| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
|
|
|
|||||||
|
|||||||||
Institute for Exercise and Environmental Medicine, Presbyterian Hospital of Dallas, Dallas 75231; and The University of Texas Southwestern Medical Center at Dallas, Texas 75235
 |
ABSTRACT |
|---|
Top
Abstract
Introduction
Methods
Results
Discussion
References
|
|---|
To determine whether dynamic
cerebral autoregulation is impaired during orthostatic stress, cerebral
blood flow (CBF) velocity in the middle cerebral artery (transcranial
Doppler) and mean arterial pressure (MAP; Finapres) were measured
continuously in 12 healthy subjects during ramped maximal lower body
negative pressure (LBNP) to presyncope. Velocity and
pressure were averaged over 6-min periods of stable data at rest and
during LBNP to examine steady-state cerebral hemodynamics. Beat-to-beat
variability of velocity and pressure were quantified by a "variation
index" (oscillatory amplitude/steady-state mean value) and by power
spectral analysis. The dynamic relationship between changes in pressure
and velocity was evaluated by the estimates of transfer and coherence
function. The results of the study were as follows.
Steady-state MAP remained relatively constant during LBNP, whereas CBF
velocity decreased progressively by 6, 15, and 21% at 
30,
40, and 50 mmHg LBNP, respectively
(P < 0.05 compared with
baseline). At the maximal level of LBNP (30 s before
presyncope) MAP decreased by 9.4% in association with a prominent
reduction in velocity by 24% (P < 0.05 compared with baseline). The variation index of pressure increased
significantly from 3.8 ± 0.3% at baseline to 4.5 ± 0.6% at
50 mmHg LBNP in association with an increase in the variation index of velocity from 6.0 ± 0.6 to 8.4 ± 0.7%
(P < 0.05). Consistently, the low-
(0.07-0.20 Hz) and high-frequency (0.20-0.30 Hz) power of
variations in pressure and velocity increased significantly at high
levels of LBNP (P < 0.05) in
association with an increase in transfer function gain (24% at
50 mmHg, P < 0.05). We conclude that the damping effects of
autoregulation on variations in CBF velocity are diminished
during orthostatic stress in association with substantial falls in
steady-state CBF velocity. We suggest that these changes may contribute
in part to the development of presyncope.
cerebral blood flow; blood pressure; orthostasis; Fourier analysis
| |
INTRODUCTION |
|---|
|
Top
Abstract
Introduction
Methods
Results
Discussion
References
|
|---|
ORTHOSTATIC SYNCOPE is a common problem affecting patients with autonomic dysfunction as well as normal individuals after bed rest or spaceflight (7). The specific mechanism of orthostatic syncope may not always be clear and probably is multifactorial (23). However, the final event leading to syncope must be ultimately a reduction in cerebral perfusion sufficient to cause loss of consciousness (24).
Recently, we and other investigators have shown that, even without a significant change in mean arterial pressure, steady-state cerebral blood flow (CBF) velocity measured in the middle cerebral artery (MCA) by transcranial Doppler (TCD) decreases substantially during lower body negative pressure (LBNP)-induced orthostatic stress (6, 24, 37). If we assume that the changes in CBF velocity are proportional to the changes in CBF (22, 28), these findings seem to be at odds with the traditional concept of autoregulation, which would predict a relatively constant CBF within a wide range of perfusion pressure (32). Therefore, we have speculated that cerebral autoregulation becomes impaired during orthostatic stress and that it may contribute to the occurrence of orthostatic syncope (24, 37).
With the high temporal resolution of the TCD technique for noninvasive recording of CBF velocity in humans, it has been shown that cerebral autoregulation is a frequency-dependent phenomenon, with properties that may be characterized in the frequency domain by transfer-function analysis (4, 12, 36). For example, we have shown that in the frequency range of 0.07-0.30 Hz, beat-to-beat variations of CBF velocity measured in the MCA are closely related to spontaneous changes in mean arterial pressure (36). Furthermore, the dynamic relationship between these two variables can be modeled by a high-pass filter in the transmission of changes in arterial pressure to CBF velocity (4, 9, 36). On the basis of traditional concepts of cerebral autoregulation, we have speculated that effective autoregulation would attenuate spontaneous changes in CBF velocity in the face of variations in pressure, which would correspond to a relatively lower transfer function gain between these two variables. On the other hand, impairment of autoregulation would correspond to a higher gain with less-attenuated variations in velocity (36). Furthermore, a high correlation between changes in arterial pressure and CBF velocity evaluated by estimates of the coherence function would indicate an increased dependence of changes in velocity on pressure, suggesting impairment of autoregulation (12, 37).
We conducted the present study to evaluate the effects of orthostatic stress on the frequency components of cerebral autoregulation by using the method of transfer-function analysis between the spontaneous changes in arterial pressure and CBF velocity. We hypothesized that the attenuation effect of autoregulation on changes in CBF velocity would be diminished during orthostatic stress.
| |
METHODS |
|---|
|
Top
Abstract
Introduction
Methods
Results
Discussion
References
|
|---|
Subjects
Twelve healthy subjects (5 men, 7 women) with a mean age of 32 ± 7 yr, height of 172 ± 11 cm, and weight of 70 ± 13 kg voluntarily participated in the study. All were nonsmokers and were free of known cardiovascular, pulmonary, and cerebrovascular disorders. Each subject was informed of the experimental procedures and signed a written consent form approved by the Institutional Review Boards of The University of Texas Southwestern Medical Center and Presbyterian Hospital of Dallas.LBNP
Progressive LBNP was used to decrease central blood volume in a graded fashion and to facilitate physiological evaluation during orthostatic stress. Subjects were placed supine in a Plexiglas LBNP box that was sealed at the level of the iliac crests. Suction was provided by a vacuum pump and was controlled with a variable autotransformer. The negative pressure of the chamber was monitored with a manometer. After at least a 30-min baseline period of quiet rest, the magnitude of the suction was increased in a stepwise fashion according to the following protocol:15 mmHg for 13 min, 30 mmHg for 13 min, and
then increasing negative pressure increments by 10 mmHg every 13 min to the point of maximal tolerance. LBNP was terminated if the
subject developed signs and/or symptoms of presyncope: sudden
onset of nausea, sweating, light-headedness, bradycardia, or
hypotension (sustained systolic blood pressure <80 mmHg).
