vasodilator responses to hypercapnia in 7 young men (YM), 8 young women (YW), 7 older men (OM), and 6 older women (OW) before (CON) and during cyclooxygenase (COX) inhibition via indomethacin (INDO). There was no age by sex interaction in middle cerebral artery velocity responses to hypercapnia (MCAv Slope). However, when accounting for mean arterial pressure during hypercapnia, there was an age by sex interaction in cerebrovascular conductance index (CVCi Slope). YM demonstrated higher CVCi Slope (1.27 ± 0.21 AU) compared with YW (0.65 ± 0.10 AU) and older adults (0.58 ± 0.10 AU in OM; 0.66 ± 0.06 AU in OW; p&lt;0.05 for all). There was no difference in CVCi Slope between YW and OW, indicating that the age‐associated reduction in CVCi Slope only pertains to men. During INDO, there was an age by sex interaction for the ΔCVCi Slope (from CON to INDO) with YM having a greater slope compared with both YW (0.72 ± 0.15 vs. 0.27 ± 0.13 AU; p&lt;0.01) and OM (0.26 ± 0.18 AU; p&lt;0.01). Taken together, our results suggest that sex differences exist in the cerebrovascular response to hypercapnia with and without COX inhibition and that the effect of age is different in women compared to men.

Cerebrovascular reactivity is associated with maximal aerobic capacity in healthy older adults

Recently, several high-impact reviews suggest that regular aerobic exercise is beneficial for maintaining cognitive function in aging adults. Higher cerebral blood flow and/or cerebrovascular reactivity may explain the favorable effect of exercise on cognition. In addition, prostaglandin-mediated vasodilator responses may be influenced by regular exercise. Therefore, our purpose was to evaluate middle cerebral artery (MCA) vasodilator responses in healthy adults before and after cyclooxygenase inhibition. A total of 16 young (26 ± 6 yr; 8 males, 8 females) and 13 older (64 ± 6 yr; 7 males, 6 females) healthy adults participated in the study. Aerobic fitness was determined by maximal aerobic capacity (Vo2max) on a cycle ergometer. MCA velocity (MCAv) was measured at baseline and during stepped hypercapnia (2%, 4%, and 6% FiCO2) before and after cyclooxygenase inhibition using indomethacin. To account for differences in blood pressure, cerebrovascular conductance index (CVCi) was calculated as MCAv/mean arterial pressure. Cerebrovascular reactivity slopes were calculated from the correlation between either MCAv or CVCi and end-tidal CO2. Young adults demonstrated greater MCAv reactivity (1.61 ± 0.17 vs. 1.06 ± 0.15 cm·s(-1)·mmHg(-1); P < 0.05) and CVCi reactivity (0.015 ± 0.002 vs. 0.007 ± 0.002 cm·s(-1)·mmHg(-1); P < 0.05) compared with the older adults. There was no association between cerebrovascular reactivity and Vo2max in the combined group of subjects; however, in older adults MCAv reactivity was correlated with maximal aerobic fitness (r = 0.64; P < 0.05). Furthermore, the change in MCAv reactivity (between baseline and indomethacin trials) was also associated with Vo2max (r = 0.59; P < 0.05) in older adults. Cerebral vasodilator responses to hypercapnia were associated with maximal aerobic capacity in healthy older adults. These results may explain the physiological link between regular aerobic exercise and improved cognitive function in aging adults.

α1‐Adrenergic receptor control of the cerebral vasculature in humans at rest and during exercise

