Acute isometric and dynamic exercise do not alter cerebral sympathetic nerve activity in healthy humans.

The impact of physiological stressors on cerebral sympathetic nervous activity (SNA) remains controversial. We hypothesized that cerebral noradrenaline (NA) spillover, an index of cerebral SNA, would not change during both submaximal isometric handgrip (HG) exercise followed by a post-exercise circulatory occlusion (PECO), and supine dynamic cycling exercise. Twelve healthy participants (5 females) underwent simultaneous blood sampling from the right radial artery and right internal jugular vein. Right internal jugular vein blood flow was measured using Duplex ultrasound, and tritiated NA was infused through the participants' right superficial forearm vein. Heart rate was recorded via electrocardiogram and blood pressure was monitored using the right radial artery. Total NA spillover increased during HG (P = 0.049), PECO (P = 0.006), and moderate cycling exercise (P = 0.03) compared to rest. Cerebral NA spillover remained unchanged during isometric HG exercise (P = 0.36), PECO after the isometric HG exercise (P = 0.45), and during moderate cycling exercise (P = 0.94) compared to rest. These results indicate that transient increases in blood pressure during acute exercise involving both small and large muscle mass do not engage cerebral SNA in healthy humans. Our findings suggest that cerebral SNA may be non-obligatory for exercise-related cerebrovascular adjustments.

Directional sensitivity of the cerebral pressure-flow relationship during forced oscillations induced by oscillatory lower body negative pressure.

A directional sensitivity of the cerebral pressure-flow relationship has been described using repeated squat-stands. Oscillatory lower body negative pressure (OLBNP) is a reproducible method to characterize dynamic cerebral autoregulation (dCA). It could represent a safer method to examine the directional sensitivity of the cerebral pressure-flow relationship within clinical populations and/or during pharmaceutical administration. Therefore, examining the cerebral pressure-flow directional sensitivity during an OLBNP-induced cyclic physiological stress is crucial. We calculated changes in middle cerebral artery mean blood velocity (MCAv) per alterations to mean arterial pressure (MAP) to compute ratios adjusted for time intervals (ΔMCAvT/ΔMAPT) with respect to the minimum-to-maximum MCAv and MAP, for each OLBNP transition (0 to -90 Torr), during 0.05 Hz and 0.10 Hz OLBNP. We then compared averaged ΔMCAvT/ΔMAPT during OLBNP-induced MAP increases (INC) (ΔMCAvT/ΔMAPTINC) and decreases (DEC) (ΔMCAvT/ΔMAPTDEC). Nineteen healthy participants [9 females; 30 ± 6 years] were included. There were no differences in ΔMCAvT/ΔMAPT between INC and DEC at 0.05 Hz. ΔMCAvT/ΔMAPTINC (1.06 ± 0.35 vs. 1.33 ± 0.60 cm⋅s-1/mmHg; p = 0.0076) was lower than ΔMCAvT/ΔMAPTDEC at 0.10 Hz. These results support OLBNP as a model to evaluate the directional sensitivity of the cerebral pressure-flow relationship.

Time-domain methods for quantifying dynamic cerebral blood flow autoregulation: Review and recommendations. A white paper from the Cerebrovascular Research Network (CARNet).

Cerebral Autoregulation (CA) is an important physiological mechanism stabilizing cerebral blood flow (CBF) in response to changes in cerebral perfusion pressure (CPP). By maintaining an adequate, relatively constant supply of blood flow, CA plays a critical role in brain function. Quantifying CA under different physiological and pathological states is crucial for understanding its implications. This knowledge may serve as a foundation for informed clinical decision-making, particularly in cases where CA may become impaired. The quantification of CA functionality typically involves constructing models that capture the relationship between CPP (or arterial blood pressure) and experimental measures of CBF. Besides describing normal CA function, these models provide a means to detect possible deviations from the latter. In this context, a recent white paper from the Cerebrovascular Research Network focused on Transfer Function Analysis (TFA), which obtains frequency domain estimates of dynamic CA. In the present paper, we consider the use of time-domain techniques as an alternative approach. Due to their increased flexibility, time-domain methods enable the mitigation of measurement/physiological noise and the incorporation of nonlinearities and time variations in CA dynamics. Here, we provide practical recommendations and guidelines to support researchers and clinicians in effectively utilizing these techniques to study CA.