Instrumentation
Heart rate (HR) was monitored continuously by electrocardiogram (ECG), and arterial pressure was also measured continuously in the finger by using photoplethysmography (Finapres, Ohmeda). Intermittent arterial pressure was recorded in the arm by electrosphygmomanometry (Suntech) with a microphone placed over the brachial artery and the Korotkoff sounds gated to the ECG. Spontaneous respiratory frequency was monitored by using a piezoelectric pneumograph (Protech).CBF velocity was obtained continuously in the MCA by TCD ultrasonography. A 2-MHz Doppler probe (DWL Elektronische Systeme) was placed over the temporal window and fixed at a constant angle and position with an adjustable headgear to obtain optimal signals from the MCA according to standard techniques (1). Breath-to-breath end-tidal CO2 was also monitored continuously via a nasal cannula by using a mass spectrometer (model MGA 1100, Marquette Electronics).
Procedures
All experiments were performed in the morning, at least 2 h after the subjects consumed a light breakfast and >12 h after their last caffeinated or alcoholic beverage, in a quiet, environmentally controlled laboratory, with an ambient temperature of 25°C. After the subjects rested in the supine position for at least 30 min, 6-min beat-to-beat values of HR, finger arterial pressure, and CBF velocity were recorded during spontaneous respiration as baseline data for spectral- and transfer-function analysis. At the end of baseline data acquisition,15 mmHg LBNP was applied with a 2-min period at the
beginning for stabilization of cardiovascular hemodynamics. Then, 6 min
of beat-to-beat arterial pressure and CBF velocity were collected for
both the steady-state mean value and spectral- and transfer-function
analysis. This procedure was repeated at each level of LBNP until the
criteria for termination of LBNP were satisfied. The servo-reset
mechanism of the Finapres instrument was turned off during the 6 min of
steady-state measurements to permit an uninterrupted period of data
collection. The accuracy and reliability of this technique for
recording of arterial pressure have been evaluated in numerous studies
(19, 30). In our laboratory, the beat-to-beat mean values and pulsatile
waveforms of arterial pressure measured in the brachial artery with an
indwelling catheter are tracked well with the Finapres recordings (36).
The intermittent arterial pressure measured in the arm was also
monitored at each stage of LBNP.
Data Analysis
The analog arterial pressure and peak envelope of Doppler CBF velocity were sampled simultaneously at 100 Hz and digitized at 12 bits (Multi-Dop X2, DWL). Real time beat-to-beat values of mean arterial pressure and mean CBF velocity were calculated and stored for off-line analysis.Data preprocessing. Beat-to-beat changes of mean pressure and velocity were aligned with the R-wave peaks of the ECG to construct discrete time series based on beat numbers. Then, a line was interpolated between the adjacent values of pressure or velocity to form a continuous time series for the pressure or velocity, respectively. The linearly interpolated time series were resampled at 1 Hz for time- and frequency-domain analysis. The resampling frequency was determined via the spectral analysis of spontaneous changes in pressure and velocity and was based on the Nyquist theorem (33).
Time-domain analysis. For steady-state data analysis, mean values of the time series were obtained from a 6-min average of the beat-to-beat changes in pressure and velocity. To quantify the spontaneous changes of pressure and velocity, the calculated mean values were subtracted from each of the corresponding time series to offset the time series changing around a zero value. Then, the time series were rectified and averaged to estimate mean oscillatory amplitudes of pressure and velocity. For statistical comparison, a "variation index" was defined as the mean oscillatory amplitude divided by the mean value of the steady-state data (similar to a coefficient of variation) and estimated at baseline and each level of LBNP. Comparison of the variation index of velocity to pressure allows comparison of proportional changes in velocity to proportional changes in pressure.
Frequency-domain analysis. The autospectra of changes in pressure and velocity and the cross spectrum between these two signals were calculated by the Welch method (27). The autospectrum is the result of Fourier transform of a given time series and represents the power distribution of the signal in different frequency components. The cross spectrum reflects how changes in velocity are related to changes in pressure at specific frequencies (3). The transfer function between changes in pressure and velocity was estimated as the cross spectrum divided by the autospectrum of pressure (3). In the present study, to compare dynamic properties of the cerebrovascular system under different steady-state conditions, the time series of pressure and velocity were first normalized by their steady-state mean values for transfer-function estimation (16). The transfer-function gain and phase spectrum were then derived from the real and imaginary part of the complex transfer function by standard methods (3).
The linearity of the system and reliability of the transfer-function estimation were evaluated by a coherence function (3, 26). When the coherence function approaches 1 in a specific frequency range, it suggests a linear relationship and high signal-to-noise ratio between two variables, and therefore it is a reliable estimation of the transfer function. On the other hand, coherence approximating 0 may indicate either a nonlinear relationship, severe noise in the experimental data, or simply no relation between two variables, and thus it is a poor estimation of the transfer function (3, 26). Furthermore, to test the hypothesis that a low coherence (<0.5) between changes in pressure and velocity may indicate intrinsic nonlinearities in cerebral hemodynamics (36), correlation analysis between the estimates of coherence function and the spectral power of pressure was conducted in the present study. In a linear system, the coherence function is independent of the power of the input signal (3, 26). Conversely, nonlinear systems demonstrate significant dependent of coherence function on the power of the input signal (26). On the basis of a previous study of coherence-function analysis (36), spectral powers of pressure and velocity were calculated in the frequency ranges of 0.02-0.07 Hz (the very-low-frequency power), 0.07-0.20 Hz (the low-frequency power), and 0.20-0.30 Hz (the high-frequency power), respectively. The mean values of transfer gain, phase, and coherence function in the above frequency ranges were also calculated for statistical analysis.Statistical Analysis
Changes in hemodynamic variables and the spectral and the transfer-function index at each level of LBNP were compared by using one-way ANOVA with Duncan's post hoc tests for multiple comparisons. A value of P < 0.05 was accepted as statistically significant, and all data were represented as means ± SE. Statistics were performed by using a personal computer-based software program (ABstat, Anderson Bell).| |
RESULTS |
|---|
|
Top
Abstract
Introduction
Methods
Results
Discussion
References
|
|---|
Hemodynamic Responses to LBNP
All of the subjects completed the experimental protocol through at least40 mmHg LBNP. Five of twelve subjects ended the maximal
LBNP test at the level of 50 mmHg, three at 60 mmHg, three at 70 mmHg, and one at 80 mmHg, giving a group
averaged tolerance level of 60 ± 10 mmHg.
