This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Zaharchuk, G. Articles by Kim, S.-G. Search for Related Content PubMed PubMed Citation Articles by Zaharchuk, G. Articles by Kim, S.-G. Related Collections Animal models of human disease Brain Circulation and Metabolism Computerized tomography and Magnetic Resonance Imaging Pathology of Stroke

(Stroke. 1999;30:2197-2205.)
© 1999 American Heart Association, Inc.

Original Contributions

Cerebrovascular Dynamics of Autoregulation and Hypoperfusion

An MRI Study of CBF and Changes in Total and Microvascular Cerebral Blood Volume During Hemorrhagic Hypotension

Greg Zaharchuk, PhD; Joseph B. Mandeville, PhD; Alexei A. Bogdanov, Jr, PhD; Ralph Weissleder, MD, PhD; Bruce R. Rosen, MD, PhD John J. A. Marota, MD, PhD

From the Harvard-MIT Division of Health Sciences and Technology (G.Z., B.R.R.), Harvard Medical School, Boston, and Massachusetts Institute of Technology, Cambridge; the Department of Radiology (J.B.M., B.R.R.), Massachusetts General Hospital Nuclear Magnetic Resonance (MGH-NMR) Center (2301); the Center for Molecular Imaging Research (A.A.B., R.W.); and the Department of Anesthesia and Critical Care (J.J.A.M.), Massachusetts General Hospital, Boston, Mass.

Correspondence to Greg Zaharchuk, PhD, MGH-NMR Center (2301), 149 13th St, Charlestown, MA 02129. E-mail gregz{at}nmr.mgh.harvard.edu

	Abstract

Top Abstract Introduction Materials and Methods Results Discussion References Introduction  References

 
Background and Purpose—To determine how cerebral blood flow (CBF), total and microvascular cerebral blood volume (CBV), and blood oxygenation level–dependent (BOLD) contrast change during autoregulation and hypotension using hemodynamic MRI.

Methods—Using arterial spin labeling and steady-state susceptibility contrast, we measured CBF and changes in both total and microvascular CBV during hemorrhagic hypotension in the rat (n=9).

Results—We observed CBF autoregulation for mean arterial blood pressure (MABP) between 50 and 140 mm Hg, at which average CBF was 1.27±0.44 mL · g^-1 · min^-1 (mean±SD). During autoregulation, total and microvascular CBV changes were small and not significantly different from CBF changes. Consistent with this, no significant BOLD changes were observed. For MABP between 10 and 40 mm Hg, total CBV in the striatum increased slightly (+7±12%, P<0.05) whereas microvascular CBV decreased (-15±17%, P<0.01); on the cortical surface, total CBV increases were larger (+21±18%, P<0.01) and microvascular CBV was unchanged (3±22%, P>0.05). With severe hypotension, both total and microvascular CBV decreased significantly. Over the entire range of graded global hypoperfusion, there were increases in the CBV/CBF ratio.

Conclusions—Parenchymal CBV changes are smaller than those of previous reports but are consistent with the small arteriolar fraction of total blood volume. Such measurements allow a framework for understanding effective compensatory vasodilation during autoregulation and volume-flow relationships during hypoperfusion.

Key Words: magnetic resonance imaging • autoregulation • global ischemia • cerebral blood volume • cerebral blood flow

	Introduction

Top Abstract Introduction Materials and Methods Results Discussion References Introduction  References

 
Many organ systems, including the brain, have the ability to autoregulate blood flow, despite large changes in systemic mean arterial blood pressure (MABP).^{1 2 3 4 5} Because of technical difficulties, few autoregulation studies have additionally examined cerebral blood volume fraction (CBV) changes.^{6 7 8} CBV is thought to be an important determinant of intracranial pressure (ICP), as a result of the fixed volume of the cranial cavity.^{9 10} Because increased ICP has been implicated in ischemic tissue damage and risk of brain herniation, proper understanding of CBV dynamics may be important in the assessment of clinical manipulations, particularly in the setting of intracranial pathology.

To maintain CBF when MABP is decreasing, cerebrovascular resistance (CVR) must decrease, and most researchers have assumed that this vasodilation requires a large CBV increase.^{7 11 12} However, evidence for this has been inconsistent in previous literature reports. Most previous measurements have been made on the cortical surface and used either indirect CBV markers (eg, mean transit time and separate measurement of blood flow)⁷ or localized properties, such as pial vessel diameter, that may not reflect parenchymal CBV.^{2 13 14 15} The large CBV changes (>100%) reported by some studies appear to require active mechanisms for capillary and venous dilation to be consistent with known distributions of resistance and blood volume in arterial, capillary, and venous compartments. This may reflect the effects of measuring CBV changes on the cortical surface, known to have a greater proportion of arteries and arterioles than the parenchyma. Grubb et al⁸ described a much smaller CBV increase of 18% at 35 mm Hg in brain parenchyma with X-ray fluorescence, whereas studies with a photoelectric technique reported no CBV changes during hemorrhagic hypotension.⁶

Below the autoregulated range, flow becomes pressure-dependent, which leads to global hypoperfusion; the behavior of CBV during hypoperfusion may be different from that during autoregulation. Global and focal models have suggested that volume-flow mismatch (ie, high or preserved CBV with low CBF) may be a feature of early ischemia^{16 17 18 19} and represent tissue at risk of infarction.^{16 20 21} Such regions have been observed in humans and tend to progress to infarction without intervention.^{20 22}

Steady-state susceptibility contrast MRI measurements of relative regional CBV provide a unique combination of high sensitivity, accuracy for measurement of CBV changes, and high temporal resolution for in vivo studies.^{23 24 25} In addition, the technique may be sensitized to vascular size, permitting measurement of both total and microvascular blood volume.^{26 27} Continuous assessment of perfusion by tagging, including volume and water extraction (CAPTIVE) imaging, which combines susceptibility contrast with arterial spin-labeling (ASL), permits frequently repeated equilibrium measurement of both CBF and CBV.²⁸ The present article reports the first application of hemodynamic MRI techniques to examine volume-flow relationships during successful autoregulation and global hypoperfusion caused by hemorrhagic hypotension. We have measured CBF with ASL and compared these values with those of previously published reports. Additionally, we have measured how total and microvascular CBV changes with MABP in several brain regions. Finally, we have examined how gradient and spin echo blood oxygen level–dependent (BOLD) effects change with MABP.

	Materials and Methods

Top Abstract Introduction Materials and Methods Results Discussion References Introduction  References

 
Animal Preparation
All experimental protocols were approved by the Office of Laboratory Animal Research at Massachusetts General Hospital. Sprague-Dawley rats (321±25 g, n=12; Charles River Laboratories Inc, Wilmington, Mass) were mechanically ventilated, paralyzed, and anesthetized with 0.7% halothane in a 2:1 mixture of air:oxygen. Two femoral intra-arterial catheters were placed: 1 for monitoring MABP and drawing arterial blood gases and hematocrit (these were measured in more than half of the animals), the other for arterial blood withdrawal. A femoral intravenous catheter allowed administration of the contrast agent. Arterial blood withdrawal (rate, 4 to 20 mL/h) was used to reduce MABP at approximately 1 mm Hg/min. Animals were placed in a head holder (David Kopf Instruments) inside a surface radiofrequency coil with the brain 1 cm above the heart.