A systematic review, meta-analysis, and meta-regression amalgamating the driven approaches used to quantify dynamic cerebral autoregulation.

Numerous driven techniques have been utilized to assess dynamic cerebral autoregulation (dCA) in healthy and clinical populations. The current review aimed to amalgamate this literature and provide recommendations to create greater standardization for future research. The PubMed database was searched with inclusion criteria consisting of original research articles using driven dCA assessments in humans. Risk of bias were completed using Scottish Intercollegiate Guidelines Network and Methodological Index for Non-Randomized Studies. Meta-analyses were conducted for coherence, phase, and gain metrics at 0.05 and 0.10 Hz using deep-breathing, oscillatory lower body negative pressure (OLBNP), sit-to-stand maneuvers, and squat-stand maneuvers. A total of 113 studies were included, with 40 of these incorporating clinical populations. A total of 4126 participants were identified, with younger adults (18-40 years) being the most studied population. The most common techniques were squat-stands (n = 43), deep-breathing (n = 25), OLBNP (n = 20), and sit-to-stands (n = 16). Pooled coherence point estimates were: OLBNP 0.70 (95%CI:0.59-0.82), sit-to-stands 0.87 (95%CI:0.79-0.95), and squat-stands 0.98 (95%CI:0.98-0.99) at 0.05 Hz; and deep-breathing 0.90 (95%CI:0.81-0.99); OLBNP 0.67 (95%CI:0.44-0.90); and squat-stands 0.99 (95%CI:0.99-0.99) at 0.10 Hz. This review summarizes clinical findings, discusses the pros/cons of the 11 unique driven techniques included, and provides recommendations for future investigations into the unique physiological intricacies of dCA.

Quantification of dynamic cerebral autoregulation: welcome to the jungle!

PURPOSE: Patients with dysautonomia often experience symptoms such as dizziness, syncope, blurred vision and brain fog. Dynamic cerebral autoregulation, or the ability of the cerebrovasculature to react to transient changes in arterial blood pressure, could be associated with these symptoms. METHODS: In this narrative review, we go beyond the classical view of cerebral autoregulation to discuss dynamic cerebral autoregulation, focusing on recent advances pitfalls and future directions. RESULTS: Following some historical background, this narrative review provides a brief overview of the concept of cerebral autoregulation, with a focus on the quantification of dynamic cerebral autoregulation. We then discuss the main protocols and analytical approaches to assess dynamic cerebral autoregulation, including recent advances and important issues which need to be tackled. CONCLUSION: The researcher or clinician new to this field needs an adequate comprehension of the toolbox they have to adequately assess, and interpret, the complex relationship between arterial blood pressure and cerebral blood flow in healthy individuals and clinical populations, including patients with autonomic disorders.

Maternal and Fetal Cardiovascular Responses to Acute High-Intensity Interval and Moderate-Intensity Continuous Training Exercise During Pregnancy: A Randomized Crossover Trial.