Steady-state responses of systemic and cerebral hemodynamics to LBNP
are presented in Table 1. As expected, systolic and pulse pressure decreased at high levels of LBNP
in association with a significant increase in HR
(P < 0.05; Table 1). In contrast to
the well-maintained mean arterial pressure, CBF velocity decreased
progressively by 6, 15, and 21% at 30, 40, and 50
mmHg LBNP, respectively (P < 0.05;
Table 1). Compared with baseline, the averaged mean arterial pressure over 30 s immediately before the release of maximal LBNP was decreased by 9.4% from 89 ± 5 to 81 ± 6 mmHg
(P < 0.05) in association with a
further fall in the CBF velocity by 24% from 67 ± 6 to 51 ± 3 cm/s (P < 0.05). Representative CBF
velocity and arterial pressure waveforms from one subject at rest and
immediately before the onset of presyncope are shown in Fig.
1. In contrast to previous observations
(24), in the present study we found that the steady-state mean value of
end-tidal CO2 also decreased by 13 and 20% at 40 and 50 mmHg LBNP, respectively
(P < 0.05) in association with a
constant respiratory rate (Table 1).
|
|
Variability Analysis
Representative beat-to-beat changes of mean arterial pressure and CBF velocity from one subject at rest and during LBNP are shown in Fig. 2. At baseline, mean arterial pressure varied around a steady-state value of 75 mmHg while mean CBF velocity varied around a steady-state value of 80 cm/s (Fig. 2). With increasing LBNP, steady-state values of pressure increased slightly, whereas steady-state values of velocity decreased progressively at high levels of LBNP (Fig. 2). In comparison with these steady-state changes in pressure and velocity, variability of pressure and velocity with a roughly 10-s rhythm (~0.1 Hz) increased simultaneously at40,
50, and 60 mmHg LBNP (Fig. 2). For all subjects, the variation index of beat-to-beat changes in pressure increased significantly from 3.8 ± 0.3% at baseline to 4.5 ± 0.6% at
50 mmHg LBNP (P < 0.05; Fig.
3A).
Coincident with these changes in pressure, the variation index in
velocity also increased significantly from 6.0 ± 0.6 to 8.4 ± 0.7% at 50 mmHg LBNP (P < 0.05; Fig. 3B).
|
|
Representative frequency-domain analysis of beat-to-beat changes in
pressure and velocity at baseline is shown in Fig.
4. For all subjects, there were no
significant changes in the spectral power of pressure and velocity in
the very-low-frequency range during LBNP. However, compared with
baseline, the spectral power of arterial pressure in the low-frequency
range increased significantly from 3.9 ± 0.9 at baseline to 10.5 ± 4.1 mmHg2 at 50 mmHg
LBNP (P < 0.05; Fig.
5A), and
the power in the high-frequency range increased significantly from 0.2 ± 0.1 at baseline to 1.2 ± 0.8 mmHg2 at 50 mmHg
(P < 0.05) (Fig.
5B). In association with these
changes in pressure, the spectral power of velocity in the
low-frequency range increased significantly from 5.1 ± 1.3 at
baseline to 9.6 ± 3.8 (cm/s)2
at 50 mmHg LBNP (P < 0.05;
Fig 5C), and the power in the
high-frequency range increased significantly from 0.5 ± 0.1 at baseline to 1.2 ± 0.3 (cm/s)2 at 50 mmHg
(P < 0.05; Fig.
5D).
|
|
Transfer Function
Low-frequency transfer gain increased significantly by 24% at50 mmHg LBNP (compared with baseline,
P < 0.05) in association with a
trend toward an increase in high-frequency gain (Fig.
6, A and
B). In the low-frequency range, at
baseline, there was a positive phase of change in velocity to pressure
(40 ± 12°), and this positive phase was smaller in the
high-frequency range (16 ± 19°) (Fig.
6D). Compared with baseline values,
no significant change in the phase was observed during LBNP (Fig. 6,
C and
D).
|
Coherence Function
For all subjects, coherence function in the very-low, low-, and high-frequency range at baseline was 0.45 ± 0.24, 0.65 ± 0.17, and 0.65 ± 0.21, respectively. No significant changes in coherence function were observed for the entire group during LBNP. However, in the very-low-frequency range, coherence function at baseline in eight subjects was lower than 0.5 (0.30 ± 0.12) in association with a lower spectral power of pressure, whereas in the other four subjects coherence function was higher than 0.5 (0.74 ± 0.11) associated with a higher spectral power of pressure (Fig. 7), suggesting that estimates of coherence function may be influenced by the spectral power of pressure. This speculation was supported by the fact that in those eight subjects with a typically low coherence function at baseline, coherence increased significantly during LBNP in association with a trend toward increases in spectral power of pressure (Fig. 7), whereas in the other four subjects coherence decreased significantly during LBNP in association with significant decreases in the spectral power of pressure (Fig. 7). Further analysis showed a significant linear correlation between the estimates of coherence function and spectral power of pressure in the very-low-frequency range (Fig. 8).
|
|
| |
DISCUSSION |
|---|
|
Top
Abstract
Introduction
Methods
Results
Discussion
References
|
|---|
The principal findings in the present study are that spontaneous variability of mean arterial pressure and CBF velocity increases significantly during LBNP in association with an augmentation of the transfer-function gain between these two variables at high levels of LBNP. These findings suggest that the attenuation effect of cerebral autoregulation on variations in CBF velocity are diminished during this form of orthostatic stress. We speculate that this impairment of dynamic autoregulation, in association with the substantial fall in the steady-state value of CBF velocity during LBNP, may contribute to orthostatic syncope.
