Cerebral Autoregulation In Humans Research Articles

Test-retest reliability of transfer function analysis metrics for assessing dynamic cerebral autoregulation to spontaneous blood pressure oscillations.

Transfer function analysis (TFA) is a widely used method for assessing dynamic cerebral autoregulation in humans. In the present study, we assessed the test-retest reliability of established TFA metrics derived from spontaneous blood pressure oscillations and based on 5min recordings. The TFA-based gain, phase and coherence in the low-frequency range (0.07-0.20Hz) from 19 healthy volunteers, 37 patients with subarachnoid haemorrhage and 19 patients with sepsis were included. Reliability assessments included the smallest real difference (SRD) and the coefficient of variance for comparing consecutive 5min recordings, temporally separated 5min recordings and consecutive recordings with a minimal length of 10 min. In healthy volunteers, temporally separating the 5min recordings led to a 0.38 (0.01-0.79) cms-1mmHg-1 higher SRD for gain (P=0.032), and extending the duration of recordings did not affect the reliability. In subarachnoid haemorrhage, temporal separation led to a 0.85 (-0.13 to 1.93) cms-1mmHg-1 higher SRD (P=0.047) and a 20 (-2 to 41)% higher coefficient of variance (P=0.038) for gain, but neither metric was affected by extending the recording duration. In sepsis, temporal separation increased the SRD for phase by 94 (23-160)° (P=0.006) but was unaffected by extending the recording. A recording duration of 8 min was required to achieve stable gain and normalized gain measures in healthy individuals, and even longer recordings were required in patients. In conclusion, a recording duration of 5 min appears insufficient for obtaining stable and reliable TFA metrics when based on spontaneous blood pressure oscillations, particularly in critically ill patients with subarachnoid haemorrhage and sepsis.

Non-Invasive Mapping of Cerebral Autoregulation Using Near-Infrared Spectroscopy: A Study Protocol.

The ability of cerebral vessels to maintain a fairly constant cerebral blood flow is referred to as cerebral autoregulation (CA). Using near-infrared spectroscopy (NIRS) paired with arterial blood pressure (ABP) monitoring, continuous CA can be assessed non-invasively. Recent advances in NIRS technology can help improve the understanding of continuously assessed CA in humans with high spatial and temporal resolutions. We describe a study protocol for creating a new wearable and portable imaging system that derives CA maps of the entire brain with high sampling rates at each point. The first objective is to evaluate the CA mapping system's performance during various perturbations using a block-trial design in 50 healthy volunteers. The second objective is to explore the impact of age and sex on regional disparities in CA using static recording and perturbation testing in 200 healthy volunteers. Using entirely non-invasive NIRS and ABP systems, we hope to prove the feasibility of deriving CA maps of the entire brain with high spatial and temporal resolutions. The development of this imaging system could potentially revolutionize the way we monitor brain physiology in humans since it would allow for an entirely non-invasive continuous assessment of regional differences in CA and improve our understanding of the impact of the aging process on cerebral vessel function.

P.031 The effect of burst suppression on cerebral blood flow and autoregulation in animals and humans - a systematic review

Background: Burst suppression (BS) is an EEG pattern in which there are isoelectric periods interspersed with bursts of cortical activity. Targeting BS through anesthetic administration is used as a tool in the neuro-ICU but its relationship with cerebral blood flow (CBF) and cerebral autoregulation (CA) is unclear. We performed a systematic review investigating the effect of BS on CBF and CA in animals and humans. Methods: We searched MEDLINE, BIOSIS, EMBASE, SCOPUS, and Cochrane library from inception to July 2022. The data that were collected included study population, methods to induce and measure BS, and the effect on CBF and CA. Results: In total 45 animal and 26 human studies were included in the final review. In almost all the studies, BS was induced using an anaesthetic. In most of the animal and human studies, BS was associated with a decrease in CBF and cerebral metabolism, even if the mean arterial pressure remained constant. The effect on CA during periods of stress (hypercapnia, hypothermia, etc.) was variable. Conclusions: BS is associated with a reduction in cerebral metabolic demand and CBF, which may explain its usefulness in patients with brain injury. More evidence is needed to elucidate the connection between BS and CA.

Point-Counterpoint: Transfer function analysis of dynamic cerebral autoregulation: To band or not to band?

