Assessment of cerebral autoregulation using time-domain cross-correlation analysis

Time domain cross-correlation analysis of pre-filtered mean arterial blood pressure (MABP) and mean cerebral blood flow velocity (MCBFV) was applied to assess the cerebral autoregulation (CA). Beat-to-beat time series of spontaneous arterial blood pressure and cerebral blood flow velocity were obtained from 13 young normal volunteers with the Finapres device and the transcranial Doppler for periods of approximately 5 min in the supine position. Cross-correlation functions (CCFs) were estimated using a 64 beat wide moving window. Mean CCF patterns were obtained for each subject and for the entire population. The MABP and MCBFV signals were bandpass filtered in the very low-frequency range (VLF, 0.015–0.07 Hz), low-frequency range (LF, 0.07–0.15 Hz) and high-frequency range (HF, 0.15–0.40 Hz) before applying CCF for the purpose of studying the effect of different bandwidths on the resulting mean CCFs. Results revealed that the corresponding time lags of the peak values of the MABP–MCBFV CCFs increased significantly between the LF and HF frequency ranges (LF: −1.20±0.91 s, HF: −0.07±0.42 s, p<0.001; paired sign test). The left-shift (negative lag) of the CCF peak between MABP and MCBFV is a result of the phase-lead property. The increasing time lag of the CCF peak indicated evidence of the autoregulatory disturbance. The CCF of pre-filtered spontaneous MABP and MCBFV could be a useful tool to estimate the CA dynamic response.     

Preserved dynamic cerebral autoregulation in the middle cerebral artery among persons with migraine

Migraine affects the autonomous nervous system and a recent investigation has also proposed a severe disturbance of dynamic cerebral blood flow regulation in the middle cerebral artery during spontaneous blood pressure oscillations. This study investigates whether dynamic cerebral autoregulation is impaired in persons with migraine among a normal cohort. Out of 94 adults studied to establish normal values for dynamic autoregulation, 19 suffered from migraine according to IHS criteria (10 of them with aura). Transcranial Doppler sonography and fingerplethysmography were used to determine dynamic autoregulation of both middle cerebral arteries following spontaneous low frequency (0.06–0.12 Hz) blood pressure fluctuations (phase and gain of transfer function, correlation coefficient indices Dx and Mx). No significant differences were found for the low frequency variability of blood pressure (power spectral density) and various indices of dynamic cerebral autoregulation between persons with and without migraine. Moreover, no differences were observed between persons with migraine, with and without aura. This study based on a normal cohort does not support the presence of generally impaired cerebral autoregulation dynamics in persons with migraine. Future studies should focus on posterior circulation and particular cerebellar autoregulation.     

Static autoregulation in humans: a review and reanalysis

IntroductionCerebral autoregulation (CA) is a theoretical construct characterized by the relationship between mean arterial pressure (MAP) and cerebral blood flow (CBF). We performed a comprehensive literature search to provide an up-to-date review on the static relationship between MAP and CBF.MethodsThe results are based on 40 studies (49 individual experimental protocols) in healthy subjects between 18 and 65 years. Exclusion criteria were: a ΔMAP <5%, hypoxia/hyperoxia or hypo/hypercapnia, and unstable levels (<2 min stages). The partial pressure of arterial CO₂ (PaCO₂) was measured in a subset of the included studies (n = 28); therefore, CBF was also adjusted to account for small changes in PaCO₂.ResultsThe linear regression coefficient between MAP and CBF (or velocity) of 0.82 ± 0.77%ΔCBF/%ΔMAP during decreases in MAP (n = 23 experiments) was significantly different than the relationship of 0.21 ± 0.47%ΔCBF/%ΔMAP during increases (n = 26 experiments; p < 0.001). After correction for increases/decreases in PaCO₂, the slopes were not significantly different: 0.64 ± 1.16%ΔCBF/%ΔMAP (n = 16) and 0.39 ± 0.30%ΔCBF/%ΔMAP (n = 12) for increased vs. decreased MAP changes, respectively (p = 0.60).ConclusionThe autoregulatory ability of the cerebral circulation appears to be more active in buffering increases in MAP as compared to reductions in MAP. However, the statistical finding of hysteresis is lost following an attempt to correct for PaCO₂.     