Methodological Considerations and Limitations
The present study of CBF in humans required a technique that is safe and noninvasive and that allows estimates of CBF on a beat-to-beat basis. To meet these requirements, we used the TCD technology to measure CBF velocity in the MCA (1). It is important to emphasize that measurements of velocity do not necessarily reflect changes in flow. Changes in flow are proportional to changes in velocity only if the diameter of the insonated MCA remains constant. Angiographic study (17) and direct visualization of the MCA during surgery (13) have suggested that, during a variety of stimuli known to affect CBF, the diameter of the MCA changes minimally (<3.0%). However, small changes in diameter are difficult to measure and may produce large changes in velocity. The assumption made in this study is that changes in diameter of the MCA are minimal; therefore, beat-to-beat changes in mean velocity may represent predominantly beat-to-beat changes in CBF.In the present study, we used transfer-function analysis to quantify dynamic cerebral autoregulation during LBNP. The validity and accuracy of this technique rely on the basic assumptions that the system being analyzed is linear and the signal-to-noise ratio of the experimental data is high. However, most physiological systems, if not all, have intrinsic nonlinearities, and experimental data have different levels of noise that are dependent on the experimental conditions. Thus, as a commonly accepted criterion, the coherence function between the input and output of a system has been estimated to assess the quality of transfer-function analysis.
In the present study, mean values of the coherence function between changes in pressure and velocity in both the low (0.07-0.20 Hz) and high-frequency range (0.20-0.30 Hz) were above 0.5 at baseline and at each level of LBNP, suggesting that the estimation of the transfer function was acceptable. In contrast, as previously reported (36), coherence function in the very-low-frequency range was below 0.5. Therefore, transfer-function gain and phase were not calculated in the very-low-frequency range in this study. Further correlation analysis between the estimates of coherence function and the spectral power of arterial pressure supports the hypothesis that the low coherence in this very-low-frequency range represents a fundamental nonlinearity of cerebral hemodynamics. However, because we do not know the specific properties of nonlinearity in the cerebral circulation, it is difficult to assess to what degree this nonlineartiy would have influences on the estimation of transfer function in the low- and high-frequency ranges by the current method (26). Nevertheless, the finding of reduced autoregulatory control over cerebral circulation, as indicated by the augmented transfer-function gain during LBNP, is consistent with the time-domain observation of increases in the variation index of CBF velocity in the present study.
Finally, as has been determined in studies of other vascular beds (8), changes in the dynamic components of cerebral autoregulation as quantified by transfer-function analysis may not necessarily reflect changes in static cerebral autoregulation. Evaluation of dynamic autoregulation by transfer-function analysis may reveal properties of different regulatory mechanisms with different time responses to transient changes in pressure, whereas assessment of static autoregulation may reveal the regulatory capacity of the cerebrovascular bed in response to steady-state changes in pressure (32).
CBF Variability During LBNP
With the development of the TCD technique for noninvasive and continuous measurement of CBF velocity, several studies have indicated that pulsatile CBF velocity measured in the human MCA changes spontaneously over a wide frequency range (29, 34). Although it has been shown that these variations occur simultaneously with intracranial pressure B waves (29) and oscillations in arterial pressure (34), the underlying mechanisms are not clear. To our knowledge, two possible mechanisms could be formulated. 1) Changes in CBF velocity reflect changes in flow that are primarily caused by variations in arterial pressure. It has been shown that systemic arterial pressure changes spontaneously with amplitudes and frequencies similar to those observed in CBF velocity (31, 36). Therefore, if autoregulatory changes in cerebrovascular resistance and/or intracranial pressure cannot perfectly compensate for the variations in arterial pressure, there must exist fluctuations in CBF in response to changes in arterial pressure. In fact, numerous studies have demonstrated spontaneous changes in CBF, ranging from measurements in the internal carotid artery (28) to the cerebral microcirculation (18). Thus, if the diameter of insonated MCA remains relatively constant (13, 17), changes in CBF velocity could primarily reflect the changes in CBF caused by variations in arterial pressure and/or downstream vascular resistance. 2) Alternatively, if autoregulation is so effective that the changes in vascular resistance and/or intracranial pressure would be able to compensate completely for the changes in arterial pressure, CBF would remain relatively constant. In this situation, changes in CBF velocity may reflect changes in the diameter of the insonated MCA. Because we have observed almost parallel beat-to-beat changes in velocity and pressure, a constant CBF would suggest active vasomotion in the MCA in association with the spontaneous changes in pressure, which, if true, probably reflects dynamic cerebral autoregulation in large arteries (11). Although we cannot distinguish between these two possibilities in the present study, recent studies comparing TCD measurement of CBF velocity in the MCA with the measurements of CBF by other methods suggest that changes in CBF velocity can reliably reflect changes in CBF in humans under a wide range of changes in perfusion pressure (22, 28). Therefore, it is most likely that the spontaneous changes in CBF velocity observed in the present study may reflect spontaneous changes in CBF.The simultaneous increases in the variability of pressure and velocity in both the time and frequency domain during LBNP observed in the present study are consistent with the hypothesis that the spontaneous changes in CBF velocity and presumably flow were primarily caused by the changes in arterial pressure. This speculation is further supported by the observations that variations in the CBF velocity seem to be entrained or synchronized with the changes in the arterial pressure at about 0.1 Hz at high levels of LBNP (Fig. 2).
We caution that the mechanisms of spontaneous changes in CBF velocity may be different at different time scales, particularly when the coherence function between the changes in arterial pressure and velocity is low in the very-low-frequency range. However, further correlation analysis showed that the estimates of coherence function were influenced by the power of arterial pressure in the very-low-frequency range, suggesting a nonlinear relationship rather than the absence of a relationship between these two variables. It should be mentioned that, although this correlation is significant, the degree of correlation is relatively low (r2 = 0.31). Thus, we cannot exclude the possibility that some types of nonlinearity between changes in pressure and velocity may not be revealed by the correlation-analysis strategy and/or that some portion of the changes in velocity may not be related to changes in pressure in the very-low-frequency range.