Transfer function analysis (TFA) is the most frequently adopted method for assessing dynamic cerebral autoregulation (CA) with continuously recorded arterial blood pressure (ABP) and cerebral blood flow velocity (CBFV). Conventionally, values of autoregulatory metrics (e.g., gain and phase) derived from TFA are averaged within three frequency bands separated by cut-off frequencies at 0.07 Hz and 0.20 Hz, respectively, to represent the efficiency of dynamic CA. However, this is of increasing concerns, as there remains no solid evidence for choosing these specific cut-off frequencies, and the rigid adoption of these bands can stifle further developments in TFA of dynamic CA. In this 'Point-Counterpoint' mini-review, we provide evidence against the fixed banding, indicate possible alternatives, and call for awareness of the risk of the 'one-size-fits-all' banding becoming dogmatic. We conclude that we need to remain open to the multiple possibilities offered by TFA to realize its full potential in studies of human dynamic CA.

The critical closing pressure contribution to dynamic cerebral autoregulation in humans: influence of arterial partial pressure of CO2.

Dynamic cerebral autoregulation (CA) is often expressed by the mean arterial blood pressure (MAP)-cerebral blood flow (CBF) relationship, with little attention given to the dynamic relationship between MAP and cerebrovascular resistance (CVR). In CBF velocity (CBFV) recordings with transcranial Doppler, evidence demonstrates that CVR should be replaced by a combination of a resistance-area product (RAP) with a critical closing pressure (CrCP) parameter, the blood pressure value where CBFV reaches zero due to vessels collapsing. Transfer function analysis of the MAP-CBFV relationship can be extended to the MAP-RAP and MAP-CrCP relationships, to assess their contribution to the dynamic CA response. During normocapnia, both RAP and CrCP make a significant contribution to explaining the MAP-CBFV relationship. Hypercapnia, a surrogate state of depressed CA, leads to marked changes in dynamic CA, that are entirely explained by the CrCP response, without further contribution from RAP in comparison with normocapnia. Dynamic cerebral autoregulation (CA) is manifested by changes in the diameter of intra-cerebral vessels, which control cerebrovascular resistance (CVR). We investigated the contribution of critical closing pressure (CrCP), an important determinant of CVR, to explain the cerebral blood flow (CBF) response to a sudden change in mean arterial blood pressure (MAP). In 76 healthy subjects (age range 21-70years, 36 women), recordings of MAP (Finometer), CBF velocity (CBFV; transcranial Doppler ultrasound), end-tidal CO2 (capnography) and heart rate (ECG) were performed for 5min at rest (normocapnia) and during hypercapnia induced by breathing 5% CO2 in air. CrCP and the resistance-area product (RAP) were obtained for each cardiac cycle and their dynamic response to a step change in MAP was calculated by means of transfer function analysis. The recovery of the CBFV response, following a step change in MAP, was mainly due to the contribution of RAP during both breathing conditions. However, CrCP made a highly significant contribution during normocapnia (P<0.0001) and was the sole determinant of changes in the CBFV response, resulting from hypercapnia, which led to a reduction in the autoregulation index from 5.70±1.58 (normocapnia) to 4.14±2.05 (hypercapnia; P<0.0001). In conclusion, CrCP makes a very significant contribution to the dynamic CBFV response to changes in MAP and plays a major role in explaining the deterioration of dynamic CA induced by hypercapnia. Further studies are needed to assess the relevance of CrCP contribution in physiological and clinical studies.

Assessment of dynamic cerebral autoregulation in humans: Is reproducibility dependent on blood pressure variability?

We tested the influence of blood pressure variability on the reproducibility of dynamic cerebral autoregulation (DCA) estimates. Data were analyzed from the 2nd CARNet bootstrap initiative, where mean arterial blood pressure (MABP), cerebral blood flow velocity (CBFV) and end tidal CO2 were measured twice in 75 healthy subjects. DCA was analyzed by 14 different centers with a variety of different analysis methods. Intraclass Correlation (ICC) values increased significantly when subjects with low power spectral density MABP (PSD-MABP) values were removed from the analysis for all gain, phase and autoregulation index (ARI) parameters. Gain in the low frequency band (LF) had the highest ICC, followed by phase LF and gain in the very low frequency band. No significant differences were found between analysis methods for gain parameters, but for phase and ARI parameters, significant differences between the analysis methods were found. Alternatively, the Spearman-Brown prediction formula indicated that prolongation of the measurement duration up to 35 minutes may be needed to achieve good reproducibility for some DCA parameters. We conclude that poor DCA reproducibility (ICC<0.4) can improve to good (ICC > 0.6) values when cases with low PSD-MABP are removed, and probably also when measurement duration is increased.

A Novel Nonlinear System Identification for Cerebral Autoregulation in Human: Computer Simulation and Validation.