Risk factors for disordered cerebral autoregulation during hypothermic cardiopulmonary bypass

Disordered cerebral autoregulation during cardiopulmonary bypass (CPB) is regarded as one of the causes of neurological dysfunction after cardiac surgery. However, little documentation of risk factors associated with cerebral autoregulation during CPB has been reported. Sixty consecutive patients undergoing coronary artery bypass were classified into subgroups according to whether they had preoperative cerebrovascular disease (CVD), hypertension (HT), or diabetes (DM). Cerebral oxygenation was monitored by jugular venous bulb oxygen saturation (SjvO₂) and near-infrared spectroscopy parameter (%Oxy-Hb) during the operation, and the relationships between these values and intraoperative parameters were evaluated. The results showed that SjvO₂ and %Oxy-Hb in the CVD+group were lower than in the CVD-group. Multiple stepwise regression analysis on SjvO₂ and %Oxy-Hb in the CVD+ group revealed that only MAP was a predictive factor and that there was a positive correlation between MAP and both SjvO₂ and %Oxy-Hb (r=.651,r=.693, respectively,P<0.0001). The coexistence of HT and DM increased the strength of the correlation between MAP and SjvO₂ (r=.863,p<0.0001) PaCO₂ was the predictive factor in the CVD- group. A positive correlation was found with SjvO₂ (r=.458,P>0.0001), and the correlation was stronger in patients without any risk factors (r=.671,P=0.0001). The results suggested that patients with CVD, HT, and DM may experience failure of cerebral pressureflow autoregulation and cerebrovascular reactivity during CPB.This paper was presented at the 52th Annual Meeting of the Japanese Association for Thoracic Surgery on October 7, 1999     

Myogenic and metabolic feedback in cerebral autoregulation: Putative involvement of arachidonic acid-dependent pathways

The present paper presents a mechanistic model of cerebral autoregulation, in which the dual effects of the arachidonic acid metabolites 20-hydroxyeicosatetraenoic acid (20-HETE) and epoxyeicosatrienoic acids (EETs) on vascular smooth muscle mediate the cerebrovascular adjustments to a change in cerebral perfusion pressure (CPP). 20-HETE signalling in vascular smooth muscle mediates myogenic feedback to changes in vessel wall stretch, which may be modulated by metabolic feedback through EETs released from astrocytes and endothelial cells in response to changes in brain tissue oxygen tension. The metabolic feedback pathway is much faster than 20-HETE-dependent myogenic feedback, and the former thus initiates the cerebral autoregulatory response, while myogenic feedback comprises a relatively slower mechanism that functions to set the basal cerebrovascular tone. Therefore, assessments of dynamic cerebral autoregulation, which may provide information on the response time of the cerebrovasculature, may specifically be used to yield information on metabolic feedback mechanisms, while data based on assessments of static cerebral autoregulation represent the integrated functionality of myogenic and metabolic feedback.     

Dynamic cerebral autoregulation assessment using chaotic analysis in diabetic autonomic neuropathy

Cerebral autoregulation (CA) was assessed by chaotic analysis based on mean arterial blood pressure (MABP) and mean cerebral blood flow velocity (MCBFV) in 19 diabetics with autonomic neuropathy (AN) and 11 age-matched normal subjects. MABP in diabetics dropped significantly in response to tilting (91.6 ± 14.9 vs. 74.1 ± 13.4 mmHg, P < 0.05). Valsalva ratio of heart rate was reduced in diabetics compared to normal (1.1 ± 0.1 vs. 1.5 ± 0.2, P < 0.05). It indicated AN affects the vasomotor tone of peripheral vessels and baroreflex. Nonlinear results showed higher correlation dimension values of MABP and MCBFV in diabetics compared to normal, especially MABP (3.7 ± 2.3 vs. 2.0 ± 0.8, P < 0.05). It indicated CA is more complicated in diabetics. The lower Lyapunov exponent and the higher Kolmogorov entropy values in diabetics indicated less predictable behavior and higher chaotic degree. This study suggests impaired autoregulation would be more chaotic and less predictable.     

Maintenance of cerebral blood flow and metabolism during pharmacological hypotension in aged hypertensive rats

Cerebral blood flow (CBF) and cerebral oxygen metabolism (CMRO2) were measured in aged (24 month) spontaneously hypertensive rats (SHR) during sodium nitroprusside (SNP) and nitroglycerin induced hypotension. Both CBF and CMRO2 were decreased in SHR during hypotension induced with SNP. Significant decrements in CMRO2 were observed in aged SHR during even moderate hypotension (80-90 torr). Cerebral autoregulatory responses during nitroglycerin infusion in aged SHR were similar to SNP treated WKY and CMRO2 was maintained at control levels under all hypotensive test conditions. These results indicate that aged SHR are susceptible to cerebral ischemia during SNP induced hypotension, probably due to the combined effects of aging and hypertension on the cerebral vasculature. NTG moderated the decreases in CBF and CMRO2 seen during hypotensive challenges and may decrease the risk of stroke during hypotensive anesthesia.     