CAPTIVE Measurements
In a group of rats (n=7) imaged at 4.7 T, the contrast agent methoxypoly(ethylene glycol)-polypropylene-dysprosium-diethylenetriaminepentaacetic acid (MPEG-PL-Dy-DTPA) (180 µmol/kg) was infused immediately after the acquisition of coronal baseline images. In 3 of these rats, plasma contrast agent concentration was measured (Galbraith Laboratories) before hemorrhage and during mild and severe hypotension.

In a single slice located at bregma, ASL measurements were performed with the following parameters: conventional gradient echo, repetition time (TR)/echo time (TE), 4000/5 ms; field of view (FOV), 25 mm; slice thickness, 2 mm; imaging matrix, 32x32; frequency offset, 3 kHz; gradient, 0.5 G/cm; and labeling time, 3.7 s with a 0.2-s postlabeling delay to minimize transit time effects.²⁹ CBF was calculated by the following:

where f is perfusion (mL · g^-1 · min^-1), is the brain:blood water partition coefficient (0.88),³⁰ T_1b is brain T₁ (1.5 s), is the degree of labeling (0.7 before contrast and 0.6 after contrast),²⁸ and S_label and S_control are the MR signals in the presence and absence of labeling, respectively.

Multislice (8 slices, 1-mm slice thickness) gradient echo (TR/TE, 2000/25 ms) and spin echo (TR/TE, 2000/60 ms) imaging with the same in-plane resolution was performed to measure total and microvascular CBV changes, respectively. Relative CBV images were created at each MABP level by calculating changes in transverse relaxivity (R2* or R2) on the basis of precontrast and postcontrast images. Fractional CBV changes were calculated as follows:

where the baseline relaxivity R2(P₀) is the average of measurements taken with MABP of 90 to 99 mm Hg. Using the full multislice data set, we measured CBV in 3 separate regions-of-interest (ROIs): striatum, cortex, and cortical rim. Additionally, to facilitate direct comparison with the CBF data, we further analyzed CBV changes in the whole brain at the level of bregma. ROIs were drawn conservatively to minimize CSF and partial volume effects (Figure 1).

View larger version (27K): [in this window] [in a new window]   Figure 1. Multislice MRI spin echo coronal images of rat brain, which show ROIs for hemodynamic measurements. Arrow, Coronal slice at the bregma level, at which both CBV and CBF measurements were made. Additional CBV measurements were made in striatum (yellow), cortex (green), and on the cortical rim (blue). These regions were drawn conservatively to minimize partial volume effects.

In another group of rats (n=2), CBV changes were imaged by used of an echo-planar sequence at 2 T, with the contrast agent monocrystalline iron oxide nanocolloid (MION) (12 mg Fe per kilogram). Imaging parameters were as follows: FOV, 25 mm; thickness, 1 mm; matrix size, 32x32; gradient echo TR/TE, 5 s/25 ms; spin echo TR/TE, 5 s/60 ms.

BOLD Studies
To measure and control for BOLD, a third group of rats (n=3) was imaged at 4.7 T. CBF and spin and gradient echo imaging was performed using the same parameters as in the CAPTIVE studies without infusion of contrast agent.

Statistical Analysis
All measurements in individual animals were binned on the basis of 10-mm Hg subdivisions. Standard deviations were calculated from these binned measurements in different animals. For comparison, the data were broken into 3 groups on the basis of MABPs of 50 to 140 mm Hg ("autoregulation"), 10 to 40 mm Hg ("mild hypoperfusion"), and <10 mm Hg ("severe hypoperfusion"). For the autoregulation range, linear regression was performed to compare the linear slopes. To permit comparison with CBV, the CBF data were converted to percentage change on the basis of the baseline (90- to 99-mm Hg) level. Differences between parameters during autoregulation and hypoperfusion were compared with the use of Student's 2-tailed t test using the Bonferroni correction for multiple comparisons.

	Results

Top Abstract Introduction Materials and Methods Results Discussion References Introduction  References

 
The physiological parameters of the animals are presented in Table 1; only hematocrit changed significantly, decreasing from 38±3% before hemorrhage to 29±4% measured during both mild and severe hypotension. An 11% to 18% decrease in plasma contrast agent concentration was measured, which was not significantly different from the initial level.

View this table: [in this window] [in a new window]   Table 1. Physiological Measurements

Because we detected no significant differences in CBF measured with and without the contrast agent MPEG-PL-Dy-DTPA, the CBF data (Figure 2) represent averages from 9 rats at 4.7 T (in 1 rat, CBF could not be measured for technical reasons). For the autoregulated range, CBF reactivity was 0.004±0.001 (mL · g^-1 · min^-1)/mm Hg, which rose to 0.0235±0.003 (mL · g^-1 · min^-1)/mm Hg for MABP below 50 mm Hg. Between 50 and 140 mm Hg, whole-brain CBF in the slice at bregma was 1.27±0.44 mL · g^-1 · min^-1 (59 measurements in 9 rats).

View larger version (24K): [in this window] [in a new window]   Figure 2. Absolute CBF vs MABP (mean±SD, n=9). Linear least-squares fit to the CBF data between 50 to 140 mm Hg is shown.

Because we detected no significant differences between CBV changes in rats studied with MION and MPEG-PL-Dy-DTPA, the results for total and microvascular CBV (Figure 3) were averaged across 9 rats (n=2 at 2 T and n=7 at 4.7 T). CBV changes in striatum, cortex, and bregma slice were similar. Regression analysis of total and microvascular CBV in the entire slice at the bregma over the autoregulated range (50 to 140 mm Hg) showed small but significant positive slopes that were not significantly different from the CBF slope or from each other (Table 2). Despite >2-fold reduction in MABP, no increases in either microvascular or total CBV from baseline were observed in brain parenchyma during CBF autoregulation.

View larger version (44K): [in this window] [in a new window]   Figure 3. Total CBV (•) and microvascular CBV () changes versus MABP in (a) whole brain at the level of bregma, (b) striatum, and (c) cortex and (d) on the cortical rim (mean±SD, n=9). The dashed line is the CBV prediction based on the flow changes when applying the Grubb relationship, V/V0= (F/F0)0.38.31

View this table: [in this window] [in a new window]   Table 2. Linear Correlation of Hemodynamic Parameters During Autoregulation

The Grubb relationship (V/V₀=(F/F₀)^0.38),³¹ shown as the dashed lines in Figure 3, accurately predicted total and microvascular CBV over the autoregulated CBF range. During hypoperfusion, it continued to fit microvascular CBV but underestimated total CBV. Between 10 and 40 mm Hg, small total CBV increases (10%) were seen in striatum, cortex, and the whole-brain slice at bregma, whereas microvascular CBV decreased in these regions (Table 3). On the cortical rim, total CBV increases were greater (+21±18%, P<0.01), whereas microvascular CBV did not change significantly from baseline (+3±22%, P>0.05). For all regions, the change in total CBV was consistently greater than the change in microvascular CBV during mild hypoperfusion, and all CBV changes were smaller than CBF decreases (-47±25%, 0.67±0.42 mL · g^-1 · min^-1). With severe hypotension (<10 mm Hg), total and microvascular CBV fell significantly in all regions, and larger decreases were seen in microvascular than in total CBV (Table 3).