Cerebral autoregulation in healthy humans was studied using a novel methodology adapted from Bendat nonlinear analysis technique. A computer simulation of a high-pass filter in parallel with a cubic nonlinearity followed by a low-pass filter was analyzed. A linear system transfer function analysis showed an incorrect estimate of the gain, cut-off frequency, and phase of the high-pass filter. By contrast, using our nonlinear systems identification, yielded the correct gain, cut-off frequency, and phase of the linear system, and accurately quantified the nonlinear system and following low-pass filter. Adding the nonlinear and linear coherence function indicated a complete description of the system. Cerebral blood flow velocity and arterial pressure were measured in six data sets. Application of the linear and nonlinear systems identification techniques to the data showed a high-pass filter, like the linear transfer function, but the gain was smaller. The phase was similar between the two techniques. The linear coherence was low for frequencies below 0.1Hz but improved by including a nonlinear term. The linear + nonlinear coherence was approximately 0.9 across the frequency bandwidth, indicating an improved description over the linear system analysis of the cerebral autoregulation system.

Measuring stream processing systems adaptability under dynamic workloads

Data streaming belongs to the Big Data ecosystem, which generates high-frequency data streams featuring time-varying characteristics that challenge the traditional stream processing systems capacities. To deal with this problem, many self-adaptive stream processing systems have been proposed. Despite the evolution of self-adaptive systems, there is still a lack of standardized benchmarking systems to enable scientists to evaluate the autonomic capacities of their solutions. In this work, we propose an index called AI-SPS inspired by the human cerebral auto-regulation process. The index quantifies the capacity of an adaptive stream processing systems to self-adapt in the presence of highly dynamic workloads. An index of this nature will help the scientific community generate fair comparisons among literature with the aim of creating better solutions. We validate our proposal by evaluating the adaptive behavior of two state of the art self-adaptive stream processing systems. Tests were performed using real traffic datasets adapted specifically to stress the processing system. Results show that the proposed index quantifies the adaptation capacity of self-adaptive stream processing systems effectively.

Relative contributions of sympathetic, cholinergic, and myogenic mechanisms to cerebral autoregulation.

Prior work aimed at improving our understanding of human cerebral autoregulation has explored individual physiological mechanisms of autoregulation in isolation, but none has attempted to consolidate the individual roles of these mechanisms into a comprehensive model of the overall cerebral pressure-flow relationship. We retrospectively analyzed this relationship before and after pharmacological blockade of α-adrenergic-, muscarinic-, and calcium channel-mediated mechanisms in 43 healthy volunteers to determine the relative contributions of the sympathetic, cholinergic, and myogenic controllers to cerebral autoregulation. Projection pursuit regression was used to assess the effect of pharmacological blockade on the cerebral pressure-flow relationship. Subsequently, ANCOVA decomposition was used to determine the cumulative effect of these 3 mechanisms on cerebral autoregulation and whether they can fully explain it. Sympathetic, cholinergic, and myogenic mechanisms together accounted for 62% of the cerebral pressure-flow relationship (P<0.05), with significant and distinct contributions from each of the 3 effectors. ANCOVA decomposition demonstrated that myogenic effectors were the largest determinant of the cerebral pressure-flow relationship, but their effect was outside of the autoregulatory region where neurogenic control appeared prepotent. Our results suggest that myogenic effects occur outside the active region of autoregulation, whereas neurogenic influences are largely responsible for cerebral blood flow control within it. However, our model of cerebral autoregulation left 38% of the cerebral pressure-flow relationship unexplained, suggesting that there are other physiological mechanisms that contribute to cerebral autoregulation.

Why is the neural control of cerebral autoregulation so controversial?

Cerebral autoregulation refers to the mechanisms that act to keep cerebral blood flow (CBF) constant during changes in blood pressure. The mechanisms of cerebral autoregulation, especially in humans, are poorly understood but are undoubtedly multifactorial and likely reflect many redundant pathways that potentially differ between species. Whether sympathetic nervous activity influences CBF and/or cerebral autoregulation in humans remains controversial. Following a brief introduction to cerebral autoregulation, this review highlights the likely reasons behind the controversy of the neural control of cerebral autoregulation. Finally, suggestions are provided for further studies to improve the understanding of the neural control of CBF regulation.

The cerebovasculature: a smooth (muscle) operator?

The cerebovasculature: a smooth (muscle) operator?