Differential cerebrovascular CO2 reactivity in anterior and posterior cerebral circulations

The potential differences in cerebrovascular responses between the anterior and posterior circulations to changes in CO₂ are unclear in humans. Using transcranial Doppler ultrasound, we compared the CO₂ reactivity of the (1) BA and PCA and (2) MCA and PCA during hyperoxic rebreathing in supine position. The reactivity in the BA and PCA was similar in both absolute (1.27 ± 0.5 and 1.27 ± 0.6 cm/s/Torr; P = 0.992) and relative (3.98 ± 1.3 and 3.66 ± 1.5%/Torr CO₂; P = 0.581) measures, suggesting that the PCA is an adequate surrogate measure of reactivity for the BA. The MCA reactivity was greater than the PCA in absolute (2.09 ± 0.7 and 1.22 ± 0.5 cm/s/Torr CO₂; P < 0.001), but not relative measures (3.25 ± 1.0 and 3.56 ± 1.6%/Torr CO₂; P = 0.629). Our findings (a) confirm regional differences in the absolute reactivity in the human brain and (b) suggest that in cerebrovascular studies investigating functions mediated by posterior brain structures (e.g., control of breathing), the posterior vasculature should also be insonated.     

Analysis of dynamic cerebral autoregulation using an ARX model based on arterial blood pressure and middle cerebral artery velocity simulation

The study aimed to model the cerebrovascular system, using a linear ARX model based on data simulated by a comprehensive physiological model, and to assess the range of applicability of linear parametric models. Arterial blood pressure (ABP) and middle cerebral arterial blood flow velocity (MCAV) were measured from 11 subjects non-invasively, following step changes in ABP, using the thigh cuff technique. By optimising parameters associated with autoregulation, using a non-linear optimisation technique, the physiological model showed a good performance (r=0.83±0.14) in fitting MCAV. An additional five sets of measured ABP of length 236±154 s were acquired from a subject at rest. These were normalised and rescaled to coefficients of variation (CV=SD/mean) of 2% and 10% for model comparisons. Randomly generated Gaussian noise with standard deviation (SD) from 1% to 5% was added to both ABP and physiologically simulated MCAV (SMCAV), with ‘normal’ and ‘impaired’ cerebral autoregulation, to simulate the real measurement conditions. ABP and SMCAV were fitted by ARX modelling, and cerebral autoregulation was quantified by a 5 s recovery percentage R5% of the step responses of the ARX models. The study suggests that cerebral autoregulation can be assessed by computing the R5% of the step response of an ARX model of appropriate order, even when measurement noise is considerable.     

Nonstationarity of dynamic cerebral autoregulation

Dynamic cerebral autoregulation (dCA), the transient response of cerebral blood flow (CBF) to rapid changes in arterial blood pressure (BP), is usually quantified by parameters extracted from time- or frequency-domain analysis. Reproducibility studies of dCA parameters and consideration of the physiological determinants of the dynamic BP-CBF relationship provide strong indications that dCA is a nonstationary process. As a consequence, new analytical approaches are needed to estimate dCA parameters with greater temporal resolution thus allowing its longitudinal patterns of variability to be assessed in health and disease states. Techniques proposed for this task include ARMA models with moving windows, recursive least-squares, Laguerre–Volterra networks, wavelet phase synchronisation, and multimodal pressure-flow analysis. Initial results with these techniques have revealed the influence of some key determinants of dCA nonstationarity, such as PaCO₂, as well as their ability to reflect dCA impairment in different clinical conditions. One key priority for future work is the development and validation of multivariate time-varying techniques to minimise the influence to the many co-variates which contribute to dCA nonstationarity.     

Modeling of nonlinear physiological systems with fast and slow dynamics. II. Application to cerebral autoregulation

Dynamic autoregulation of cerebral hemodynamics in healthy humans is studied using the novel methodology of the Laguerre–Volterra network for systems with fast and slow dynamics (Mitsis, G. D., and V. Z. Marmarelis, Ann. Biomed. Eng. 30:272–281, 2002). Since cerebral autoregulation is mediated by various physiological mechanisms with significantly different time constants, it is used to demonstrate the efficacy of the new method. Results are presented in the time and frequency domains and reveal that cerebral autoregulation is a nonlinear and dynamic (frequency-dependent) system with considerable nonstationarities. Quantification of the latter reveals greater variability in specific frequency bands for each subject in the low and middle frequency range (below 0.1 Hz). The nonlinear dynamics are prominent also in the low and middle frequency ranges, where the frequency response of the system exhibits reduced gain. © 2002 Biomedical Engineering Society. PAC2002: 8719Uv, 8719La, 8710+e     