View this table: [in this window] [in a new window]   Table 3. Hemodynamic Changes During Autoregulation and Hypoperfusion

An example in 1 animal of volume-flow mismatch is shown in Figure 4. A large (>50%) CBF decrease between the autoregulation and hypoperfusion range was evident. Total and microvascular CBV changes were much smaller and not immediately evident. In the parenchyma, there was a small increase in total CBV but a small decrease in microvascular CBV. On the cortical surface, total CBV was noticeably increased.

View larger version (107K): [in this window] [in a new window]   Figure 4. a, Spin echo anatomical image and (b) CBF, (c) total CBV, and (d) microvascular CBV measured during successful autoregulation (50 to 140 mm Hg) and the same (e through g) during hypoperfusion (10 to 40 mm Hg), which demonstrated volume-flow mismatch. Although a CBF decrease of about 50% is visually apparent, changes in CBV are not. In this example, total CBV in striatum and cortex increased slightly, whereas microvascular CBV decreased slightly. A larger increase in total CBV was observed on the cortical rim.

Results from the BOLD experiments are shown in Figure 5. Although there was a trend toward increased relaxivity during mild hypoperfusion for both gradient and spin echo BOLD, these changes were not statistically significant (P>0.05). Maximum spin and gradient echo transverse relaxivity increases (R2 and R2*) were +1.0±0.8 s^-1 and +3.4±3.5 s^-1, respectively. For comparison, the average baseline R2 and R2* for the CAPTIVE images were between 4 and 5 s^-1 and 13 and 18 s^-1, respectively; for the MION studies, these same values were 11 s^-1 and 33 s^-1.

View larger version (49K): [in this window] [in a new window]   Figure 5. Changes in R2* (•) and R2 (), ascribed to BOLD contrast, vs MABP in (a) whole brain at the level of bregma, (b) striatum, and (c) cortex and (d) on the cortical rim (mean±SD, n=3). No significant changes from baseline (P>0.05) were observed.

	Discussion

Top Abstract Introduction Materials and Methods Results Discussion References Introduction  References

 
Cerebral Blood Flow
Although ASL techniques for quantitative measurement of CBF look promising in the study of dynamic physiological changes,³² few studies have addressed their quantitative accuracy.^{29 33 34 35} Because both baseline CBF and the range of CBF autoregulation have been well characterized in the rat, we could test the validity of these ASL measurements. The baseline measurement of autoregulated CBF (1.27±0.44 mL · g^-1 · min^-1) is consistent with other studies that use a variety of techniques.^{36 37 38} Below about 50 mm Hg, CBF became highly dependent on MABP, and this lower limit compares well with previous rodent studies.^{39 40 41} These measurements demonstrate that ASL is consistent with more invasive flow methods and confirmed that autoregulation was present in our animal model.

Cerebral Blood Volume
CBV can be determined by both dynamic and steady-state susceptibility contrast MRI.^{42 43} This method cannot measure absolute CBV, but it does permit quantitative evaluation of CBV changes.^{24 25} During CBF autoregulation, we observed the same behavior for both total and microvascular CBV, a positive linear correlation with a slope not significantly different from that for CBF (Figure 3, Table 2). Whether CBV is constant, decreases, or increases as MABP is reduced by hemorrhagic hypotension is controversial. Many studies of CBV during autoregulation have used cranial windows and have consistently shown that pial arterial diameter increases as MABP decreases.^{2 14 15} In a literature review, Powers¹¹ speculated that CBV should increase by 75% as MABP decreases from 120 to 60 mm Hg. Using autoradiographic CBF measurements and tracer kinetic methods to estimate mean transit time, Ferrari et al⁷ measured 100% to 250% increases in CBV on the cortical surface during hemorrhagic hypotension in dogs. These large CBV increases may be specific to the cortical surface, which is known to have a greater proportion of arterial and arteriolar CBV. Also, CBV determined indirectly from transit time and separate autoradiographic CBF measurements during low flow conditions may be inaccurate.^{44 45 46} In the present study, CBV measurements were made in both the deeper structures and on the cortical rim and showed that total CBV increases near the cortical surface were greater than those within the parenchyma (Table 3, Figure 3). The total CBV increase of 21±18% on the cortical rim is still smaller than those of these previous measurements and could possibly reflect the effects of partial volume averaging.

Several earlier studies suggest that parenchymal CBV changes are significantly smaller than those on the cortical surface.^{6 8} Grubb et al⁸ used X-ray fluorescence to measure CBV changes in monkey frontal cortex. They reported that CBV increased linearly by 18% as MABP declined to 35 mm Hg. However, for CBV values obtained between 50 and 140 mm Hg, those data showed no significant CBV changes (P>0.10). Tomita et al⁶ described a method consisting of a subcortical lamp that transilluminated 4 mm of cortex in the cat, which allowed measurement of CBV in tissue consisting of both parenchyma and cortical surface and found that CBV was constant during autoregulation.

Our observation that CBV does not increase during autoregulation appears counterintuitive, because some vessels must vasodilate to decrease CVR. This observation is consistent, however, with flow control by arterioles, which represent only a small fraction of overall CBV. By observing tissue-indicator dilution curves, Tomita et al⁴⁷ estimated the entire arterial fraction of brain CBV to be about 15%. Arterioles (15 to 100 µm), a subset of this small arterial CBV, are estimated to represent <3% to 5% of total CBV.⁴⁸ Therefore, even doubling arteriolar volume without changes in other compartments would cause only a 3% to 7% rise in total CBV and a smaller effect on microvascular CBV.

Accordingly, we modeled the cerebral circulation using active arteriolar resistance elements with zero compliance that are placed proximal to passive capillary and venous compartments with constant resistance and compliance, following conventional windkessel theory.⁴⁹ In this model, which is a simplification of that proposed by Mandeville et al,⁵⁰ CBV in capillaries and veins increases only if the pressure difference across them increases. Arterioles act as flow regulators and adjust resistance to maintain flow, consistent with compelling evidence that smooth muscle–laden arterioles and precapillary sphincters regulate CBF.^{51 52} The ability of arterioles to maintain nearly constant postarteriolar pressure with small volume changes is efficient and especially adaptive in the brain, in which volume changes must be tightly regulated because of the rigid cranium.^{9 52}

In a more complete formulation of this model,⁵⁰ postarteriole resistance must increase as blood volume decreases. This leads to a nonlinear relationship between CBF and CBV in which CBV changes are always smaller. The relationship can be formulated as a power law that depends on the exact assumptions of the model; a reasonable estimate was empirically determined by Grubb³¹ during hypercapnia: V/V₀=(F/F₀)^0.38. The dashed lines in Figure 3 show the expected CBV given by the Grubb formula on the basis of the CBF changes. On the autoregulatory plateau, the Grubb formula appeared valid, in which small CBF decreases were mirrored by even smaller CBV changes. During hypoperfusion, the Grubb relationship was consistent with microvascular CBV changes but significantly underestimated total CBV. The model assumes passive postarteriolar reactivity and neglects CBV contributions from large arteries and veins. Thus, it is not surprising that the model more accurately describes microvascular CBV, which is highly weighted by capillaries, instead of total CBV, which is sensitive to the vasodilation of large arteries and veins.