We tested the hypothesis that pharmacological blockade of α(1)-adrenoreceptors (by prazosin), at rest and during steady-state dynamic exercise, would impair cerebral autoregulation and result in cerebral vasodilatation in healthy humans. In 10 subjects, beat-to-beat mean arterial pressure and mean middle cerebral artery blood velocity were determined at rest and during low (Ex90) and moderate workload (Ex130) on an upright bicycle ergometer without and with prazosin. Plasma noradrenaline concentrations increased significantly from rest to Ex130 during control conditions (from 1.8 ± 0.2 to 3.2 ± 0.3 pmol (ml plasma)(-1)). In the control conditions, the transfer function gain between mean arterial pressure and mean middle cerebral artery blood velocity in the low-frequency range was decreased at Ex90 (P = 0.035) and Ex130 (P = 0.027) from rest. A significant increase in critical closing pressure (CCP) was also observed in the control conditions from rest to Ex90 to Ex130 (from 18 ± 3 to 24 ± 4 to 31 ± 4 mmHg). An average of 74 ± 2% blockade of blood pressure response was achieved with oral prazosin. Following blockade, plasma noradrenaline concentrations further increased at rest and during Ex130 from the control value (from 2.6 ± 0.3 to 4.4 ± 0.5 pmol (ml plasma)(-1)). Prazosin also resulted in an increase in low-frequency gain (P < 0.003) compared with the control conditions. Prazosin blockade abolished the increases in CCP during Ex130 and increased the cerebrovascular conductance index (P = 0.018). These data indicate that in the control conditions a strengthening of cerebral autoregulation occurred with moderate dynamic exercise that is associated with an increase in CCP as a result of the exercise-mediated augmentation of sympathetic activity. Given that α(1)-adrenergic receptor blockade attenuated the increase in dynamic cerebral autoregulation and CCP, we conclude that increases in sympathetic activity have a role in establishing cerebral vascular tone in humans.

Impaired hypoxic cerebral vasodilation in younger adults with metabolic syndrome

Metabolic syndrome (MetSyn) increases the risk of cerebrovascular disease and stroke; however, its impact on human cerebral circulation remains unclear. Reduced cerebral dilation is also associated with an increased risk of stroke and may occur in MetSyn adults. We hypothesised that MetSyn adults would exhibit reduced cerebral vasodilation to hypoxia and hypercapnia. Middle cerebral artery velocity (MCAv) was insonated with Doppler ultrasound in younger (approximately 35 years) MetSyn and healthy adults. We measured mean arterial blood pressure (MABP), arterial oxygen saturation (S(p)O(2)) and end tidal carbon dioxide (Pet (CO2)). Cerebrovascular conductance index (CVCi) was calculated as MCAv*100/MABP. Cerebral vasodilation (ΔCVCi) to hypoxia (S(p)O(2) = 90% and 80%) and hypercapnia (+10 mm Hg Pet (CO2)) was assessed. Baseline MCAv was similar, while adults with MetSyn had lower baseline CVCi. MetSyn adults demonstrated markedly reduced ΔCVCi compared to healthy adults in response to hypoxia (90% S(p)O(2): 1±2 vs 6±2; 80% S(p)O(2): 5±2 vs 15±3 cm/s/mmHg, p<0.05). Both groups demonstrated similar ΔCVCi to hypercapnia (18±2 vs 20±2 cm/s/mmHg). These data are the first to demonstrate that younger MetSyn adults have impaired hypoxia-mediated cerebral vasodilation prior to clinically overt cerebrovascular disease. These findings provide novel insight into cerebrovascular disease onset in MetSyn adults.

Age‐related differences in cerebrovascular reactivity in response to COX inhibition

Reduced cerebral blood flow and reactivity may explain age‐related changes in cognitive function. We examined cerebrovascular reactivity, and the potential role of prostaglandins, in young and old healthy humans. Middle cerebral artery velocity (MCAv) responses to stepped hypercapnia were measured in young (26±2y; 6M/5F) and old (66±2y, 3M/4F) adults before (PRE) and 90 min after (POST) oral indomethacin (1.2mg/kg). To account for any changes in blood pressure, cerebrovascular conductance index (CVCi) was calculated as the MCAv divided by mean arterial pressure. Cerebrovascular reactivity slopes were calculated using linear regression between either MCA velocity or CVCi and end‐tidal CO2. There were no differences between young and old adults in height, weight, BMI, or brachial blood pressures. Young adults demonstrated greater MCAv (53.7±6.7 vs. 32.0±3.3), MCAv reactivity (1.62±0.21 vs. 0.94±0.10), and CVCi (0.66±0.08 vs. 0.39±0.04) compared with old adults at PRE (P&lt;0.05 for all). In both young and old adults, MCAv, MCAv reactivity, CVCi, and CVCi reactivity decreased between PRE and POST measurements. Furthermore, any age‐related differences in these cerebrovascular variables were abolished by indomethacin. These results suggest that cerebral blood flow and cerebrovascular reactivity is attenuated in aging adults and that this reduction may be mediated by prostaglandins.NIH: AG16574‐11PP2

