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Quantitative measurements of cerebral blood oxygen saturation using magnetic resonance imaging.

A quantitative estimate of cerebral blood oxygen saturation is of critical importance in the investigation of cerebrovascular disease because of the fact that it could potentially provide information on tissue viability in vivo. In the current study, a multi-echo gradient and spin echo magnetic resonance imaging sequence was used to acquire images from eight normal volunteer subjects. All images were acquired on a Siemens 1.5T Symphony whole-body scanner (Siemens, Erlangen, Germany). A theoretical signal model, which describes the signal dephasing phenomena in the presence of deoxyhemoglobin, was used for postprocessing of the acquired images and obtaining a quantitative measurement of cerebral blood oxygen saturation in vivo. With a region-of-interest analysis, a mean cerebral blood oxygen saturation of 58.4%+/-1.8% was obtained in the brain parenchyma from all volunteers. It is in excellent agreement with the known cerebral blood oxygen saturation under normal physiologic conditions in humans. Although further studies are needed to overcome some of the confounding factors affecting the estimates of cerebral blood oxygen saturation, these preliminary results are encouraging and should open a new avenue for the noninvasive investigation of cerebral oxygen metabolism under different pathophysiologic conditions using a magnetic resonance imaging approach.

Cerebrovascular Circulation↗

Quantitation of regional cerebral blood flow corrected for partial volume effect using O-15 water and PET: I. Theory, error analysis, and stereologic comparison.

Limited spatial resolution of positron emission tomography (PET) can cause significant underestimation in the observed regional radioactivity concentration (so-called partial volume effect or PVE) resulting in systematic errors in estimating quantitative physiologic parameters. The authors have formulated four mathematical models that describe the dynamic behavior of a freely diffusible tracer (H215O) in a region of interest (ROI) incorporating estimates of regional tissue flow that are independent of PVE. The current study was intended to evaluate the feasibility of these models and to establish a methodology to accurately quantify regional cerebral blood flow (CBF) corrected for PVE in cortical gray matter regions. Five monkeys were studied with PET after IV H2(15)O two times (n = 3) or three times (n = 2) in a row. Two ROIs were drawn on structural magnetic resonance imaging (MRI) scans and projected onto the PET images in which regional CBF values and the water perfusable tissue fraction for the cortical gray matter tissue (hence the volume of gray matter) were estimated. After the PET study, the animals were killed and stereologic analysis was performed to assess the gray matter mass in the corresponding ROIs. Reproducibility of the estimated parameters and sensitivity to various error sources were also evaluated. All models tested in the current study yielded PVE-corrected regional CBF values (approximately 0.8 mL x min(-1) x g(-1) for models with a term for gray matter tissue and 0.5 mL x min(-1) x g(-1) for models with a term for a mixture of gray matter and white matter tissues). These values were greater than those obtained from ROIs tracing the gray matter cortex using conventional H2(15)O autoradiography (approximately 0.40 mL x min(-1) x g(-1)). Among the four models, configurations that included two parallel tissue compartments demonstrated better results with regards to the agreement of tissue time-activity curve and the Akaike's Information Criteria. Error sensitivity analysis suggested the model that fits three parameters of the gray matter CBF, the gray matter fraction, and the white matter fraction with fixed white matter CBF as the most reliable and suitable for estimating the gray matter CBF. Reproducibility with this model was 11% for estimating the gray matter CBF. The volume of gray matter tissue can also be estimated using this model and was significantly correlated with the results from the stereologic analysis. However, values were significantly smaller compared with those measured by stereologic analysis by 40%, which can not be explained by the methodologic errors. In conclusion, the partial volume correction was essential in quantitation of regional CBF. The method presented in this article provided the PVE-corrected regional CBF in the cortical gray matter tissue. This study also suggests that further studies are required before using MRI derived anatomic information for PVE correction in PET.

Animals↗

Quantitation of regional cerebral blood flow corrected for partial volume effect using O-15 water and PET: II. Normal values and gray matter blood flow response to visual activation.