Like any other method based on an intravascular tracer, the method used in this study assumed constant contrast agent levels. The removal of whole blood and the hemodilution response evoked in the animal could lead to a decrease in plasma contrast agent concentration with time. Because these measurements suggest that CBV does not increase as much as some previous reports suggest, it was important to quantify this potential error. The systemic hematocrit decrease during the experiment was 9%, leading to a contrast agent dilution of 30% to 40%, given the assumption that extravascular tissue water was solely responsible for the hematocrit changes. Because of this large potential error source, we directly measured contrast agent concentration in a subset of animals and found a far smaller decrease (11% to 18%), which was not statistically significant. Although we cannot rule out that these reported CBV changes may be underestimated by 11% to 18% and that small CBV increases could be present during autoregulation, these data argue against large (>100%) parenchymal CBV increases.

Graded Global Hypoperfusion
Once the capacity for autoregulation was exceeded, postarteriolar pressure was no longer maintained, CBF decreased, and extra-arteriolar vasodilatory mechanisms appeared to become active (we observed a small total CBV increase and the uncoupling of total and microvascular CBV from flow). The behavior of CBV within this MABP range, at which mild hypoperfusion gives way to frank ischemia, may illuminate pathophysiological events that occur during carotid occlusive disease and stroke.

Positron emission tomographic studies in humans and primates during the initial 48 hours of stroke have documented relatively mild total CBV changes from -25% to +25%.^{21 53 54 55 56 57} Positron emission tomographic and single-photon emission computed tomographic studies in humans with carotid occlusive disease have indicated 20% to 50% CBV increases, but 20% CBV decreases have been reported in subarachnoid hemorrhage.^{12 58} Tomita et al¹⁶ observed both CBV increases and decreases during the first hour of MCA occlusion in cats. Other experiments suggest that CBV may decrease over time during prolonged ischemia.^{18 19 28} CBV-CBF mismatches have also been noted during early ischemic stroke^{18 19 20 21 59} and during chronic carotid occlusive disease.^{12 20 22 60} The central volume principle states that the total CBV/CBF ratio is equal to the mean transit time⁶¹ ; therefore, CBV increases extend the time available for nutrient exchange. Accordingly, preserved CBV with low CBF may be an appropriate response to low perfusion pressure that would enhance the potential for oxygen extraction.^{11 20}

During hypoperfusion, we observed a small increase in total CBV, which supports previous evidence that flow decreases before maximal vasodilation is achieved.¹¹ Because flow decreased with MABP in this range, volume-flow mismatch (preserved volume in the setting of low flow) was an essential feature of early global hypoperfusion. Gibbs et al²¹ have suggested that the CBF/CBV ratio (the inverse of the classic mean transit time) is a marker of perfusion pressure. In contrast, our data suggest that the CBF/total CBV ratio and the CBF/microvascular CBV ratio do not change significantly over the autoregulatory range. However, if perfusion pressure is taken to signify capillary perfusion pressure, our results are concordant, because we hypothesize that both the postarteriolar pressure and the CBF/CBV ratio are held constant during autoregulation. Once CBF decreased, both the CBF/total CBV and the CBF/microvascular CBV ratios were highly correlated with MABP, but this was due to a large CBF decrease coupled with smaller CBV changes. The possibility that chronic changes in the CBF/CBV ratio occur in the setting of preserved flow could not be tested directly by this study.

Microvascular Versus Total CBV Changes During Hypoperfusion
According to nuclear magnetic resonance theory, gradient echo measurements reflect total CBV, whereas spin echo images are primarily sensitive to microvascular CBV.^{23 26 27 62} Østergaard et al,⁶³ by applying a quantitative approach to dynamic spin echo MRI, demonstrated that spin echo CBV measurements reflect a relative volume that is 40% of total CBV measured by positron emission tomography, consistent with estimates of small-vessel volume fraction in the brain.⁶⁴ CBV maps made with spin and gradient echo sequences have reported differences between the vascular structure in normal brain and in tumors, in which large disorganized vessels result from angiogenesis.⁶⁵

We ascribe differences between total and microvascular CBV during hypoperfusion to large-vessel vasodilation once the autoregulatory capacity of arterioles is exhausted, given that the Grubb formula appears to predict microvascular CBV but not total CBV changes (see dashed lines in Figure 3). One limitation of the MRI technique is that it cannot distinguish arteries from veins, both of which are capable of active vasodilation.^{14 15 66} Because veins make up a greater fraction of baseline total CBV, the total CBV changes we observed were likely to have been due to venous vasodilation. If so, this behavior is consistent with the low-pressure hyperemia state identified by Tomita et al.¹⁶

Microvascular CBV may be particularly sensitive to changes that occur in the capillary bed during ischemia. We observed differences between microvascular and total CBV in the parenchyma only during hypoperfusion (P<0.01, Table 3). Theoretically, >95% of the microvascular CBV signal arises from vessels with sizes between 4 and 30 µm.⁶² Because this largely comprises the capillary bed, which has no smooth muscle and faces a progressive decrease in perfusion pressure, it is not surprising that vasodilation is absent. Decreases in the diameters of distal cortical vessels have been noted during reduction of MABP.⁶⁷ Microvascular CBV may thus be a more direct indicator of capillary perfusion and tissue viability than total CBV, which includes both arterial and venous effects.

BOLD Changes
Because deoxyhemoglobin is paramagnetic⁶⁸ and acts as a weak contrast agent, changes in deoxyhemoglobin content affect transverse relaxivity rates and thus form the basis of BOLD contrast.^{69 70} Therefore, we examined the possibility that our CBV measurements, also based on transverse relaxivity changes, might be affected by BOLD. Such transverse relaxivity changes were found to be roughly an order of magnitude smaller than those observed during the measurement of CBV with exogenous contrast agents. Because BOLD consists of intravascular and extravascular components, the contrast agent is likely to further mitigate possible BOLD errors in the CBV measurement by eliminating the intravascular contribution. Small BOLD effects during autoregulation are consistent with the findings of small CBF and total CBV changes, given constant oxygen consumption.

Particularly significant for functional MRI studies is that our data showed only minor changes in CBV or BOLD signal during a factor–of-2 reduction in MABP from 140 to 70 mm Hg. Functional MRI is now being applied to stimuli that alter blood pressure, such as pharmacological challenges using BOLD^{71 72 73} and CBV.²⁴ In these studies, BOLD and CBV changes were found to be temporally not correlated with MABP. The data presented in this study strengthen the hypothesis that these hemodynamic markers can be used to infer neuronal activity even in the presence of systemic blood pressure changes.