OBJECTIVE: We aimed to compare maternal and fetal cardiovascular responses to an acute bout of high-intensity interval training (HIIT) versus moderate-intensity continuous training (MICT) during pregnancy. METHODS: Fifteen women with a singleton pregnancy (27.3 ± 3.5 weeks of gestation, 33 ± 4 years of age) were recruited. Following a peak fitness test, participants engaged in a session of HIIT (10 × 1-min intervals ≥ 90% maximum heart rate [HRmax]) interspersed with 1 min of active recovery) and MICT (30 min at 64-76% HRmax) 48 h apart in random order. Maternal HR, blood pressure, middle (MCAv), and posterior cerebral artery blood velocity (PCAv), as well as respiratory measures were monitored continuously throughout HIIT/MICT. Fetal heart rate, as well as umbilical systolic/diastolic (S/D) ratio, resistive index (RI), and pulsatility index (PI) were assessed immediately before and after exercise. RESULTS: Average maternal heart rate was higher for HIIT (82 ± 5% HRmax) compared with MICT (74 ± 4% HRmax; p < 0.001). During the HIIT session, participants achieved a peak heart rate of 96 ± 5% HRmax (range of 87-105% HRmax). Maternal cerebral blood velocities increased with exercise but was not different between HIIT and MICT for MCAv (p = 0.340) and PCAv (p = 0.142). Fetal heart rate increased during exercise (p = 0.244) but was not different between sessions (HIIT: Δ + 14 ± 7 bpm; MICT: Δ + 10 ± 10 bpm). Metrics of umbilical blood flow decreased with exercise and were not different between exercise sessions (PI: p = 0.707; S/D ratio: p = 0.671; RI: p = 0.792). Fetal bradycardia was not observed, and S/D ratio, RI, and PI remained within normal ranges both before and immediately after all exercise sessions. CONCLUSIONS: An acute bout of HIIT exercise consisting of repeated 1-min near-maximal to maximal exertions, as well as MICT exercise is well tolerated by both mother and fetus. CLINICAL TRIAL REGISTRATION: NCT05369247.

Impact of sex on the cerebrovascular response to incremental aerobic exercise in moderately trained endurance athletes.

The cerebrovascular response to incremental aerobic exercise is comparable between males and females. Whether this response can be found in moderately trained athletes remains unknown. We aimed to examine the effect of sex on the cerebrovascular response to incremental aerobic exercise until volitional exhaustion in this population. Twenty-two moderately trained athletes (11 M/11 F; age: 25 ± 5 vs. 26 ± 6 yr, P = 0.6478; peak oxygen consumption: 55.8 ± 5.2 vs. 48.3 ± 4 mL/kg/min; P = 0.0011; training volume: 532 ± 173 vs. 466 ± 151 min/wk, P = 0.3554) performed a maximal ergocycle exercise test. Systemic and cerebrovascular hemodynamics were measured. At rest, middle cerebral artery mean blood velocity (MCAvmean; 64.1 ± 12.7 vs. 72.2 ± 15.3 cm·s-1; P = 0.2713) was not different between groups, whereas partial pressure of end-tidal carbon dioxide ([Formula: see text], 42 ± 3 vs. 37 ± 2 mmHg, P = 0.0002) was higher in males. During the MCAvmean ascending phase, changes in MCAvmean (intensity: P < 0.0001, sex: P = 0.3184, interaction: P = 0.9567) were not different between groups. Changes in cardiac output ([Formula: see text]) (intensity: P < 0.0001, sex: P < 0.0001, interaction: P < 0.0001) and [Formula: see text] (intensity: P < 0.0001, sex: P < 0.0001, interaction: P < 0.0001) were higher in males. During the MCAvmean descending phase, changes in MCAvmean (intensity: P < 0.0001, sex: P = 0.5522, interaction: P = 0.4828) and [Formula: see text] (intensity: P = 0.0550, sex: P = 0.0003, interaction: P = 0.2715) were not different between groups. Changes in [Formula: see text] (intensity P < 0.0001, sex: P < 0.0001, interaction: P = 0.0280) were higher in males. These results suggest the MCAvmean response during exercise is comparable between moderately trained males and females notwithstanding differences in the response of key cerebral blood flow determinants.NEW & NOTEWORTHY The results of this study suggest the cerebrovascular response between moderately endurance-trained males and females is comparable in spite of a higher arterial carbon dioxide and cardiac output in males compared with females during incremental aerobic exercise until volitional exhaustion. This could help in providing a better understanding of the key differences in cerebral blood flow regulation between males and females during aerobic exercise.

Cerebral blood flow pulsatility and cerebral artery stiffness acutely decrease during hemodialysis.