One of the most limiting factors for the accurate quantification of physiologic parameters with positron emission tomography (PET) is the partial volume effect (PVE). To assess the magnitude of this contribution to the measurement of regional cerebral blood flow (rCBF), the authors have formulated four kinetic models each including a parameter defining the perfusable tissue fraction (PTF). The four kinetic models used were 2 one-tissue compartment models with (Model A) and without (Model B) a vascular term and 2 two-tissue compartment models with fixed (Model C) or variable (Model D) white matter flow. Furthermore, rCBF based on the autoradiographic method was measured. The goals of the study were to determine the following in normal humans: (1) the optimal model, (2) the optimal length of fit, (3) the model parameters and their reproducibility, and (4) the effects of data acquisition (2D or 3D). Furthermore, the authors wanted to measure the activation response in the occipital gray matter compartment, and in doing so test the stability of the PTF, during perturbations of rCBF induced by visual stimulation. Eight dynamic PET scans were acquired per subject (n = 8), each for a duration of 6 minutes after IV bolus injection of H2(15)O. Four of these scans were performed using 2D and four using 3D acquisition. Visual stimulation was presented in four scans, and four scans were during rest. Model C was found optimal based on Akaike's Information Criteria (AIC) and had the smallest coefficient of variance after a 6-minute length of fit. Using this model the average PVE corrected rCBF during rest in gray matter was 1.07 mL x min(-1) x g(-1) (0.11 SD), with an average coefficient of variance of 6%. Acquisition mode did not affect the estimated parameters, with the exception of a significant increase in the white matter rCBF using the autoradiographic method (2D: 0.17 mL x min(-1) x g(-1) (0.02 SD); 3D: 0.21 mL x min(-1) x g(-1) (0.02 SD)). At a 6-minute fit the average gray matter CBF using Models C and D were increased by 100% to 150% compared with Models A and B and the autoradiographic method. There were no significant changes in the perfusable tissue fraction by the activation induced rCBF increases. The largest activation response was found using Model C (median = 39.1%). The current study clearly demonstrates the importance of PVE correction in the quantitation of rCBF in normal humans. The potential use of this method is to cost-effectively deliver PVE corrected measures of rCBF and tissue volumes without reference to imaging modalities other than PET.

Adult↗

Physiologically based model of acute ischemic stroke.

In the treatment of acute ischemic stroke most of the clinical trials have failed, contrasting with promising results in the preclinical stages. This continuing discrepancy suggests some misconceptions in the understanding of acute ischemic stroke. One possible method for identifying the shortcomings of present-day approaches is to integrate all the available knowledge into a single mathematical model and to subject that model to challenges via simulations with available experimental data. As a first stage, then, the authors developed a simplified model, defining the structure and the different parameters that represent the phenomena that occur during the hyperacute phase of ischemic stroke. First, the different critical points of the evolution of ischemic stroke, based on the available evidence on the pathophysiology of stroke, were identified. Those key steps were then related to the quantitative data obtained by magnetic resonance imaging and positron emission tomography scan. These two techniques allow the measurement of diverse key markers of cerebral metabolism: cerebral blood flow (CBF), oxygen extraction factor, cerebral metabolism rate of oxygen, and the apparent diffusion coefficient of water, among others. Those markers were organized together through mathematical equations, and changed over time in order to describe the evolution of an acute ischemic stroke. At each time during the evolution of stroke those parameters are summarized in a parameter called survival delay. This parameter made possible the definition of three different states for tissues-functional, infarcted, salvageable-as end point. Once the model was designed, simulations were performed to explore its internal validity. Simulation results were consistent with the reality of acute ischemic stroke and did not reveal any major drawbacks in the use of the model. The more rapid the decrease in CBF, the larger is the final infarcted area. The model also allowed for the characterization of two types of tissue in the penumbra: tissues with an initial metabolic impairment and tissues altered owing to the closeness of the ischemic area. The results of this experiment were consistent with what is known of acute ischemic stroke. The model integrated different markers of acute ischemic stroke into a single entity in order to mimic acute ischemic stroke, and has been shown to have a reasonable degree of internal validity.