Conclusions
Measurement of CBF, total CBV, and microvascular CBV changes with MRI during autoregulation and graded global hypoperfusion in the same animal is a powerful method for the study of cerebral hemodynamics. These measurements support the extant literature on CBF autoregulation but challenge existing notions of CBV reactivity. As a result of possible decreases in the plasma contrast agent concentration, we could not rule out small CBV increases of 10% to 20%; however, our results support the concept that CBV changes during hemorrhagic hypotension are far less than the 75% to 250% changes reported by some previous studies. Intriguing differences between total and microvascular CBV that implicated large-vessel vasodilation were seen during graded global hypoperfusion. CBV-CBF mismatch was an essential component of early global hypoperfusion. Such observations support incidental observations during acute ischemia and may have significant implications for understanding the temporal evolution and underlying relevance of tissue hemodynamic measurements during stroke.

	Acknowledgments

 
This work was supported by the following NIH grants: RO1-HL39810, RO1-NS35258-01, 5 PO1-DA09467, and 2 PO1-CA48729. We extend our thanks to Dr Michael A. Moskowitz for valuable technical discussions and encouragement.

Received June 22, 1999; accepted July 29, 1999.

	References

Top Abstract Introduction Materials and Methods Results Discussion References Introduction  References

 
1. Roy CS, Sherrington CS. On the regulation of the blood-supply of the brain. J Physiol (Lond).. 1890;11:85–108.

2. Forbes HS. The cerebral circulation, I: observation and measurement of pial vessels. Arch Neurol Psych.. 1928;19:751–761.

3. Dumke PR, Schmidt CF. Quantitative measurements of cerebral blood flow in the macaque monkey. Am J Physiol.. 1942;138:421–431.

4. Lassen NA. Autoregulation of cerebral blood flow. Circ Res. 1964;15(suppl I):I-201—I-204.

5. Rapela CF, Green HD. Autoregulation of cerebral blood flow. Circ Res. 1964;15(suppl I):I-205—I-211.

6. Tomita M, Gotoh F, Sato T, Amano, Tanahashi TN, Tanaka K, Yamamoto M. Photoelectric method for estimating hemodynamic changes in regional cerebral tissue. Am J Physiol.. 1978;235:H56–H63.

7. Ferrari M, Wilson DA, Hanley DF, Traystman RJ. Effects of graded hypotension on cerebral blood flow, blood volume, and mean transit time. Am J Physiol.. 1992;262:H1908–H1914.[Abstract/Free Full Text]

8. Grubb RL, Phelps ME, Raichle ME, Ter-Pogossian MM. The effects of arterial blood pressure on the regional cerebral blood volume by X-ray fluorescence. Stroke.. 1973;4:390–399.[Abstract/Free Full Text]

9. Bayliss WM, Hill L. On intra-cranial pressure and the cerebral circulation, part I. J Physiol (Lond).. 1895;18:334–360.

10. Ursino M, di Gianmarco P. A mathematical model of the relationship between cerebral blood volume and intracranial pressure changes: the generation of plateau waves. Ann Biomed Eng.. 1991;19:15–42.[Medline] [Order article via Infotrieve]

11. Powers WJ. Cerebral hemodynamics in ischemic cerebrovascular disease. Ann Neurol.. 1991;29:231–240.[Medline] [Order article via Infotrieve]

12. Knapp WH, von Kummer R, Kübler W. Imaging of cerebral blood flow-to-volume distribution using SPECT. J Nucl Med.. 1986;27:465–470.[Abstract/Free Full Text]

13. Fog M. Cerebral circulation: the reaction of the pial arteries to a fall in blood pressure. J Neurol Psych.. 1938;1:187–197.

14. Kontos HA, Wei EP, Navari RM, Levasseur JE, Rosenblum WI, Patterson JL. Responses of cerebral arteries and arterioles to acute hypotension and hypertension. Am J Physiol.. 1978;243:H371–H383.

15. Auer LM, Ishiyama N, Pucher R. Cerebrovascular response to intracranial hypertension. Acta Neurochir.. 1987;84:124–128.[Medline] [Order article via Infotrieve]

16. Tomita M, Gotoh F, Amano T, Tanahasi N, Tanaka K. "Low perfusion hyperemia" following middle cerebral artery occlusion in cats of different age groups. Stroke.. 1980;11:629–636.[Abstract/Free Full Text]

17. Hamberg LM, Boccalini P, Stranjalis G, Hunter GJ, Huang Z, Halpern E, Weisskoff RM, Moskowitz MA, Rosen BR. Continuous assessment of relative cerebral blood volume in transient ischemia using steady state susceptibility contrast MRI. Magn Reson Med.. 1996;35:168–173.[Medline] [Order article via Infotrieve]

18. Dijkhuizen RM, Berkelbach van der Sprenkel JW, Tulleken KAF, Nicolay K. Regional assessment of tissue oxygenation and the temporal evolution of hemodynamic parameters and water diffusion during acute focal ischemia in rat brain. Brain Res.. 1997;750:161–170.[Medline] [Order article via Infotrieve]

19. Caramia F, Huang Z, Hamberg LM, Weisskoff RM, Zaharchuk G, Moskowitz MA, Cavagna FM, Rosen BR. Mismatch between cerebral blood volume and flow index during transient focal ischemia studied with MRI and Gd-BOPTA. Magn Reson Imaging.. 1998;16:97–103.[Medline] [Order article via Infotrieve]

20. Sette G, Baron J, Mazoyer B, Levasseur M, Pappata S, Crouzel C. Local brain haemodynamics and oxygen metabolism in cerebrovascular disease. Brain.. 1989;112:931–951.[Abstract/Free Full Text]

21. Gibbs JM, Wise RJS, Leenders KL, Jones T. Evaluation of cerebral perfusion reserve in patients with carotid-artery occlusion. Lancet. 1984;i:310–314.

22. Toyama H, Takeshita G, Takeuchi A, Anno H, Ejiri K, Maeda H, Katada K, Koga S, Ishiyama N, Kanno T, Yamaoka N. Cerebral hemodynamics in patients with chronic obstructive carotid artery disease by rCBF, rCBV, and rCBV/rCBF ratio using SPECT. J Nucl Med.. 1989;31:55–60.[Abstract/Free Full Text]

23. Rosen BR, Belliveau JW, Buchbinder BR, McKinstry RC, Porkka LM, Kennedy DN, Neuder MS, Fisel CR, Aronen HJ, Kwong KK, Weisskoff RM, Cohen MS, Brady TJ. Contrast agents and cerebral hemodynamics. Magn Reson Med.. 1991;19:285–292.[Medline] [Order article via Infotrieve]

24. Mandeville JB, Marota JJA, Kosofsky BE, Keltner JR, Weissleder R, Rosen BR, Weisskoff RM. Dynamic functional imaging of relative cerebral blood volume during rat forepaw stimulation. Magn Reson Med.. 1998;39:615–624.[Medline] [Order article via Infotrieve]

25. Payen J-F, Väth A, Koenigsberg B, Bourlier V, Decorps M. Regional cerebral plasma volume response to carbon dioxide using magnetic resonance imaging. Anesthesiology.. 1998;88:984–992.[Medline] [Order article via Infotrieve]