End-stage kidney disease (ESKD) is associated with increased arterial stiffness and cognitive impairment. Cognitive decline is accelerated in ESKD patients on hemodialysis and may result from repeatedly inappropriate cerebral blood flow (CBF). The aim of this study was to examine the acute effect of hemodialysis on pulsatile components of CBF and their relation to acute changes in arterial stiffness. In eight participants (age: 63 ± 18 years, men: 5), CBF was estimated using middle cerebral artery blood velocity (MCAv) assessed with transcranial Doppler ultrasound before, during, and after a single hemodialysis session. Brachial and central blood pressure, along with estimated aortic stiffness (eAoPWV) were measured using an oscillometric device. Arterial stiffness from heart to MCA was measured as the pulse arrival time (PAT) between electrocardiogram (ECG) and transcranial Doppler ultrasound waveforms (cerebral PAT). During hemodialysis, there was a significant reduction in mean MCAv (-3.2 cm/s, p < 0.001), and systolic MCAv (-13.0 cm/s, p < 0.001). While baseline eAoPWV (9.25 ± 0.80 m/s) did not significantly change during hemodialysis, cerebral PAT increased significantly (+0.027 , p < 0.001) and was associated with reduced pulsatile components of MCAv. This study shows that hemodialysis acutely reduces stiffness of arteries perfusing the brain along with pulsatile components of blood velocity.

Influence of high-intensity interval training to exhaustion on the directional sensitivity of the cerebral pressure-flow relationship in young endurance-trained men.

We previously reported subtle dynamic cerebral autoregulation (dCA) alterations following 6 weeks of high-intensity interval training (HIIT) to exhaustion using transfer function analysis (TFA) on forced mean arterial pressure (MAP) oscillations in young endurance-trained men. However, accumulating evidence suggests the cerebrovasculature better buffers cerebral blood flow changes when MAP acutely increases compared to when MAP acutely decreases. Whether HIIT affects the directional sensitivity of the cerebral pressure-flow relationship in these athletes is unknown. In 18 endurance-trained men (age: 27 ± 6 years, VO2 max: 55.5 ± 4.7 ml·kg-1 ·min-1 ), we evaluated the impact of 6 weeks of HIIT to exhaustion on dCA directionality using induced MAP oscillations during 5-min 0.05 and 0.10 Hz repeated squat-stands. We calculated time-adjusted changes in middle cerebral artery mean blood velocity (MCAv) per change in MAP (ΔMCAvT /ΔMAPT ) for each squat transition. Then, we compared averaged ΔMCAvT /ΔMAPT during MAP increases and decreases. Before HIIT, ΔMCAvT /ΔMAPT was comparable between MAP increases and decreases during 0.05 Hz repeated squat-stands (p = 0.518). During 0.10 Hz repeated squat-stands, ΔMCAvT /ΔMAPT was lower during MAP increases versus decreases (0.87 ± 0.17 vs. 0.99 ± 0.23 cm·s-1 ·mmHg-1 , p = 0.030). Following HIIT, ΔMCAvT /ΔMAPT was superior during MAP increases over decreases during 0.05 Hz repeated squat-stands (0.97 ± 0.38 vs. 0.77 ± 0.35 cm·s-1 ·mmHg-1 , p = 0.002). During 0.10 Hz repeated squat-stands, dCA directional sensitivity disappeared (p = 0.359). These results suggest the potential for HIIT to influence the directional sensitivity of the cerebral pressure-flow relationship in young endurance-trained men.

Point/counterpoint: We should take the direction of blood pressure change into consideration for dynamic cerebral autoregulation quantification.

Accumulating evidence suggests asymmetrical responses of cerebral blood flow during large transient changes in mean arterial pressure. Specifically, the augmentation in cerebral blood flow is attenuated when mean arterial pressure acutely increases, compared with declines in cerebral blood flow when mean arterial pressure acutely decreases. However, common analytical tools to quantify dynamic cerebral autoregulation assume autoregulatory responses to be symmetric, which does not seem to be the case. Herein, we provide the rationale supporting the notion we need to consider the directional sensitivity of large and transient mean arterial pressure changes when characterizing dynamic cerebral autoregulation.