Cerebral autoregulation is compromised during simulated fluctuations in gravitational stress

Gravity places considerable stress on the cardiovascular system but cerebral autoregulation usually protects the cerebral blood vessels from fluctuations in blood pressure. However, in conditions such as those encountered on board a high-performance aircraft, the gravitational stress is constantly changing and might compromise cerebral autoregulation. In this study we assessed the effect of oscillating orthostatic stress on cerebral autoregulation. Sixteen (eight male) healthy subjects [aged 27 (1) years] were exposed to steady-state lower body negative pressure (LBNP) at –15 and –40 mmHg and then to oscillating LBNP at the same pressures. The oscillatory LBNP was applied at 0.1 and 0.2 Hz. We made continuous recordings of RR-interval, blood pressure, cerebral blood flow velocity (CBFV), respiratory frequency and end-tidal CO₂. Oscillations in mean arterial pressure (MAP) and CBFV were assessed by autoregressive spectral analysis. Respiration was paced at 0.25 Hz to avoid interference from breathing. Steady-state LBNP at –40 mmHg significantly increased low-frequency (LF, 0.03–0.14 Hz) powers of MAP (P<0.01) but not of CBFV. Oscillatory 0.1 Hz LBNP (0 to –40 mmHg) significantly increased the LF power of MAP to a similar level as steady-state LBNP but also resulted in a significant increase in the LF power of CBFV (P<0.01). Oscillatory LBNP at 0.2 Hz induced oscillations in MAP and CBFV at 0.2 Hz. Cross-spectral analysis showed that the transfer of LBNP-induced oscillations in MAP onto the CBFV was significantly greater at 0.2 Hz than at 0.1 Hz (P<0.01). These results show that the ability of the cerebral vessels to modulate fluctuations in blood pressure is compromised during oscillatory compared with constant gravitational stress. Furthermore, this effect seems to be more pronounced at higher frequencies of oscillatory stress.     

Effect of adrenergic blockade on autoregulation of the cerebral blood flow during orthostatic tests

In experiments on rats under local anesthesia the action of phentolamine and propranolol on autoregulation of the cerebral blood flow (ACB) was studied during orthostatic tests (OT). The cerebral blood flow was measured in the carotid system, the venous pressure in the cerebral vessels, and the perfusion pressure in the carotid arteries; the resistance of the cerebral vessels was calculated. OT were simulated by tilting a special table with the animal (head upward or downward) through 40–80° from the horizontal plane. The results showed that adrenergic blockade in most cases of OT disturbed ACB: phentolamine led to a passive increase in the cerebral blood flow in response to an increase in perfusion pressure, whereas propranolol, on the other hand, caused a passive decrease in the cerebral blood flow in response to a fall of perfusion pressure.Department of Pharmacology, Pyatigorsk Pharmaceutical Institute. (Presented by Academicaian of the Academy of Medical Sciences of the USSR V. V. Zakusov.) Translated from Byulleten' Éksperimental'noi Biologii i Meditsiny, Vol. 86, No. 9, pp. 309–311, September, 1978.     

Oscillations in cerebral blood flow and cortical oxygenation in Alzheimer's disease

In Alzheimer's disease (AD) cerebrovascular function is at risk. Transcranial Doppler, near-infrared spectroscopy, and photoplethysmography are noninvasive methods to continuously measure changes in cerebral blood flow velocity (CBFV), cerebral cortical oxygenated hemoglobin (O₂Hb), and blood pressure (BP). In 21 patients with mild to moderate AD and 20 age-matched controls, we investigated how oscillations in cerebral blood flow velocity (CBFV) and O₂Hb are associated with spontaneous and induced oscillations in blood pressure (BP) at the very low (VLF = 0.05 Hz) and low frequencies (LF = 0.1 Hz). We applied spectral and transfer function analysis to quantify dynamic cerebral autoregulation and brain tissue oxygenation. In AD, cerebrovascular resistance was substantially higher (34%, AD vs. control: Δ = 0.69 (0.25) mm Hg/cm/second, p = 0.012) and the transmission of very low frequency (VLF) cerebral blood flow (CBF) oscillations into O₂Hb differed, with increased phase lag and gain (Δ phase 0.32 [0.15] rad; Δ gain 0.049 [0.014] μmol/cm/second, p both < 0.05). The altered transfer of CBF to cortical oxygenation in AD indicates that properties of the cerebral microvasculature are changed in this disease.     