26. Fisel CR, Ackerman JL, Buxton RB, Garrido L, Belliveau JW, Rosen BR, Brady TJ. MR contrast due to microscopically heterogeneous magnetic susceptibility: numerical simulations and applications to cerebral physiology. Magn Reson Med.. 1991;17:336–347.[Medline] [Order article via Infotrieve]

27. Weisskoff RM, Zuo CS, Boxerman JL, Rosen BR. Microscopic susceptibility variation and transverse relaxation: theory and experiment. Magn Reson Med.. 1994;31:601–610.[Medline] [Order article via Infotrieve]

28. Zaharchuk G, Bogdanov AA Jr, Marota JJA, Shimizu-Sasamata M, Weisskoff RM, Kwong KK, Jenkins BG, Weissleder R, Rosen BR. Continuous assessment of perfusion by tagging including volume and water extraction (CAPTIVE): a steady-state contrast agent techniques for measuring blood flow, relative blood volume fraction, and the water extraction fraction. Magn Reson Med.. 1998;40:666–678.[Medline] [Order article via Infotrieve]

29. Alsop DC, Detre JA. Reduced transit time sensitivity in noninvasive magnetic resonance imaging of human cerebral blood flow. J Cereb Blood Flow Metab.. 1996;16:1236–1249.[Medline] [Order article via Infotrieve]

30. Iida H, Kanno I, Miura S, Murakami M, Takahashi K, Uemura K. A determination of the regional brain/blood partition coefficient of water using dynamic positron emission tomography. J Cereb Blood Flow Metab.. 1989;9:874–885.[Medline] [Order article via Infotrieve]

31. Grubb RL, Raichle ME, Eichling JO, Ter-Pogossian MM. The effects of changes in PaCO2 on cerebral blood volume, blood flow, and vascular mean transit time. Stroke.. 1974;5:630–639.[Abstract/Free Full Text]

32. Detre JA, Leigh JS, Williams DS, Koretsky AP. Perfusion imaging. Magn Reson Med.. 1992;23:37–45.[Medline] [Order article via Infotrieve]

33. Walsh EG, Minematsu K, Leppo J, Moore SC. Radioactive microsphere validation of a volume localized continuous saturation perfusion measurement. Magn Reson Med.. 1994;31:147–153.[Medline] [Order article via Infotrieve]

34. Ye FQ, Mattay VS, Jezzard P, Frank JA, Weinberger DR, McLaughlin AC. Correction for vascular artifacts in cerebral blood flow values measured by using arterial spin tagging techniques. Magn Reson Med.. 1997;37:226–235.[Medline] [Order article via Infotrieve]

35. Tsekos NV, Zhang F, Merkle H, Nagayama M, Iadecola C, Kim S-G. Quantitative measurements of cerebral blood flow in rats using the FAIR technique: correlation with previous iodoantipyrine studies. Magn Reson Med.. 1998;39:564–573.[Medline] [Order article via Infotrieve]

36. Hoffman W. Regional cerebral blood flow measurement in rats with radioactive microspheres. Life Sci.. 1983;33:1075–1080.[Medline] [Order article via Infotrieve]

37. Nagasawa H, Kogure K. Correlation between cerebral blood flow and histologic changes in a new rat model of middle cerebral artery occlusion. Stroke.. 1989;20:1037–1043.[Abstract/Free Full Text]

38. Tsuchidate R, He Q-P, Smith M-L, Siesjö BK. Regional cerebral blood flow during and after 2 hrs of middle cerebral artery occlusion in the rat. J Cereb Blood Flow Metab.. 1997;17:1066–1073.[Medline] [Order article via Infotrieve]

39. Dirnagl U, Pulsinelli W. Autoregulation of cerebral blood flow in experimental focal brain ischemia. J Cereb Blood Flow Metab.. 1990;10:327–336.[Medline] [Order article via Infotrieve]

40. Verhaegen MJ, Todd MM, Hindman BJ, Warner TS. Cerebral autoregulation in moderate hypothermia in rats. Stroke.. 1993;24:407–414.[Abstract/Free Full Text]

41. Dalkara T, Irikura K, Huang Z, Panahian N, Moskowitz MA. Cerebrovascular responses under controlled and monitored physiological conditions in the anesthetized mouse. J Cereb Blood Flow Metab.. 1995;15:631–638.[Medline] [Order article via Infotrieve]

42. Villringer A, Rosen BR, Belliveau JW, Ackerman JL, Lauffer RB, Buxton RB, Chao Y, Wedeen VJ, Brady TJ. Dynamic imaging with lanthanide chelates in normal brain: contrast due to magnetic susceptibility effects. Magn Reson Med.. 1988;6:164–174.[Medline] [Order article via Infotrieve]

43. Rosen BR, Belliveau JW, Vevea JM, Brady TJ. Perfusion imaging with NMR contrast agents. Magn Reson Med.. 1990;14:249–265.[Medline] [Order article via Infotrieve]

44. Zierler KL. Equations for measuring blood flow by external monitoring of radioisotopes. Circ Res.. 1965;16:309–321.[Abstract/Free Full Text]

45. Lassen NA. Cerebral transit of an intravascular tracer may allow measurement of regional blood volume but not regional blood flow. J Cereb Blood Flow Metab.. 1984;4:633–634.[Medline] [Order article via Infotrieve]

46. Weisskoff RM, Chesler DA, Boxerman JL, Rosen BR. Pitfalls in MR measurements of tissue blood flow with intravascular tracers: which mean transit time? Magn Reson Med.. 1993;29:553–559.[Medline] [Order article via Infotrieve]

47. Tomita M, Gotoh F, Amano T. Transfer function through regional cerebral cortex evaluated by a photoelectric method. Am J Physiol.. 1983;245:H385–H398.

48. Berne RM, Levy MN. Cardiovascular Physiology. St Louis, Mo: Mosby-Year Book; 1992.

49. Frank O. Die Grundform des arteriellen Pulses. Zeit Biol.. 1899;85:91–130.

50. Mandeville JB, Marota JJ, Ayata C, Zaharchuk G, Moskowitz MA, Rosen BR, Weisskoff RM. Evidence of a cerebrovascular post-arteriole windkessel with delayed compliance. J Cereb Blood Flow Metab.. 1999;19:679–689.[Medline] [Order article via Infotrieve]

51. Zweifach WB. Quantitative studies of microcirculatory structure and function. Circ Res.. 1974;34:834–866.

52. Mchedlishvili GI. Arterial Behavior and Blood Circulation in the Brain. New York, NY: Plenum Press; 1986.

53. Pozzilli C, Itoh M, Matsuzawa T, Fukuda H, Abe Y, Sato T, Takeda S, Ido T. Positron emission tomography in minor ischemic stroke using oxygen-15 steady-state technique. J Cereb Blood Flow Metab.. 1986;7:127–142.