Cerebral autoregulation dynamics in endurance-trained individuals

Aerobic fitness may be associated with reduced orthostatic tolerance. To investigate whether trained individuals have less effective regulation of cerebral vascular resistance, we studied the middle cerebral artery (MCA) mean blood velocity (V(mean)) response to a sudden drop in mean arterial pressure (MAP) after 2.5 min of leg ischemia in endurance athletes and untrained subjects (maximal O(2) uptake: 69 ± 7 vs. 42 ± 5 ml O(2)·min(-1)·kg(-1); n = 9 for both, means ± SE). After cuff release when seated, endurance athletes had larger drops in MAP (94 ± 6 to 62 ± 5 mmHg, -39%, vs. 99 ± 5 to 73 ± 4 mmHg, -26%) and MCA V(mean) (53 ± 3 to 37 ± 2 cm/s, -30%, vs. 58 ± 3 to 43 ± 2 cm/s, -25%). The athletes also had a slower recovery to baseline of both MAP (25 ± 2 vs. 16 ± 1 s, P < 0.01) and MCA V(mean) (15 ± 1 vs. 11 ± 1 s, P < 0.05). The onset of autoregulation, determined by the time point of increase in the cerebrovascular conductance index (CVCi = MCA V(mean)/MAP) appeared later in the athletes (3.9 ± 0.4 vs. 2.7 ± 0.4s, P = 0.01). Spectral analysis revealed a normal MAP-to-MCA V(mean) phase in both groups but ~40% higher normalized MAP to MCA V(mean) low-frequency transfer function gain in the trained subjects. No significant differences were detected in the rates of recovery of MAP and MCA V(mean) and the rate of CVCi regulation (18 ± 4 vs. 24 ± 7%/s, P = 0.2). In highly trained endurance athletes, a drop in blood pressure after the release of resting leg ischemia was more pronounced than in untrained subjects and was associated with parallel changes in indexes of cerebral blood flow. Once initiated, the autoregulatory response was similar between the groups. A delayed onset of autoregulation with a larger normalized transfer gain conforms with a less effective dampening of MAP oscillations, indicating that athletes may be more prone to instances of symptomatic cerebral hypoperfusion when MAP declines.

Transcranial Doppler estimation of cerebral blood flow and cerebrovascular conductance during modified rebreathing

Clinical transcranial Doppler assessment of cerebral vasomotor reactivity (CVMR) uses linear regression of cerebral blood flow velocity (CBFV) vs. end-tidal CO(2) (Pet(CO(2))) under steady-state conditions. However, the cerebral blood flow (CBF)-Pet(CO(2)) relationship is nonlinear, even for moderate changes in CO(2). Moreover, CBF is increased by increases in arterial blood pressure (ABP) during hypercapnia. We used a modified rebreathing protocol to estimate CVMR during transient breath-by-breath changes in CBFV and Pet(CO(2)). Ten healthy subjects (6 men) performed 15 s of hyperventilation followed by 5 min of rebreathing, with supplemental O(2) to maintain arterial oxygen saturation constant. To minimize effects of changes in ABP on CVMR estimation, cerebrovascular conductance index (CVCi) was calculated. CBFV-Pet(CO(2)) and CVCi-Pet(CO(2)) relationships were quantified by both linear and nonlinear logistic regression. In three subjects, muscle sympathetic nerve activity was recorded. From hyperventilation to rebreathing, robust changes occurred in Pet(CO(2)) (20-61 Torr), CBFV (-44 to +104% of baseline), CVCi (-39 to +64%), and ABP (-19 to +23%) (all P < 0.01). Muscle sympathetic nerve activity increased by 446% during hypercapnia. The linear regression slope of CVCi vs. Pet(CO(2)) was less steep than that of CBFV (3 vs. 5%/Torr; P = 0.01). Logistic regression of CBF-Pet(CO(2)) (r(2) = 0.97) and CVCi-Pet(CO(2)) (r(2) = 0.93) was superior to linear regression (r(2) = 0.91, r(2) = 0.85; P = 0.01). CVMR was maximal (6-8%/Torr) for Pet(CO(2)) of 40-50 Torr. In conclusion, CBFV and CVCi responses to transient changes in Pet(CO(2)) can be described by a nonlinear logistic function, indicating that CVMR estimation varies within the range from hypocapnia to hypercapnia. Furthermore, quantification of the CVCi-Pet(CO(2)) relationship may minimize the effects of changes in ABP on the estimation of CVMR. The method developed provides insight into CVMR under transient breath-by-breath changes in CO(2).