Sex-specific effects of cardiorespiratory fitness on age-related differences in cerebral hemodynamics.

There is a positive association between cardiorespiratory fitness and cognitive health, but the interaction between cardiorespiratory fitness and aging on cerebral hemodynamics is unclear. These potential interactions are further influenced by sex differences. The purpose of this study was to determine the sex-specific relationships between cardiorespiratory fitness, age, and cerebral hemodynamics in humans. Measurements of unilateral middle cerebral artery blood velocity (MCAv) and cerebral pulsatility index obtained using transcranial Doppler ultrasound and cardiorespiratory fitness [maximal oxygen consumption (V̇o2max)] obtained from maximal incremental exercise tests were retrieved from study records at three institutions. A total of 153 healthy participants were included in the analysis (age = 42 ± 20 yr, range = 18-83 yr). There was no association between V̇o2max and MCAv in all participants (P = 0.20). The association between V̇o2max and MCAv was positive in women, but no longer significant after age adjustment (univariate: P = 0.01; age-adjusted: P = 0.45). In addition, there was no association between V̇o2max and MCAv in men (univariate: P = 0.25, age-adjusted: P = 0.57). For V̇o2max and cerebral pulsatility index, there were significant negative associations in all participants (P < 0.001), in men (P < 0.001) and women (P < 0.001). This association remained significant when adjusting for age in women only (P = 0.03). In summary, higher cardiorespiratory fitness was associated with a lower cerebral pulsatility index in all participants, and the significance remained only in women when adjusting for age. Future studies are needed to determine the sex-specific impact of cardiorespiratory fitness improvements on cerebrovascular health.NEW & NOTEWORTHY We present data pooled from three institutions to study the impact of age, sex, and cardiorespiratory fitness on cerebral hemodynamics. Cardiorespiratory fitness was positively associated with middle cerebral artery blood velocity in women, but not in men. Furthermore, cardiorespiratory fitness was inversely associated with cerebral pulsatility index in both men and women, which remained significant in women when adjusting for age. These data suggest a sex-specific impact of cardiorespiratory fitness on resting cerebral hemodynamics.

Directional sensitivity of the cerebral pressure-flow relationship in young healthy individuals trained in endurance and resistance exercise.

NEW FINDINGS: What is the central question of this study? Does habitual exercise modality affect the directionality of the cerebral pressure-flow relationship? What is the main finding and its importance? These data suggest the hysteresis-like pattern of dynamic cerebral autoregulation appears present in long-term sedentary and endurance-trained individuals, but absent in resistance-trained individuals. This is the first study to expand knowledge on the directional sensitivity of the cerebral pressure-flow relationship to trained populations. ABSTRACT: Evidence suggests the cerebrovasculature may be more efficient at dampening cerebral blood flow (CBF) variations when mean arterial pressure (MAP) transiently increases, compared to when it decreases. Despite divergent MAP and CBF responses to acute endurance and resistance training, the long-term impact of habitual exercise modality on the directionality of dynamic cerebral autoregulation (dCA) is currently unknown. Thirty-six young healthy participants (sedentary (n = 12), endurance-trained (n = 12), and resistance-trained (n = 12)) undertook a 5-min repeated squat-stand protocol at two forced MAP oscillation frequencies (0.05 and 0.10 Hz). Middle cerebral artery mean blood velocity (MCAv) and MAP were continuously monitored. We calculated absolute (ΔMCAvT /ΔMAPT ) and relative (%MCAvT /%MAPT ) changes in MCAv and MAP with respect to the transition time intervals of both variables to compute a time-adjusted ratio in each MAP direction, averaged over the 5-min repeated squat-stand protocols. At 0.10 Hz repeated squat-stands, ΔMCAvT /ΔMAPT and %MCAvT /%MAPT were lower when MAP increased compared with when MAP decreased for sedentary (ΔMCAvT /ΔMAPT : P = 0.032; %MCAvT /%MAPT : P = 0.040) and endurance-trained individuals (ΔMCAvT /ΔMAPT : P = 0.012; %MCAvT /%MAPT P = 0.007), but not in the resistance-trained individuals (ΔMCAvT /ΔMAPT : P = 0.512; %MCAvT /%MAPT P = 0.666). At 0.05 Hz repeated squat-stands, time-adjusted ratios were similar for all groups (all P > 0.605). These findings suggest exercise training modality does influence the directionality of the cerebral pressure-flow relationship and support the presence of a hysteresis-like pattern during 0.10 Hz repeated squat-stands in sedentary and endurance-trained participants, but not in resistance-trained individuals. In future studies, assessment of elite endurance and resistance training habits may further elucidate modality-dependent discrepancies on directional dCA measurements.