54. Heiss W-D, Huber M, Fink G, Herholz K, Pietrzyk U, Wagner R, Wienhard K. Progressive derangement of peri-infarct viable tissue in ischemic stroke. J Cereb Blood Flow Metab.. 1992;12:193–203.[Medline] [Order article via Infotrieve]

55. Furlan M, Marchal G, Viader F, Derlon J-M, Baron J-C. Spontaneous neurological recovery after stroke and the fate of the ischemic penumbra. Ann Neurol.. 1996;40:216–226.[Medline] [Order article via Infotrieve]

56. Pappata S, Fiorelli M, Rommel T, Hartmann A, Dettmers C, Yamaguchi T, Chabriat H, Poline JB, Crouzel C, di Giamberardino L, Baron JC. PET study of changes in local brain hemodynamics and oxygen metabolism after unilateral middle cerebral artery occlusion in baboons. J Cereb Blood Flow Metab.. 1992;13:416–424.

57. Powers WJ, Grubb RL Jr, Darriet D, Raichle ME. Cerebral blood flow and cerebral metabolic rate of oxygen requirements for cerebral function and viability in humans. J Cereb Blood Flow Metab.. 1985;5:600–608.[Medline] [Order article via Infotrieve]

58. Yundt KD, Grubb RL, Diringer MN, Powers WJ. Autoregulatory vasodilation of parenchymal vessels is impaired during cerebral vasospasm. J Cereb Blood Flow Metab.. 1998;18:419–424.[Medline] [Order article via Infotrieve]

59. Powers WJ, Grubb RL, Raichle ME. Physiological responses to focal cerebral ischemia in humans. Ann Neurol.. 1984;16:546–552.[Medline] [Order article via Infotrieve]

60. Powers WJ, Fox PT, Raichle ME. The effect of carotid artery disease on the cerebrovascular response to physiologic stimulation. Neurology. 1988;38:1475–1478.[Abstract/Free Full Text]

61. Stewart GN. Researches on the circulation time in organs and on the influences which affect it, parts I-III. J Physiol (Lond).. 1894;15:1.

62. Boxerman JL, Hamberg LM, Rosen BR, Weisskoff RM. MR contrast due to intravascular magnetic susceptibility perturbations. Magn Reson Med.. 1995;34:555–566.[Medline] [Order article via Infotrieve]

63. Østergaard L, Smith DF, Vestergaard-Poulsen P, Hansen SB, Gee AD, Gjedde A, Gyldensted C. Absolute cerebral blood flow and blood volume measured by magnetic resonance imaging bolus tracking: comparison with positron emission tomography values. J Cereb Blood Flow Metab.. 1998;18:425–432.[Medline] [Order article via Infotrieve]

64. Pawlik G, Rackl A, Bing RJ. Quantitative capillary topography and blood flow in the cerebral cortex of cats: an in vivo microscopic study. Brain Res.. 1981;208:35–58.[Medline] [Order article via Infotrieve]

65. Dennie J, Mandeville JB, Boxerman JL, Packard SD, Rosen BR, Weisskoff RM. NMR imaging of changes in vascular morphology due to tumor angiogenesis. Magn Reson Med.. 1998;40:793–799.[Medline] [Order article via Infotrieve]

66. Tomita M. Significance of cerebral blood volume. In: Tomita M, Sawata T, Naritomi H, Heiss W-D, eds. Cerebral Hyperemia and Ischemia: From the Standpoint of Cerebral Blood Volume. Amsterdam, Netherlands: Excerpta Medica; 1988:3–31.

67. Hunziker O, Emmenegger H, Frey H. Morphometric characterization of the capillary network in the cat's brain cortex: a comparison of the physiological state and hypovolemic conditions. Acta Neuropathol (Berl).. 1974;29:57–63.[Medline] [Order article via Infotrieve]

68. Pauling L, Coryell CD. The magnetic properties and structure of hemoglobin, oxyhemoglobin, and carbonmonoxyhemoglobin. Proc Natl Acad Sci U S A.. 1936;22:210–216.[Free Full Text]

69. Thulborn KR, Waterton JC, Matthews PM, Radda GK. Oxygenation dependence of the transverse relaxation time of water protons in whole blood at high field. Biochim Biophys Acta.. 1982;714:265–270.[Medline] [Order article via Infotrieve]

70. Ogawa S, Lee TM, Nayak AS, Glynn P. Oxygenation-sensitive contrast in magnetic resonance image of rodent brain at high magnetic fields. Magn Reson Med.. 1990;14:68–78.[Medline] [Order article via Infotrieve]

71. Breiter HC, Gollub RL, Weisskoff RM, Kennedy DN, Makris N, Berke JD, Goodman JM, Kantor HL, Gastfriend DR, Riorden JP, Mathew RT, Rosen BR, Hyman SE. Acute effects of cocaine on human brain activity and emotion. Neuron.. 1997;19:591–611.[Medline] [Order article via Infotrieve]

72. Stein E, Pankiewicz J, Harsch H, Cho J, Fuller S, Hoffmann R, Hawkins M, Rao S, Bandettini P, Bloom A. Nicotine-induced limbic cortical activation in the human brain: a functional MRI study. Am J Psych.. 1998;155:1009–1015.[Abstract/Free Full Text]

73. Chen YI, Galpern WR, Brownell A-L, Matthews RT, Bogdanov M, Isacson O, Keltner JR, Beal MF, Rosen BR, Jenkins BG. Detection of dopaminergic neurotransmitter activity using pharmacological MRI: correlation with PET, microdialysis, and behavioral data. Magn Reson Med.. 1997;37:389–398.

Editorial Comment

An MRI Study of CBF and Changes in Total and Microvascular Cerebral Blood Volume During Hemorrhagic Hypotension

Costantino Iadecola, MD, Guest Editor Seong-Gi Kim, PhD, Guest Editor

Laboratory of Cerebrovascular Biology and Stroke, Department of Neurology, Center for Magnetic Resonance Research, University of Minnesota, Minneapolis, Minnesota

	Introduction

Top Abstract Introduction Materials and Methods Results Discussion References Introduction  References

 
The accompanying article investigates the cerebrovascular effects of hypotension using magnetic resonance imaging-based techniques to measure CBF and CBV in anesthetized rats. CBV was measured after intravenous injection of a long-lasting contrast agent. Using gradient and spin-echo imaging, the authors were able to discriminate between total and microvascular CBV. As anticipated, CBF changed little with hypotension up to arterial pressure (AP) of 60 mm Hg, reflecting the presence of cerebrovascular autoregulation. Below 60 mm Hg, CBF decreased passively with the reduction in AP, which suggests that the autoregulatory capacity of the cerebrovascular bed was exceeded. Unlike CBF, total CBV increased when AP was reduced in the autoregulated range, whereas microvascular CBV did not change. Assuming that changes in CBV reflect corresponding changes in vascular diameter, these observations suggest that cerebral autoregulatory adjustments during hypotension occur predominantly in larger vessels, presumably, on the arterial side of the vascular tree. These important, albeit indirect, observations provide additional evidence that pial arterioles play a critical role in CBF regulation. Furthermore, they underscore the power of MRI-based techniques to monitor, in a virtually noninvasive manner, the intimate hemodynamic changes occurring in the cerebral circulation.