Impaired dynamic cerebral autoregulation in young adults with mild depression

The incidence of depression is increasing, especially in the young adult population. Impaired cognitive function is one of the characteristics of depression, which may be related to impaired cerebral autoregulation (CA). We investigated the characteristics of CA in young adults with mild depression, as well as its validity for identifying patients with depression. Patients (aged 18–35 years) with Hamilton Depression Rating Scale (HAMD) scores ranging from 8 to 17 and a first episode of mild depression were enrolled in this study. Healthy volunteers were recruited as controls. Noninvasive continuous arterial blood pressure and bilateral middle cerebral artery blood flow velocity were simultaneously recorded from each subject. Transfer function analysis was applied to derive phase difference, gain, coherence and rate of recovery for the assessment of CA. Forty-three patients and 43 healthy controls were enrolled. Phase difference values were significantly compromised in young adults with mild depression and were negatively correlated with HAMD scores. Rate of recovery values estimated from depressed patients was significantly lower. The validity in identifying patients with depression was favorable for the phase difference. The cutoff phase difference value was 29.66. Our findings suggest that dynamic CA was impaired in young patients with mild depression and negatively correlated with HAMD scores. CA represented by phase difference can be used as an objective auxiliary examination of depression, and has clinical diagnostic value for the early identification of patients with depression.     

Reproducibility and variability of dynamic cerebral autoregulation during passive cyclic leg raising

Dynamic cerebral autoregulation (dCA) estimates require mean arterial blood pressure (MABP) fluctuations of sufficient amplitude. Current methods to induce fluctuations are not easily implemented or require patient cooperation. In search of an alternative method, we evaluated if MABP fluctuations could be increased by passive cyclic leg raising (LR) and tested if reproducibility and variability of dCA parameters could be improved.Middle cerebral artery cerebral blood flow velocity (CBFV), MABP and end tidal CO₂ (PetCO₂) were obtained at rest and during LR at 0.1 Hz in 16 healthy subjects. The MABP–CBFV phase difference and gain were determined at 0.1 Hz and in the low frequency (LF) range (0.06–0.14 Hz). In addition the autoregulation index (ARI) was calculated.The LR maneuver increased the power of MABP fluctuations at 0.1 Hz and across the LF range. Despite a clear correlation between both phase and gain reproducibility and MABP variability in the rest condition, only the reproducibility of gain increased significantly with the maneuver. During the maneuver patients were breathing faster and more irregularly, accompanied by increased PetCO₂ fluctuations and increased coherence between PetCO₂ and CBFV. Multiple regression analysis showed that these concomitant changes were negatively correlated with the MABP–CBFV phase difference at 0.1 Hz Variability was not reduced by LR for any of the dCA parameters.The clinical utility of cyclic passive leg raising is limited because of the concomitant changes in PetCO₂. This limits reproducibility of the most important dCA parameters. Future research on reproducibility and variability of dCA parameters should incorporate PetCO₂ variability or find methods to keep PetCO₂ levels constant.     

The role of adenosine in autoregulation of cerebral blood flow

We have investigated the role of adenosine, a purine nucleoside and potent vasodilator of cerebral pial vessels, during both acute (0–60 sec) and sustained (2–5 min) changes in cerebral perfusion pressure. Brain adenosine concentrations are rapidly increased within 5 sec of the onset of systemic hypotension and parallel, in a temporal fashion, the changes in pial vessel diameter and alterations in cerebral vascular resistance. During sustained hypotension, brain levels of adenosine are increased even within the autoregulatory range. These data are constant with the hypothesis that adenosine is an important metabolic factor in cerebral autoregulation.     

Frequency-domain analysis of cerebral autoregulation from spontaneous fluctuations in arterial blood pressure

The dynamic relationship between spontaneous fluctuations of arterial blood pressure (ABP) and corresponding changes in crebral blood flow velocity (CBFV) is studied in a population of 83 neonates. Static and dynamic methods are used to identify two subgroups showing either normal (group A, n=23) or impaired (group B, n=21) cerebral autoregulation. An FFT algorithm is used to estimate the coherence and transfer function between CBFV and ABP. The significance of the linear dependence between these two variables in demonstrated by mean values of squared coherence >0.50 for both groups in the frequency range 0.02–0.50 Hz. However, group A has significanlty smaller coherences than group B in the frequency ranges 0.02–0.10 Hz and 0.33–0.49 Hz. The phase response of group A is also significantly more positive than that of group B, with slopes of 9.3±1.05 and 1.80±1.2 rad Hz⁻¹, respectively. The amplitude frequency response is also significantly smaller for group A in relation to group B for the frequency range 0.25–0.43 Hz. These results suggest that transfer function analysis may be able to identify different components of cerebral autoregulation and also provide a deeper understanding of recent findings by other investigators.