Prenatal exercise and cardiovascular health (PEACH) study: impact of acute and chronic exercise on cerebrovascular hemodynamics and dynamic cerebral autoregulation.

We performed a randomized controlled trial measuring dynamic cerebral autoregulation (dCA) using a sit-to-stand maneuver before (SS1) and following (SS2) an acute exercise test at 16-20 wk gestation (trimester 2, TM2) and then again at 34-37 wk gestation (third trimester, TM3). Following the first assessment, women were randomized into exercise training or control (standard care) groups; women in the exercise training group were prescribed moderate intensity aerobic exercise for 25-40 min on 3-4 days per week for 14 ± 1 wk. Resting seated mean blood velocity in the middle cerebral artery (MCAvmean) was lower in TM3 than in TM2 but not impacted by exercise training intervention. No metric of dCA was impacted by gestational age or exercise training during SS1. During SS2, there were greater absolute and relative decreases in mean arterial blood pressure (MAP) and MCAvmean, but this was not impacted by the intervention. There was also no difference in the relationship between the decrease in MCAvmean compared with the decrease in MAP (%/%) or the onset of the regulatory response with respect to acute exercise, gestational age, or intervention; however, rate of regulation was faster in women in the exercise group following acute exercise (interaction effect, P = 0.048). These data highlight the resilience of the cerebral circulation in that dCA was well maintained or improved in healthy pregnant women between TM2 and TM3. However, future work addressing the impact of acute and chronic exercise on dCA in women who are at risk for cardiovascular complications during pregnancy is needed.NEW & NOTEWORTHY These data represent the first assessments of dynamic cerebral autoregulation in pregnancy using a sit-to-stand. We used a randomized controlled trial to show dynamic cerebral autoregulation is not impacted by gestational age or by chronic exercise. However, there are larger decreases in blood pressure and cerebral blood velocity following sit-to-stand after acute exercise without adverse events. These data highlight the adaptability of the cerebral circulation during pregnancy to accommodate large changes in the cardiovascular system.

Reproducibility and diurnal variation of the directional sensitivity of the cerebral pressure-flow relationship in men and women.

The cerebral pressure-flow relationship has directional sensitivity, meaning the augmentation in cerebral blood flow is attenuated when mean arterial pressure (MAP) increases versus MAP decreases. We used repeated squat-stands (RSS) to quantify it using a novel metric. However, its within-day reproducibility and the impacts of diurnal variation and biological sex are unknown. Study aims were to evaluate this metric for: 1) within-day reproducibility and diurnal variation in middle cerebral artery (MCA; ΔMCAvT/ΔMAPT) and posterior cerebral artery (PCA; ΔPCAvT/ΔMAPT) and 2) sex differences. ΔMCAvT/ΔMAPT and ΔPCAvT/ΔMAPT were calculated at 7 timepoints (08:00-17:00) in 18 participants (8 women; 24 ± 3 yr) using the minimum-to-maximum MCAv or PCAv and MAP for each RSS at 0.05 Hz and 0.10 Hz. Relative metric values were also calculated (%MCAvT/%MAPT, %PCAvT/%MAPT). Intraclass correlation coefficient (ICC) evaluated reproducibility, which was good (0.75-0.90) to excellent (>0.90). Time-of-day impacted ΔMCAvT/ΔMAPT (0.05 Hz: P = 0.002; 0.10 Hz: P = 0.001), %MCAvT/%MAPT (0.05 Hz: P = 0.035; 0.10 Hz: P = 0.009), and ΔPCAvT/ΔMAPT (0.05 Hz: P = 0.024), albeit with small/negligible effect sizes. MAP direction impacted both arteries' metric at 0.10 Hz (all P < 0.024). Sex differences in the MCA only (P = 0.003) vanished when reported in relative terms. These findings demonstrate that this metric is reproducible throughout the day in the MCA and PCA and is not impacted by biological sex.NEW & NOTEWORTHY The findings of the current study indicate that our time-adjusted metric to evaluate the directional sensitivity of the cerebral pressure-flow relationship is reproducible throughout the day in both the anterior and posterior cerebral circulations. Although a diurnal variation was noted across the day within this metric, this appeared to be of minimal physiological relevance. Finally, the metric is not impacted by biological sex.