One of the intriguing findings in the present study is that the aforementioned increases in the spontaneous changes in the CBF velocity and arterial pressure during LBNP were associated with a substantial fall in the steady-state value of CBF velocity even without any changes in the steady-state value of mean arterial pressure (6, 24). This result is consistent with the hypothesis that the autoregulatory curve may shift rightward during LBNP (24). With this curve shift, steady-state CBF velocity, and presumably flow, may decrease without any change in steady-state perfusion pressure. Furthermore, because the operational point of perfusion pressure and flow may fall into the lower limit of autoregulation in association with this curve shift, variations of flow would passively follow the changes in pressure. In this situation, increases in spontaneous changes in arterial pressure would lead to increases in spontaneous changes in velocity, as we have observed in the present study. Finally, it is also possible that the substantial decreases in the steady-state CBF velocity during LBNP may reduce shear stress-mediated nitric oxide synthase and inhibit nitric oxide-mediated modulation of vascular tone, thus leading to increases in the amplitude of spontaneous flow oscillation (10).
Cerebral Autoregulation
The specific mechanisms of the fall in steady-state CBF velocity during LBNP are not clear. We have hypothesized that the reduction in CBF velocity during LBNP was caused by cerebral vasoconstriction probably associated with an augmented sympathetic nerve activity (24). The significant increase in HR and reduction in pulse pressure observed in the present study suggest a baroreflex-mediated increase in sympathetic activity and were consistent with previous studies (6, 24, 37). However, the significant decrease in the end-tidal CO2 at the high levels of LBNP observed in the present study raised the possibility that the reduction in CBF velocity may be related to CO2-mediated cerebral vasoconstriction. It is well known that CBF is sensitive to changes in arterial CO2 content (32). Reduction in arterial CO2 would lead to cerebral arteriolar and downstream vasoconstriction (2, 32). Although this possibility seems to be straightforward, it must be acknowledged that we measured end-tidal CO2, which may not always be an accurate index of arterial CO2 (20, 35). A discrepancy between end-tidal CO2 and arterial CO2 may occur during the central hypovolemia of LBNP due to increased ventilation-perfusion mismatching or increased physiological dead space (20). Indeed, one invasive study has shown that the reduction in the arterial CO2 was only ~2 Torr at60 mmHg LBNP (21). However, on the basis of the data of the
present study, we cannot exclude the possibility that the decrease in
CBF velocity was associated with augmented sympathetic activity
and/or a decrease in arterial
CO2.
The role that cerebral hemodynamics play in orthostatic stress resulting in syncope is controversial (15, 24). The most commonly accepted hypothesis is that the fall in CBF is secondary to systemic hemodynamic collapse (5). Alternatively, some investigators recently suggested that a failure of cerebral autoregulation during orthostatic stress may compromise CBF and possibly result in a centrally mediated hemodynamic collapse (14, 15). In the present study, even though the mean CBF velocity decreased substantially at high levels of LBNP, the subjects did not report any changes in their consciousness and cognitive function before the onset of presyncope. Therefore, we speculate that, although cerebral vasoconstriction may override autoregulatory function and lead to a reduction in flow, cerebral oxygen consumption may remain relatively constant via an increase in oxygen extraction to compensate for the reduction in flow. Therefore, with well-maintained systemic pressure, the reduction in CBF induced by orthostatic stress by itself is unlikely to elicit the occurrence of presyncope. However, we and other investigators have observed that, with the onset of presyncope, CBF velocity fell passively with the rapid fall in arterial pressure, suggesting that cerebral autoregulation was impaired and may contribute in part to the occurrence of presyncope (6, 15, 24).
In the present study, we sought to evaluate the efficacy of cerebral autoregulation during orthostatic stress by using the frequency-domain analysis method. The significant increases in the transfer-function gain at high levels of LBNP suggest that the attenuation effects of cerebral autoregulation on variations in CBF velocity are diminished and are consistent with the hypothesis of a rightward shift of the autoregulatory curve during LBNP (24). Furthermore, we speculate that, with the augmented transfer-function gain, hemodynamic instability of the systemic circulation, as indicated by the increases in the variations of arterial pressure during orthostatic stress (25), would have exaggerated rather than damped influences on the instability of cerebral hemodynamics as indicated by the increases in the variations of the CBF velocity.
In summary, the increases in the spectral power of spontaneous changes in arterial pressure and CBF velocity and the augmentation of transfer-function gain in association with the substantial fall in the steady-state value of CBF velocity indicate that dynamic cerebral autoregulation is impaired during this form of orthostatic stress and may contribute to orthostatic intolerance resulting in syncope.
| |
ACKNOWLEDGEMENTS |
|---|
This study was supported by National Aeronautics and Space Administration Center for Research and Training Grant AO-93-OLMSA-01 and by National Heart, Lung, and Blood Institute Grant 5-U01-HL-53206-2.
| |
FOOTNOTES |
|---|
The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. §1734 solely to indicate this fact.
Address for reprint requests: B. D. Levine, Institute for Exercise and Environmental Medicine, Presbyterian Hospital of Dallas, 7232 Greenville Ave, Dallas, TX 75231 (E-mail: Levineb{at}wpmail.phscare.org).
Received 2 January 1998; accepted in final form 1 May 1998.
| |
REFERENCES |
|---|
|
Top
Abstract
Introduction
Methods
Results
Discussion
References
|
|---|
1.
Aaslid, R.,
T. M. Markwalder,
and
H. Nornes.
Noninvasive transcranial Doppler ultrasound recording of flow velocity in basal cerebral arteries.
J. Neurosurg.
57:
769-774,
1982[Medline].
2.
Atkinson, J. L. D.,
R. E. Anderson,
and
T. M. Sundt.
The effect of carbon dioxide on the diameter of brain capillaries.
Brain Res.
517:
333-340,
1990[Medline].
3.
Bendat, J. S.,
and
A. G. Piersol.
Single input/single output relationships.
In: Engineering Applications of Correlation and Spectral Analysis. New York: Wiley, 1980, p. 78-96.
4.