Also of interest is the observation that the BOLD signal did not change during hypotension, despite changes in CBF and CBV. The BOLD contrast is thought to reflect a decrease in deoxyhemoglobin that occurs in cerebral blood vessels when cerebral perfusion increases, and is related to several parameters, including oxygen consumption, blood volume, blood flow, and arterial hematocrit.¹ BOLD changes are commonly used to map brain function with MRI.² The findings of the present study have two important implications for studies using BOLD. First, they stress that BOLD changes cannot be assumed to reflect accurately CBF changes in all physiological conditions. This applies especially to situations in which CBV changes concomitantly with CBF. Therefore, caution should be exerted when BOLD is used as an index of CBF. Second, because changes in AP do not influence the BOLD signal, it is possible that BOLD could be used to accurately monitor brain function, even in experimental settings in which AP changes. However, in view of the change in hematocrit observed here during hypotension, this latter possibility needs to be tested experimentally.

The present study was performed with halothane anesthesia. Halothane, at certain concentrations, produces vasodilation and alters cerebrovascular autoregulation.³ However, in this study autoregulation was preserved, which suggests that the concentration of halothane used was not sufficient to produce major cerebrovascular effects. Nevertheless, it would be desirable to test the effect of other anesthetics on segmental CBV during hypotension. Furthermore, it would be of interest to investigate the upper limit of autoregulation in order to determine whether the hemodynamic changes associated with hypertension follow a similar model. Studies addressing these issues would be an important extension of the excellent work described in this article.

Received June 22, 1999; accepted July 29, 1999.

	References

Top Abstract Introduction Materials and Methods Results Discussion References Introduction  References

 
1. Ogawa S, Menon RS, Tank DW, Kim SG, Merkle H, Ellermann JM, Ugurbil K. Functional brain mapping by blood oxygenation level-dependent contrast magnetic resonance imaging: a comparison of signal characteristics with a biophysical model. Biophys J.. 1993;64:803–812.[Medline] [Order article via Infotrieve]

2. Raichle ME. Behind the scenes of functional brain imaging: a historical and physiological perspective. Proc Natl Acad Sci U S A.. 1998;95:765–772.[Abstract/Free Full Text]

3. Shapiro HM. Anesthesia effects upon cerebral blood flow, cerebral metabolism, electroencephalogram and evoked potentials. In: Miller RD, ed. Anesthesia. New York, NY: Churchill Livingstone; 1986:1249–1288.

This article has been cited by other articles:

				G. Zaharchuk Theoretical Basis of Hemodynamic MR Imaging Techniques to Measure Cerebral Blood Volume, Cerebral Blood Flow, and Permeability AJNR Am. J. Neuroradiol., November 1, 2007; 28(10): 1850 - 1858. [Abstract] [Full Text] [PDF]

				J. Lilja, T. Endo, C. Hofstetter, E. Westman, J. Young, L. Olson, and C. Spenger Blood oxygenation level-dependent visualization of synaptic relay stations of sensory pathways along the neuroaxis in response to graded sensory stimulation of a limb. J. Neurosci., June 7, 2006; 26(23): 6330 - 6336. [Abstract] [Full Text] [PDF]

				B. G. Jenkins, R. Sanchez-Pernaute, A.-L. Brownell, Y.-C. I. Chen, and O. Isacson Mapping Dopamine Function in Primates Using Pharmacologic Magnetic Resonance Imaging J. Neurosci., October 27, 2004; 24(43): 9553 - 9560. [Abstract] [Full Text] [PDF]

				K. A. Witt, K. S. Mark, S. Hom, and T. P. Davis Effects of hypoxia-reoxygenation on rat blood-brain barrier permeability and tight junctional protein expression Am J Physiol Heart Circ Physiol, December 1, 2003; 285(6): H2820 - H2831. [Abstract] [Full Text] [PDF]

				C. P Derdeyn Cerebral Hemodynamics in Carotid Occlusive Disease AJNR Am. J. Neuroradiol., September 1, 2003; 24(8): 1497 - 1499. [Full Text] [PDF]

				H. Okazawa, H. Yamauchi, K. Sugimoto, and M. Takahashi Differences in Vasodilatory Capacity and Changes in Cerebral Blood Flow Induced by Acetazolamide in Patients with Cerebrovascular Disease J. Nucl. Med., September 1, 2003; 44(9): 1371 - 1378. [Abstract] [Full Text] [PDF]

				R. M. Harper, P. M. Macey, L. A. Henderson, M. A. Woo, K. E. Macey, R. C. Frysinger, J. R. Alger, K. P. Nguyen, and F. L. Yan-Go fMRI responses to cold pressor challenges in control and obstructive sleep apnea subjects J Appl Physiol, April 1, 2003; 94(4): 1583 - 1595. [Abstract] [Full Text] [PDF]

				V. S. Caviness, N. Makris, E. Montinaro, N. T. Sahin, J. F. Bates, L. Schwamm, D. Caplan, and D. N. Kennedy Anatomy of Stroke, Part II: Volumetric Characteristics With Implications for the Local Architecture of the Cerebral Perfusion System Stroke, November 1, 2002; 33(11): 2557 - 2564. [Abstract] [Full Text] [PDF]

				C. P. Derdeyn, T. O. Videen, K. D. Yundt, S. M. Fritsch, D. A. Carpenter, R. L. Grubb, and W. J. Powers Variability of cerebral blood volume and oxygen extraction: stages of cerebral haemodynamic impairment revisited Brain, March 1, 2002; 125(3): 595 - 607. [Abstract] [Full Text] [PDF]

				L. A. Henderson, P. L. Yu, R. C. Frysinger, J.-P. Galons, R. Bandler, and R. M. Harper Neural responses to intravenous serotonin revealed by functional magnetic resonance imaging J Appl Physiol, January 1, 2002; 92(1): 331 - 342. [Abstract] [Full Text] [PDF]

				L. Rohl, L. Ostergaard, C. Z. Simonsen, P. Vestergaard-Poulsen, G. Andersen, M. Sakoh, D. Le Bihan, and C. Gyldensted Viability Thresholds of Ischemic Penumbra of Hyperacute Stroke Defined by Perfusion-Weighted MRI and Apparent Diffusion Coefficient Stroke, May 1, 2001; 32(5): 1140 - 1146. [Abstract] [Full Text] [PDF]

				J. Takada, S. Ibayashi, T. Nagao, H. Ooboshi, T. Kitazono, and M. Fujishima Bradykinin Mediates the Acute Effect of an Angiotensin-Converting Enzyme Inhibitor on Cerebral Autoregulation in Rats Stroke, May 1, 2001; 32(5): 1216 - 1219. [Abstract] [Full Text] [PDF]

				J. D. Huber, K. A. Witt, S. Hom, R. D. Egleton, K. S. Mark, and T. P. Davis Inflammatory pain alters blood-brain barrier permeability and tight junctional protein expression Am J Physiol Heart Circ Physiol, March 1, 2001; 280(3): H1241 - H1248. [Abstract] [Full Text] [PDF]

This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Zaharchuk, G. Articles by Kim, S.-G. Search for Related Content PubMed PubMed Citation Articles by Zaharchuk, G. Articles by Kim, S.-G. Related Collections Animal models of human disease Brain Circulation and Metabolism Computerized tomography and Magnetic Resonance Imaging Pathology of Stroke