Utilization of the repeated squat-stand model for studying the directional sensitivity of the cerebral pressure-flow relationship.

Hysteresis in the cerebral pressure-flow relationship describes the superior ability of the cerebrovasculature to buffer cerebral blood flow changes when mean arterial pressure (MAP) increases compared with when MAP decreases. This phenomenon can be evaluated by comparing the change in middle cerebral artery mean blood velocity (MCAv) per change in MAP during either acute increases or decreases in MAP induced by repeated squat-stands (RSS). However, no real baseline can be used for this particular protocol as there is no true stable reference point. Herein, we characterized a novel metric using the greatest MAP oscillations induced by RSS without using an independent baseline value and adjusted for time intervals (ΔMCAvT/ΔMAPT). We also examined whether this metric during each RSS transition was comparable between each other over a 5-min period. ΔMCAvT/ΔMAPT was calculated using the minimum to maximum MCAv and MAP for each RSS performed at 0.05 Hz and 0.10 Hz. We compared averaged ΔMCAvT/ΔMAPT during MAP increases and decreases in 74 healthy participants [9 women; 26 (20-74) yr]. ΔMCAvT/ΔMAPT was lower for MAP increases than MAP decreases at 0.10 Hz RSS only (0.91 ± 0.34 vs. 1.01 ± 0.44 cm·s-1/mmHg; P = 0.0013). For both frequency and MAP direction, time during RSS had no effect on ΔMCAvT/ΔMAPT. This novel analytical method supports the use of the RSS model to evaluate the directional sensitivity of the pressure-flow relationship. These results contribute to the importance of considering the direction of MAP changes, depending on the oscillations frequency when evaluating dynamic cerebral autoregulation.NEW & NOTEWORTHY Repeated squat-stand maneuvers are able to examine the directional sensitivity of the cerebral pressure-flow relationship. These maneuvers induce stable physiological cyclic changes where brain blood flow changes with blood pressure increases are buffered more than blood pressure decreases. These results highlight the importance of considering directional blood pressure changes within cerebral autoregulation.

Losing the dogmatic view of cerebral autoregulation.

In 1959, Niels Lassen illustrated the cerebral autoregulation curve in the classic review article entitled Cerebral Blood Flow and Oxygen Consumption in Man. This concept suggested a relatively broad mean arterial pressure range (~60-150 mmHg) wherein cerebral blood flow remains constant. However, the assumption that this wide cerebral autoregulation plateau could be applied on a within-individual basis is incorrect and greatly variable between individuals. Indeed, each data point on the autoregulatory curve originated from independent samples of participants and patients and represented interindividual relationships between cerebral blood flow and mean arterial pressure. Nonetheless, this influential concept remains commonly cited and illustrated in various high-impact publications and medical textbooks, and is frequently taught in medical and science education without appropriate nuances and caveats. Herein, we provide the rationale and additional experimental data supporting the notion we need to lose this dogmatic view of cerebral autoregulation.

Dynamic cerebral autoregulation and cerebrovascular carbon dioxide reactivity in middle and posterior cerebral arteries in young endurance-trained women.