Blaber, A. P.,
R. L. Bondar,
F. Stein,
P. T. Dunphy,
P. Moradshahi,
M. S. Kassam,
and
R. Freeman.
Transfer function analysis of cerebral autoregulation dynamics in autonomic failure patients.
Stroke
28:
1686-1692,
1997
5.
Blomqvist, C. G.
Orthostatic hypotension.
In: Cardiology, edited by W. W. Parmley,
and K. Chaterjee. Philadelphia, PA: Lippincott, 1990, p. 1-20.
6.
Bondar, R. L.,
M. S. Kassam,
F. Stein,
P. T. Dunphy,
S. Fortney,
and
M. L. Riedesel.
Simultaneous cerebrovascular and cardiovascular responses during presyncope.
Stroke
26:
1794-1800,
1995
7.
Buckey, J. C.,
L. D. Lane,
B. D. Levine,
D. E. Watenpaugh,
S. J. Wright,
W. E. Moore,
F. A. Gaffney,
and
C. G. Blomqvist.
Orthostatic intolerance after spaceflight.
J. Appl. Physiol.
81:
7-18,
1996
8.
Daniels, F. H.,
W. J. Arendshorst,
and
R. G. Roberds.
Tubuloglomerular feedback and autoregulation in spontaneously hypertensive rats.
Am. J. Physiol.
258 (Renal Fluid Electrolyte Physiol. 27):
F1479-F1489,
1990
9.
Diehl, R. R.,
D. Linden,
D. Lucke,
and
P. Berlit.
Phase relationship between cerebral blood flow velocity and blood pressure. A clinical test of autoregulation.
Stroke
26:
1801-1804,
1995
10.
Dirnagl, U.,
U. Lindauer,
and
A. Villringer.
Nitric oxide synthase blockade enhances vasomotion in the cerebral microcirculation of anesthetized rats.
Microvasc. Res.
45:
318-323,
1993[Medline].
11.
Faraci, F. M.,
and
D. D. Heistad.
Regulation of large cerebral arteries and cerebral microvascular pressure.
Circ. Res.
66:
8-17,
1990
12.
Giller, C. A.
The frequency-dependent behavior of cerebral autoregulation.
Neurosurgery
27:
362-368,
1990[Medline].
13.
Giller, C. A.,
G. Bowman,
H. Dyer,
and
L. Mootz.
Cerebral arterial diameters during changes in blood pressure and carbon dioxide during craniotomy.
Neurosurgery
32:
737-741,
1993[Medline].
14.
Glaister, D. H.,
and
N. L. Miller.
Cerebral tissue oxygen status and psychomotor performance during lower body negative pressure (LBNP).
Aviat. Space Environ. Med.
61:
99-105,
1990[Medline].
15.
Grubb, B. P.,
G. Gerard,
K. Roush,
P. Temesy-Armos,
P. Montford,
L. Elliott,
H. Hahn,
and
P. Brewster.
Cerebral vasoconstriction during head-upright tilt-induced vasovagal syncope.
Circulation
84:
1157-1164,
1991
16.
Holstein-Rathlou, N. H.,
A. J. Wagner,
and
D. J. Marsh.
Tubuloglomerular feedback dynamics and renal blood flow autoregulation in rats.
Am. J. Physiol.
260 (Renal Fluid Electrolyte Physiol. 29):
F53-F68,
1991
17.
Huber, P.,
and
J. Handa.
Effect of contrast material, hypercapnia, hyperventilation, hypertonic glucose and papaverine on the diameter of the cerebral arteries.
Invest. Radiol.
2:
17-32,
1967[Medline].
18.
Hudetz, A. G.,
R. J. Roman,
and
D. R. Harder.
Spontaneous flow oscillations in the cerebral cortex during acute changes in mean arterial pressure.
J. Cereb. Blood Flow Metab.
12:
491-499,
1992[Medline].
19.
Imholz, B. P.,
J. J. Settels,
A. H. van der Meiraker,
K. H. Wesseling,
and
W. Wieling.
Non-invasive continuous finger blood pressure measurement during orthostatic stress compared to intra-arterial pressure.
Cardiovasc. Res.
24:
214-221,
1990
20.
Johnson, R. L.,
G. J. F. Heigenhauser,
C. C. W. Hsia,
N. L. Jones,
and
P. D. Wagner.
Determinants of gas exchange and acid-base balance during exercise.
In: Handbook of Physiology. Exercise: Regulation and Integration of Multiple Systems, edited by L. B. Rowell,
and J. T. Shepherd. Bethesda, MD: Am. Physiol. Soc., 1996, sect. 12, chapt. 12, p. 515-584.
21.
Katkov, V. E.,
V. V. Chestukhin,
L. I. Kakurin,
A. M. Babin,
and
E. M. Nikolaenko.
Central and coronary circulation of the normal man during orthostatic and lower body negative pressure tests.
Aviat. Space Environ. Med.
58:
A55-A60,
1987[Medline].
22.
Larsen, F. S.,
K. S. Olsen,
B. A. Hansen,
O. B. Paulson,
and
G. M. Knudsen.
Transcranial Doppler is valid for determination of the lower limit of cerebral blood flow autoregulation.
Stroke
25:
1985-1988,
1994[Abstract].
23.
Levine, B. D.,
J. C. Buckey,
J. M. Fritsch,
C. W. Yancy, Jr.,
D. E. Watenpaugh,
P. G. Snell,
L. D. Lane,
D. L. Eckberg,
and
C. G. Blomqvist.
Physical fitness and cardiovascular regulation: mechanisms of orthostatic intolerance.
J. Appl. Physiol.
70:
112-122,
1991
24.
Levine, B. D.,
C. A. Giller,
L. D. Lane,
J. C. Buckey,
and
C. G. Blomqvist.
Cerebral versus systemic hemodynamics during graded orthostatic stress in humans.
Circulation
90:
298-306,
1994
25.
Lipsitz, L. A.,
R. Morin,
M. Gagnon,
D. Kiely,
and
A. Medina.
Vasomotor instability preceding a tilt-induced syncope: does respiration play a role?
J. Appl. Physiol.
83:
383-390,
1997
26.
Marmarelis, V. Z.