Animals↗

A redundant ray projection completion method for an inverse fan beam computed tomography system.

An actively synchronized heart gated computed tomography (CT) system has been developed at Peter Bent Brigham Hospital, Boston, MA, for a Technicare 2020 CT scanner. For even the most precise physical synchronization of the scanning apparatus, there will usually be a few gaps in the data for a particular time slice of the cardiac cycle. Of the several gap filling methods that have been developed here, the most nearly ideal is the use of redundant ray measurements. For this type of scanner, there are no truly redundant rays, and normalization errors are particularly problematic. A practical algorithm has been devised and tested here both on phantom data and on cardiac gated data (dog heart). The reconstructions obtained were usually artifact free and showed no loss of resolution, even when up to one-third of the projection data were replaced by redundant ray measurements.

Animals↗

Quantitation of myocardial blood flow with H2 15O and positron emission tomography: assessment and error analysis of a mathematical approach.

Quantitation of regional myocardial blood flow (MBF) in absolute terms with positron emission tomography (PET) has been difficult to achieve in part because of errors induced by the relatively low spatial resolution of current tomographic instruments. We previously demonstrated that MBF could be accurately measured over a wide range of flows after intravenous administration of H2 15O when the arterial input function and myocardial radiotracer content were measured directly. To extend this quantitative approach for noninvasive estimates of MBF with PET. We recently developed and implemented a novel mathematical approach whereby partial volume and spillover effects were estimated along with flow within the operational one-compartment flow equation. Noninvasive estimates of flow correlated closely with flow measured directly with radiolabeled microspheres. In the present study, with the use of a commercially available cardiac phantom, we assessed our ability to obtain true time-activity curves from observed PET data contaminated by partial volume and spillover effects. Computer simulations demonstrated that the approach developed is relatively insensitive to most potential sources of error, but is sensitive to timing discrepancies between the arterial input function and the tissue time-activity curve. Implementation of this approach provides accurate quantitation of regional MBF in absolute terms and should be useful in noninvasive evaluation of the efficacy of treatments designed to enhance nutritional perfusion in human subjects.

Coronary Circulation↗

Physical aspects of cardiac scanning with a block detector positron tomograph.

Physical aspects relating to cardiac scanning are described for an eight ring (15 plane) positron tomograph consisting of BGO block detectors (CTI/Siemens 931-08/12). Performance parameters were derived from a cylindrical heart phantom having a "myocardial" wall of thickness varying from 3 mm to 27 mm. This phantom was inserted into a chest phantom consisting of simulated chest wall, lungs, and arms. Recovery coefficients for myocardial thicknesses of 10 mm and 15 mm were 0.75 and 0.9, respectively. Division by the transmission minus "blood pool" (extravascular density) image was found to give a variation of corrected myocardial counts within +/- 5% when transmission data were smoothed. The on-line dead time correction algorithm was found to be accurate to within 5% up to 20 mCi (740 MBq) in the axial field of view (FOV) (10.8 cm) in the central chamber of the heart phantom. However, the correction factor at this rate is approximately 3, which would imply poor use of administered dose. Counts in the image due to scatter are approximately 2% in the (cold) central cavity of the heart phantom relative to counts/pixel in the active myocardium. The presence of phantom arms in the FOV was found to have only a small effect on mean pixel counts and noise in the heart phantom image, as did movement of the arms within a reasonable range.

Calibration↗

Heterogeneity of autonomic regulation in hypertension and neurovascular contact.