Acute Hypovolemia Does Not Affect Dynamic Cerebral Autoregulation in Humans

While it is well known that cerebral perfusion pressure is the primary determinant of cerebral blood flow, it has been suggested that cardiac output and stroke volume may also play an important role. To test the role of stroke volume and cardiac output on dynamic cerebral autoregulation we performed sit to stand tests on a group of volunteers prior to and following administration of furosemide to reduce blood volume. These subjects were participating in a larger artificial gravity study. As expected furosemide resulted in a significant reduction in stroke volume while seated (63±5 vs. 51±4 mL, P=0.000). In contrast cardiac output was unchanged due to increases in heart rate (72±3 vs 94±3 bpm, P=0.000). Upon standing subjects demonstrated similar drops in SV, cardiac output and increases in HR from pre to post infusion. Blood pressure was unchanged by infusion while sitting and had similar drops upon standing (−20±4 vs −21±12 mmHg). Similarly cerebral flow velocity decreases were unchanged (−15±7 vs −17±8 mmHg). Examination of the Autoregulatory Index found no change from pre to post infusion (4.7±0.6 vs 4.8±0). These data demonstrate that hypovolemia and reduced stroke volume do not affect dynamic cerebral autoregulation or the cerebrovascular response to standing. Further work is needed to determine the role of cardiac output. Supported by NASA and VA.

Cerebral autoregulation in humans: role of the myogenic mechanism

Myogenic mechanisms have been hypothesized to account in part for cerebral autoregulation. Previous work in rats and more recent work in humans provide equivocal results. The animal data suggests that myogenic mechanisms are active at frequencies below 0.1 Hz. In contrast, the human data suggests that myogenic mechanisms are less important at these frequencies, but this was assessed using lower body negative pressure at levels beyond the threshold for syncope. Therefore, we examined cerebral blood flow responses to augmented arterial pressure oscillations with and without Ca2+ channel blockade (nicardipine) across a range of frequencies (0.03, 0.04, 0.05, 0.06, 0.07, and 0.08 Hz) and with levels of oscillatory lower body negative pressure (OLBNP) well below the threshold for syncope in humans (30 mmHg) in 16 healthy subjects. Ca2+ channel blockade resulted in an increase in mean pressure and heart rate, but decreased cerebral flow. Despite these hemodynamic changes, the transfer function relationship between flow and pressure was not significantly altered (Coherence: 0.514±0.077 vs. 0.512±0.077, Gain: 0.1740±0.0756 versus 0.2341±0.0287 at 0.03 Hz). Our data demonstrate that although myogenic mechanisms may have some role in determining tonic cerebral flow, they have no clear involvement in cerebral autoregulatory blood flow control in humans.

Cerebral autoregulation in humans: role of the cholinergic mechanisms

Cholinergic mechanisms in cerebral autoregulation remain poorly characterized. However, there is some evidence for a cholinergic role. For example, cholinesterase inhibitors improve cerebral blood flow and cerebrovascular reactivity in Alzheimer patients who respond to treatment. Therefore we examined cerebral blood flow responses to augmented arterial pressure oscillations with and without cholinergic blockade. Oscillatory lower body negative pressure (OLBNP) was used at six frequencies from 0.03 to 0.08 Hz in 9 healthy subjects with and without cholinergic blockade via glycopyrrolate. Cholinergic blockade resulted in an increase in mean blood pressure and heart rate, but had no effect on cerebral flow. The transfer function relationship to arterial pressure at frequencies greater than 0.05 Hz were significantly increased (Coherence: 0.740±0.061 vs. 0.908±0.052, Gain: 0.668±0.070 vs. 0.962±0.027 at 0.08 Hz), but both the coherence and gain of the relation remained weak at the lowest frequencies in the cerebral circulation. Our data demonstrate a strong, frequency dependent role for cholinergic regulation of blood flow in the cerebrovasculature. However, the frequency dependence is similar to the sympathetic system, and thus the two mechanisms may have complimentary or redundant roles in autoregulation.

You say resistance, I say compliance; let's call the whole thing cerebral Windkessel control

You say resistance, I say compliance; let's call the whole thing cerebral Windkessel control

Effect of Cycling Exercise on Dynamic Cerebral Autoregulation in Humans

We sought to explore the effect of cycling exercise of gradually increasing intensity on dynamic cerebral autoregulation (dCA) in humans. Ten healthy human subjects (seven men and three women; age, 27 ± 1 years, height, 176 ± 4 cm, weight, 76± 4 kg; mean ± SE) volunteered to participate in the present investigation. Their baseline data was collecting during 15 min of rest in a seated position on the cycle ergometer. Following rest, subjects pedaled at the rate of 60 rpm at mild workload (10W) for 10 min [Ex80, heart rate (HR) 88±4 bpm]. After 10 min of mild intensity exercise, the workload was increased to raise and mainatain steady-state HR at 130 bpm (Ex130). Subjects exercised at this moderate intensity for 10 min. A significant increase was found in plasma norepinephrine (NE) from rest to Ex130 (mean ± SEM, 1.8 ± 0.2 pml/ml to 3.2 ± 0.3 pml/ml, P<0.05). In addition, a significant decrease in low frequency (LF) (0.07–0.2 Hz) transfer function gain was observed at Ex130 in comparison to rest (0.88 ± 0.08 to 0.72 ± 0.05, P < 0.05) indicating an increase in dCA. The coherence between mean arterial pressure and middle cerebral artery velocity for all the exercise conditions remained greater than 0.5. These findings indicate that increased sympathetic nerve activity during cycling exercise is associated with increased dynamic cerebral autoregulation. The study was partially funded by Cardiovascular Research Institute and Tx-ACSM