Coherence and apparent transfer function measurements for nonlinear physiological systems.
Ann. Biomed. Eng.
16:
143-157,
1988[Medline].
27.
Marple, S. L., Jr.
Classical spectral estimation.
In: Digital Spectral Analysis With Applications, edited by A. V. Oppenheim. Englewood Cliffs, NJ: Prentice-Hall, 1987, p. 130-171.
28.
Newell, D. W.,
R. Aaslid,
A. Lam,
T. S. Mayberg,
and
H. R. Winn.
Comparison of flow and velocity during dynamic autoregulation testing in humans.
Stroke
25:
793-797,
1994[Abstract].
29.
Newell, D. W.,
R. Aaslid,
R. Stooss,
and
H. J. Reulen.
The relationship of blood flow velocity fluctuations to intracranial pressure B waves.
J. Neurosurg.
76:
415-421,
1992[Medline].
30.
Omboni, S.,
G. Parati,
A. Frattola,
E. Mutti,
M. Di Rienzo,
P. Catiglioni,
and
G. Mancia.
Spectral and sequence analysis of finger blood pressure variability: comparison with analysis of intra-arterial recordings.
Hypertension
22:
26-33,
1993
31.
Parati, G.,
J. P. Saul,
M. Di Rienzo,
and
G. Mancia.
Spectral analysis of blood pressure and heart rate variability in evaluating cardiovascular regulation: a critical appraisal.
Hypertension
25:
1276-1286,
1995
32.
Paulson, O. B.,
S. Strandgaard,
and
L. Edvinsson.
Cerebral autoregulation.
Cerebrovasc. Brain Metab. Rev.
2:
161-192,
1990[Medline].
33.
Proakis, J. G.,
and
D. G. Manolakis.
Introduction.
In: Digital Signal Processing Principle, Algorithms, and Applications. Upper Saddle River, NJ: Prentice-Hall, 1996, p. 21-33.
34.
Steinmeier, R.,
C. Bauhuf,
U. Hubner,
R. D. Bauer,
R. Fahlbusch,
R. Laumer,
and
I. Bondar.
Slow rhythmic oscillations of blood pressure, intracranial pressure, microcirculation, and cerebral oxygenation.
Stroke
27:
2236-2243,
1996
35.
Williams, J. S.,
and
T. G. Babb.
Differences between estimates and measured PaCO2 during rest and exercise in older subjects.
J. Appl. Physiol.
83:
312-316,
1997
36.
Zhang, R.,
J. H. Zuckerman,
C. A. Giller,
and
B. D. Levine.
Transfer function analysis of dynamic cerebral autoregulation in humans.
Am. J. Physiol.
274 (Heart Circ. Physiol. 43):
H233-H241,
1998
37.
Zhang, R.,
J. H. Zuckerman,
J. A. Pawelczyk,
and
B. D. Levine.
Effects of head-down-tilt bed rest on cerebral hemodynamics during orthostatic stress.
J. Appl. Physiol.
83:
2139-2145,
1997
This article has been cited by other articles:
|
|
 |
|
  K. Nakagawa, J. M. Serrador, S. L. LaRose, F. Moslehi, L. A. Lipsitz, and F. A. Sorond Autoregulation in the Posterior Circulation Is Altered by the Metabolic State of the Visual Cortex Stroke, June 1, 2009; 40(6): 2062 - 2067. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C Porta, G Casucci, S Castoldi, A Rinaldi, and L Bernardi Influence of respiratory instability during neurocardiogenic presyncope on cerebrovascular and cardiovascular dynamics Heart, November 1, 2008; 94(11): 1433 - 1439. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P. Arbeille, P. Kerbeci, L. Mattar, J. K. Shoemaker, and R. Hughson Insufficient flow reduction during LBNP in both splanchnic and lower limb areas is associated with orthostatic intolerance after bedrest Am J Physiol Heart Circ Physiol, November 1, 2008; 295(5): H1846 - H1854. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Y. Ogawa, K.-i. Iwasaki, K. Aoki, S. Shibata, J. Kato, and S. Ogawa Central Hypervolemia with Hemodilution Impairs Dynamic Cerebral Autoregulation Anesth. Analg., November 1, 2007; 105(5): 1389 - 1396. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 E. L. Sammons, N. J. Samani, S. M. Smith, W. E. Rathbone, S. Bentley, J. F. Potter, and R. B. Panerai Influence of noninvasive peripheral arterial blood pressure measurements on assessment of dynamic cerebral autoregulation J Appl Physiol, July 1, 2007; 103(1): 369 - 375. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. A. Rickards, K. L. Ryan, W. H. Cooke, K. G. Lurie, and V. A. Convertino Inspiratory resistance delays the reporting of symptoms with central hypovolemia: association with cerebral blood flow Am J Physiol Regulatory Integrative Comp Physiol, July 1, 2007; 293(1): R243 - R250. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. Zhang, S. Witkowski, Q. Fu, J. A.H.R. Claassen, and B. D. Levine Cerebral Hemodynamics After Short- and Long-Term Reduction in Blood Pressure in Mild and Moderate Hypertension Hypertension, May 1, 2007; 49(5): 1149 - 1155. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K.-i. Iwasaki, B. D. Levine, R. Zhang, J. H. Zuckerman, J. A. Pawelczyk, A. Diedrich, A. C. Ertl, J. F. Cox, W. H. Cooke, C. A. Giller, et al. Human cerebral autoregulation before, during and after spaceflight J. Physiol., March 15, 2007; 579(3): 799 - 810. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. H. Gibbons and R. Freeman Delayed orthostatic hypotension: A frequent cause of orthostatic intolerance. Neurology, July 11, 2006; 67(1): 28 - 32. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. D. Mitsis, R. Zhang, B. D. Levine, and V. Z. Marmarelis Cerebral hemodynamics during orthostatic stress assessed by nonlinear modeling J Appl Physiol, July 1, 2006; 101(1): 354 - 366. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. Guo, N. Tierney, F. Schaller, P. B. Raven, S. A. Smith, and X. Shi Cerebral autoregulation is preserved during orthostatic stress superimposed with systemic hypotension J Appl Physiol, June 1, 2006; 100(6): 1785 - 1792. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Ogoh, R. M. Brothers, Q. Barnes, W. L. Eubank, M. N. Hawkins, S. Purkayastha, A. O-Yurvati, and P. B. Raven The effect of changes in cardiac output on middle cerebral artery mean blood velocity at rest and during exercise J. Physiol., December 1, 2005; 569(2): 697 - 704. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Latka, M. Turalska, M. Glaubic-Latka, W. Kolodziej, D. Latka, and B. J. West Phase dynamics in cerebral autoregulation Am J Physiol Heart Circ Physiol, November 1, 2005; 289(5): H2272 - H2279. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. Schondorf, J. Benoit, and R. Stein Cerebral autoregulation is preserved in postural tachycardia syndrome J Appl Physiol, September 1, 2005; 99(3): 828 - 835. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. N Ainslie, J. C Ashmead, K. Ide, B. J Morgan, and M. J Poulin Differential responses to CO2 and sympathetic stimulation in the cerebral and femoral circulations in humans J. Physiol., July 15, 2005; 566(2): 613 - 624. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Ogoh, P. J. Fadel, R. Zhang, C. Selmer, O. Jans, N. H. Secher, and P. B. Raven Middle cerebral artery flow velocity and pulse pressure during dynamic exercise in humans Am J Physiol Heart Circ Physiol, April 1, 2005; 288(4): H1526 - H1531. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Ogoh, M. K. Dalsgaard, C. C. Yoshiga, E. A. Dawson, D. M. Keller, P. B. Raven, and N. H. Secher Dynamic cerebral autoregulation during exhaustive exercise in humans Am J Physiol Heart Circ Physiol, March 1, 2005; 288(3): H1461 - H1467. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Krishnamurthy, X. Wang, D. Bhakta, E. Bruce, J. Evans, T. Justice, and A. Patwardhan Dynamic cardiorespiratory interaction during head-up tilt-mediated presyncope Am J Physiol Heart Circ Physiol, December 1, 2004; 287(6): H2510 - H2517. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. V. Immink, B.-J. H. van den Born, G. A. van Montfrans, R. P. Koopmans, J. M. Karemaker, and J. J. van Lieshout Impaired Cerebral Autoregulation in Patients With Malignant Hypertension Circulation, October 12, 2004; 110(15): 2241 - 2245. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. Haubrich, A. Wendt, R.R. Diehl, and C. Klotzsch Dynamic Autoregulation Testing in the Posterior Cerebral Artery Stroke, April 1, 2004; 35(4): 848 - 852. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. J. Van Lieshout, W. Wieling, J. M. Karemaker, and N. H. Secher Syncope, cerebral perfusion, and oxygenation J Appl Physiol, March 1, 2003; 94(3): 833 - 848. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. Zhang, J. H. Zuckerman, K. Iwasaki, T. E. Wilson, C. G. Crandall, and B. D. Levine Autonomic Neural Control of Dynamic Cerebral Autoregulation in Humans Circulation, October 1, 2002; 106(14): 1814 - 1820. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. R. Edwards, J. K. Shoemaker, and R. L. Hughson Dynamic modulation of cerebrovascular resistance as an index of autoregulation under tilt and controlled PETCO2 Am J Physiol Regulatory Integrative Comp Physiol, September 1, 2002; 283(3): R653 - R662. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. E. Wilson, J. Cui, R. Zhang, S. Witkowski, and C. G. Crandall Skin cooling maintains cerebral blood flow velocity and orthostatic tolerance during tilting in heated humans J Appl Physiol, July 1, 2002; 93(1): 85 - 91. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. K. Wilkerson, P. N. Colleran, and M. D. Delp Acute and chronic head-down tail suspension diminishes cerebral perfusion in rats Am J Physiol Heart Circ Physiol, January 1, 2002; 282(1): H328 - H334. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. Schondorf, R. Stein, R. Roberts, J. Benoit, and W. Cupples Dynamic cerebral autoregulation is preserved in neurally mediated syncope J Appl Physiol, December 1, 2001; 91(6): 2493 - 2502. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. M. Serrador, S. J. Wood, P. A. Picot, F. Stein, M. S. Kassam, R. L. Bondar, A. H. Rupert, and T. T. Schlegel Effect of acute exposure to hypergravity (GX vs. GZ) on dynamic cerebral autoregulation J Appl Physiol, November 1, 2001; 91(5): 1986 - 1994. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. L. Hughson, M. R. Edwards, D. D. O'Leary, and J. K. Shoemaker Critical Analysis of Cerebrovascular Autoregulation During Repeated Head-Up Tilt Stroke, October 1, 2001; 32(10): 2403 - 2408. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
B. J. Carey, B. N. Manktelow, R. B. Panerai, and J. F. Potter Cerebral Autoregulatory Responses to Head-Up Tilt in Normal Subjects and Patients With Recurrent Vasovagal Syncope Circulation, August 21, 2001; 104(8): 898 - 902. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. J. van Lieshout, F. Pott, P. L. Madsen, J. van Goudoever, and N. H. Secher Muscle Tensing During Standing : Effects on Cerebral Tissue Oxygenation and Cerebral Artery Blood Velocity Stroke, July 1, 2001; 32(7): 1546 - 1551. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. B. Panerai, S. L. Dawson, P. J. Eames, and J. F. Potter Cerebral blood flow velocity response to induced and spontaneous sudden changes in arterial blood pressure Am J Physiol Heart Circ Physiol, May 1, 2001; 280(5): H2162 - H2174. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. Zhang, K. Behbehani, C. G. Crandall, J. H. Zuckerman, and B. D. Levine Dynamic regulation of heart rate during acute hypotension: new insight into baroreflex function Am J Physiol Heart Circ Physiol, January 1, 2001; 280(1): H407 - H419. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. Zhang, J. H. Zuckerman, and B. D. Levine Spontaneous fluctuations in cerebral blood flow: insights from extended-duration recordings in humans Am J Physiol Heart Circ Physiol, June 1, 2000; 278(6): H1848 - H1855. [Abstract] [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
| Visit Other APS Journals Online |