OBJECTIVE: Brainstem neurovascular contact (NVC) may interfere with central autonomic regulation and contribute to essential hypertension. We have previously shown that patients with autosomal-dominant hypertension, brachydactyly, and NVC feature extreme phenylephrine hypersensitivity due to impaired baroreflex buffering. We tested the hypothesis that similar abnormalities are present in patients with essential hypertension who have NVC. METHODS: Six patients with NVC and essential hypertension and five patients with NVC and monogenic hypertension and brachydactyly were studied. Responses to incremental phenylephrine doses were assessed before and during ganglionic blockade with trimethaphan. RESULTS: Supine blood pressure was 172 +/- 8.8/89 +/- 6.1 mmHg before ganglionic blockade. Blood pressure decreased 47 +/- 5/18 +/- 3 mmHg with trimethaphan (16 +/- 4.4/4 +/- 4.0 mmHg in autosomal-dominant hypertension, P < 0.05). Before ganglionic blockade, 25 microg phenylephrine increased systolic blood pressure 17 +/- 4 mmHg in patients with essential hypertension and 30 +/- 3 mmHg in patients with autosomal-dominant hypertension (P < 0.05). During ganglionic blockade, the same dose increased systolic blood pressure 32 +/- 1 and 33 +/- 4 mmHg in patients with essential and with autosomal-dominant hypertension, respectively (NS). CONCLUSIONS: Phenylephrine hypersensitivity due to baroreflex dysfunction is uncommon in patients with essential hypertension and NVC. This finding may suggest that the effect of NVC on autonomic regulation is heterogeneous. An alternative explanation is that radiological NVC is not necessarily functionally relevant.

Antihypertensive Agents↗

High-salt-induced increase in blood pressure: role of capsaicin-sensitive sensory nerves.

OBJECTIVE: To test the hypothesis that sensory afferents are significant functional components in preventing salt-induced increases in blood pressure. DESIGN AND METHODS: Neonatal Wistar rats were subcutaneously injected with 50 mg/kg capsaicin or vehicle on the first and second days of life. After weaning, male rats were divided into three groups and treated for 4 weeks with: control plus normal (0.5%, CON-NS) or high (4%, CON-HS) sodium diet, and capsaicin pretreatment plus HS diet (CAP-HS). Mean arterial pressure (MAP) and its response to bolus injection of calcitonin gene-related peptide (CGRP) and its antagonist, CGRP(8-37), were measured by carotid arterial catheterization. Radioimmunoassay was used to measure CGRP levels in plasma and dorsal root ganglia (DRG). Expression of components of the CGRP receptor, calcitonin receptor-like receptor (CRLR) and receptor activity modifying protein 1 (RAMP1), was determined by the use of Western blot analysis. RESULTS: Baseline MAP was increased in CAP-HS compared with CON-HS and CON-NS rats, and it was higher in CON-HS than in CON-NS rats. MAP response to exogenous CGRP was enhanced in CAP-HS and CON-HS than in CON-NS rats, but MAP response to CGRP(8-37) was increased only in CON-HS rats. Plasma CGRP levels were not different among three groups, but CGRP content in DRG was decreased in CAP-HS compared with CON-HS and CON-NS rats. CRLR expression in mesenteric resistance arteries was upregulated in CAP-HS and CON-HS compared with CON-NS rats, but RAMP1 content was not different among these groups. CONCLUSION: Chronic high-salt intake upregulates expression of mesenteric CGRP receptors without altering CGRP levels in plasma and DRG. Increased expression of mesenteric CGRP receptors may play a counter regulatory role in attenuating salt-induced increases in blood pressure.

Animals↗

Evidence for vasoconstriction mediated by the endothelin-B receptor in domestic swine.