Approach to Elucidating the Influences and Factors Affecting Circulation System in Humans in Space Environment

Many physiological changes associated with spaceflight, including decreases in orthostatic tolerance, exercise capacity, and blood volume have been reported. Orthostatic intolerance is a problem affecting many astronauts immediately postspaceflight. In particular, the relationship between orthostatic intolerance and cerebral autoregulation has been the focus of study in our research group. Although impairment of cerebral autoregulation was speculated to be one of the factors resulting in reduced post flight orthostatic tolerance, a 2-wk spaceflight study revealed that human cerebral autoregulation is preserved or even improved during and immediately after spaceflight in nonsymptomatic astronauts. To investigate the influences of the different kinds of reduction in central blood volume, we performed two ground-based studies. It is suggested that the mild intravascular dehydration partly explains the improved dynamic cerebral autoregulation observed during and immediately after a short-term spaceflight. Moreover, we also studied the relationship between orthostatic intolerance and cerebral autoregulation under hyperthermic conditions, because hyperthermia leads to orthostatic intolerance. Furthermore, we planned to conduct a study at the International Space Station (ISS) and ground-based studies to elucidate the influences and factors affecting the circulation system in humans in a space environment.

The relationship between cardiac output and dynamic cerebral autoregulation in humans

Cerebral autoregulation adjusts cerebrovascular resistance in the face of changing perfusion pressures to maintain relatively constant flow. Results from several studies suggest that cardiac output may also play a role. We tested the hypothesis that cerebral blood flow would autoregulate independent of changes in cardiac output. Transient systemic hypotension was induced by thigh-cuff deflation in 19 healthy volunteers (7 women) in both supine and seated positions. Mean arterial pressure (Finapres), cerebral blood flow (transcranial Doppler) in the anterior (ACA) and middle cerebral artery (MCA), beat-by-beat cardiac output (echocardiography), and end-tidal Pco(2) were measured. Autoregulation was assessed using the autoregulatory index (ARI) defined by Tiecks et al. (Tiecks FP, Lam AM, Aaslid R, Newell DW. Stroke 26: 1014-1019, 1995). Cerebral autoregulation was better in the supine position in both the ACA [supine ARI: 5.0 ± 0.21 (mean ± SE), seated ARI: 3.9 ± 0.4, P = 0.01] and MCA (supine ARI: 5.0 ± 0.2, seated ARI: 3.8 ± 0.3, P = 0.004). In contrast, cardiac output responses were not different between positions and did not correlate with cerebral blood flow ARIs. In addition, women had better autoregulation in the ACA (P = 0.046), but not the MCA, despite having the same cardiac output response. These data demonstrate cardiac output does not appear to affect the dynamic cerebral autoregulatory response to sudden hypotension in healthy controls, regardless of posture. These results also highlight the importance of considering sex when studying cerebral autoregulation.

Reply to Willie and Tzeng

### Interindividual Heterogeneity in Integrative Physiology to the editor: We were very pleased to read the letter from Willie and Tzeng ([12][1]) regarding our recent publication in this Journal and our focus on the importance of interindividual variability in hemodynamic variables in the control

Baroreflex, Cerebral Perfusion, and Stroke: Integrative Physiology at Its Best

To the Editor: We wish to congratulate Sykora et al for their timely review on the potential role the arterial baroreflex plays in cerebrovascular disease outcomes.1 Although it may seem intuitive that both arterial baroreflex function and cerebral blood flow (CBF) regulation are important modulators of stroke outcome, clear and consistent evidence implicating the arterial baroreflex as an independent clinical predictor of stroke-related mortality is only emerging. The authors proffer several plausible hypotheses linking baroreflex dysfunction to the etiology of acute stroke and related clinical outcomes. Among them, the proposed “cross-linked” impairment of cerebrovascular autoregulation (CA) and altered autonomic drive as part of an underlying regulatory continuum in the context of stroke require further discussion. …