The integrated responses regulating cerebral blood flow are understudied in women, particularly in relation to potential regional differences. In this study, we compared dynamic cerebral autoregulation (dCA) and cerebrovascular reactivity to carbon dioxide (CVRco2) in the middle (MCA) and posterior cerebral arteries (PCA) in 11 young endurance-trained women (age, 25 ± 4 yr; maximal oxygen uptake, 48.1 ± 4.1 mL·kg-1·min-1). dCA was characterized using a multimodal approach including a sit-to-stand and a transfer function analysis (TFA) of forced blood pressure oscillations (repeated squat-stands executed at 0.05 Hz and 0.10 Hz). The hyperoxic rebreathing test was utilized to characterize CVRco2. Upon standing, the percent reduction in blood velocity per percent reduction in mean arterial pressure during initial orthostatic stress (0-15 s after sit-to-stand), the onset of the regulatory response, and the rate of regulation did not differ between MCA and PCA (all P > 0.05). There was an ANOVA effect of anatomical location for TFA gain (P < 0.001) and a frequency effect for TFA phase (P < 0.001). However, normalized gain was not different between arteries (P = 0.18). Absolute CVRco2 was not different between MCA and PCA (1.55 ± 0.81 vs. 1.30 ± 0.49 cm·s-1/Torr, P = 0.26). Relative CVRco2 was 39% lower in the MCA (2.16 ± 1.02 vs. 3.00 ± 1.09%/Torr, P < 0.01). These findings indicate that the cerebral pressure-flow relationship appears to be similar between the MCA and the PCA in young endurance-trained women. The absence of regional differences in absolute CVRco2 could be women specific, although a direct comparison with a group of men will be necessary to address that issue.NEW & NOTEWORTHY Herein, we describe responses from two major mechanisms regulating cerebral blood flow with a special attention on regional differences in young endurance-trained women. The novel findings are that dynamic cerebral autoregulation and absolute cerebrovascular reactivity to carbon dioxide appear similar between the middle and posterior cerebral arteries of these young women.

What recording duration is required to provide physiologically valid and reliable dynamic cerebral autoregulation transfer functional analysis estimates?

Objective. Currently, a recording of 300 s is recommended to obtain accurate dynamic cerebral autoregulation estimates using transfer function analysis (TFA). Therefore, this investigation sought to explore the concurrent validity and the within- and between-day reliability of TFA estimates derived from shorter recording durations from squat-stand maneuvers.Approach. Retrospective analyses were performed on 70 young, recreationally active or endurance-trained participants (17 females; age: 26 ± 5 years, [range: 20-39 years]; body mass index: 24 ± 3 kg m-2). Participants performed 300 s of squat-stands at frequencies of 0.05 and 0.10 Hz, where shorter recordings of 60, 120, 180, and 240 s were extracted. Continuous transcranial Doppler ultrasound recordings were taken within the middle and posterior cerebral arteries. Coherence, phase, gain, and normalized gain metrics were derived. Bland-Altman plots with 95% limits of agreement (LOA), repeated measures ANOVA's, two-tailed paired t-tests, coefficient of variation, Cronbach's alpha, intraclass correlation coefficients, and linear regressions were conducted.Main results. When examining the concurrent validity across different recording durations, group differences were noted within coherence (F(4155) > 11.6,p < 0.001) but not phase (F(4155) < 0.27,p > 0.611), gain (F(4155) < 0.61,p > 0.440), or normalized gain (F(4155) < 0.85,p > 0.359) parameters. The Bland-Altman 95% LOA measuring the concurrent validity, trended to narrow as recording duration increased (60 s: < ±0.4, 120 s: < ±0.3, 180 s  < ±0.3, 240 s: < ±0.1). The validity of the 180 and 240 s recordings further increased when physiological covariates were included within regression models.Significance. Future studies examining autoregulation should seek to have participants perform 300 s of squat-stand maneuvers. However, valid and reliable TFA estimates can be drawn from 240 s or 180 s recordings if physiological covariates are controlled.

Effects of age and sex on middle cerebral artery blood velocity and flow pulsatility index across the adult lifespan.

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.