Endothelin-1 (ET-1), a potent vasoactive and mitogenic peptide, has been implicated in a number of cardiovascular diseases, including congestive heart failure, neointimal hyperplasia associated with restenosis, and hypertension. The vasoconstriction induced by ET-1 is thought to be mediated mainly by its action on ET(A) receptors on vascular smooth muscle cells. Recent studies have indicated that vasoconstriction also may be mediated by stimulation of an ET(B)-receptor subtype. Increased use of the pig as a cardiovascular model prompted us to examine the receptor profile in this species using ABT-627, a potent, nonpeptide antagonist of the ET(A) receptor. The precursor to ET-1, big ET-1 (0.02 nmol/kg/min), was infused intravenously in domestic swine, resulting in a sustained increase in mean blood pressure of 38 +/- 3 mm Hg. After stabilization of the pressor response, ABT-627 (0.1-10 microg/kg/min) or vehicle was infused for 30 min. Whereas vehicle infusion had no appreciable effect, a dose-related reversal of the pressor response to big ET-1 (11-100%) was observed by the end of the ABT-627 infusion. Blood samples were assayed for plasma concentrations of ABT-627; peak levels ranged from 9 +/- 2 to 937 +/- 168 ng/ml. In a separate group of pigs, the highest dose of ABT-627 produced only a modest reversal of the hypertensive response to an infusion of angiotensin II (300 ng/kg/min). Additional results indicate that the vasoconstrictor effects produced by sarafotoxin 6C (0.03 and 0.3 nmol/kg), an agonist of the ET(B) receptor, are not blocked by treatment with ABT-627 (10 microg/kg/min). However, complete blockade of the S6C response could be achieved using the ET(B) antagonist, A-192621 (0.33 mg/kg/min). Our results define the dose-response relation for the ET(A)-receptor antagonist ABT-627 in the vasculature of the domestic pig and suggest the presence of an ET(B)-receptor subtype that mediates vasoconstriction in this species.

Angiotensin II↗

Microsurgery for cerebral arteriovenous malformations: a dissection technique and its theoretical implications.

Surgical resection of cerebral arteriovenous malformations is often complicated by persistent bleeding from the nidus, which is difficult to manage. It has often been mentioned that the difficulty of hemostasis is caused by the fragile and pathological nature of vessels of the nidus. This may be one reason, but I hypothesize that the dissection procedure, which involves coagulation of the surface of the nidus, may cause obstruction of intranidal drainage and that this may cause increased intranidal pressure, especially at the late stage of resection. In operating on patients with cerebral arteriovenous malformations recently, I made an effort not to coagulate the surface of the nidus, and this technique has diminished hemorrhage problems effectively. I illustrate this technique herein with a resected specimen and plastic casts of the lesion.

Adult↗

Cerebral venous blood outflow: a theoretical model based on laboratory simulation.

OBJECTIVE: The cerebrovascular bed and cerebrospinal fluid circulation have been modeled extensively except for the cerebral venous outflow, which is the object of this study. METHODS: A hydraulic experiment was designed for perfusion of a collapsible tube in a pressurized chamber to simulate the venous outflow from the cranial cavity. CONCEPT: The laboratory measurements demonstrate that the majority of change in venous flow can be attributed to either inflow pressure when the outflow is open, or the upstream transmural pressure when outflow is collapsed. On this basis, we propose a mathematical model for pressure distribution along the venous outflow pathway depending on cerebral blood flow and intracranial pressure. The model explains the physiological strong coupling between intracranial pressure and venous pressure in the bridging veins, and we discuss the limits of applicability of the Starling resistor formula to the venous flow rates. The model provides a complementary explanation for ventricular collapse and origin of subdural hematomas resulting from overshunting in hydrocephalus. The noncontinuous pressure flow characteristic of the venous outflow is pinpointed as a possible source of the spontaneous generation of intracranial slow waves. CONCLUSION: A new conceptual mathematical model can be used to explain the relationship between pressures and flow at the venous outflow from the cranium.

Blood Flow Velocity↗

Adaptation of cerebral circulation to brain arteriovenous malformations increases feeding artery pressure and decreases regional hypotension.

PURPOSE: To determine how the adaptation of extranidal cerebral vessels affects feeding artery pressure, draining vein pressure, and regional hypotension due to the presence of brain arteriovenous malformations (BAVMs). CONCEPT: BAVMs cause high flows in feeding arteries and draining veins and can induce profound hypotension in the neighboring vasculature. Despite the large difference in flow, endothelial shear stress (tau) observed in vessels ipsilateral to the BAVM is similar to tau in vessels contralateral to the BAVM, suggesting that the conductance vessels successfully adapt to keep tau constant. However, because BAVMs are discovered only after they are well developed, the natural history of the adaptation process in extranidal vessels is unknown. RATIONALE: Currently, no way exists to determine experimentally the effects of adaptation of extranidal vessels in human patients. Therefore, a mathematical model of the cerebral vasculature is used to study adaptation in response to BAVMs. By comparing pressures and flows calculated before and after adaptation, the effect of adaptation of the conductance vessels on regional hemodynamics can be evaluated. DISCUSSION: Structural adaptation of the extranidal circulation seems not only to reset tau, but also to ameliorate regional hypotension induced by BAVMs. However, this compensatory mechanism also increases feeding artery pressure and thus may increase the risk of hemorrhagic stroke.

Blood Flow Velocity↗

Dependence of ejection fraction results on choice of algorithms for a cardiac phantom.

Ejection fraction results obtained from the Vanderbilt rotating cardiac phantom exhibit a strong dependence on the algorithms used to derive the time--activity curves and calculate the ejection fraction from those curves. This problem is caused because the background chamber is located behind the rotating attenuator which is used to produce the pseudo ejection fraction. As a result, the counts due to background in both the regions on the 'left ventricle' and the area assigned for background correction do not remain constant during the 'cardiac cycle'. This leads to a breakdown in the ejection fraction algorithms. Given the same data, but changing the methods by which the time--activity curves and ejection fractions are derived, ejection fraction results varying from a minimum of 45% to a maximum of 69% have been demonstrated for the 50% attenuator. Although the Vanderbilt cardiac phantom is simple to operate it must be used with caution if it is used with the intention of calibrating a particular system or comparing different protocols.

Heart↗

Evaluation of radiocardiographic methods for determination of cardiac output and right and left ventricular ejection fractions using a cardiac phantom.

Cardiac output and ejection fractions of the cardiac ventricles are valuable measures of cardiac function. Noninvasive radionuclide techniques for determination of these measures are based on analysis of different data: first passage low frequency, first passage high frequency and multigated equilibrium data. We have evaluated the principles of these methods using a dynamic cardiac phantom. Radiocardiographic determinations of cardiac output and right and left ventricular ejection fractions showed excellent correlation against true phantom values: r = 0.993 (p less than 0.001), r = 0.978 (p less than 0.01) and r = 0.943 (p less than 0.05), respectively. Thus, the findings of the present study demonstrate a high validity of current radiocardiographic measures of cardiac function.

Cardiac Output↗

Factors affecting and computation of myocardial perfusion reference images.

Many quantitative analysis methods for myocardial perfusion studies require as a central step a comparison with a 'normal' or average density distribution map or reference image. It has been recognized, however, that the normal distribution can be affected by patient attributes, including sex and weight or body habitus, and by acquisition attributes, including the choice of tracer and the position of the patient during imaging. Some authors have proposed separate reference images for the sexes and the tracer. This approach fails if a large number of binary attributes have to be considered, since one would need 2" reference images for each attribute. The problem is compounded when continuous attributes (e.g. age and weight) are included, especially if the approach is to average separate homogeneous groups for each attribute. We propose to create case-specific reference images for the interpretation of myocardial perfusion studies by creating a model based on the influence of each attribute. From a non-homogeneous population of normal cases, or cases presumed to be normal on the basis of the Diamond and Forrester stratification, the effect of patient and study attributes on the density distribution in the stress image and the density differences between rest and stress images were computed. The effects are computed by multi-linear regression, to account for cross-correlation. Significance is assigned on the basis of a partial Fisher test. The data are myocardial perfusion images matched in 3D to a template by an elastic transformation. Even though there was some cross-correlation in the data, we were able to show independent effects of sex, position (prone or supine), age, weight, tracer combination and stress method (exercise, persantine and adenosine). Taken as a whole, the multi-linear regression demonstrated a significant effect in 72% of the pixels within the myocardial volume. In addition, the distribution predicted by the model was equivalent to average images from homogeneous matched groups. In conclusion, our approach makes it possible to produce case-specific reference images without the need for multiple homogeneous large groups to produce averages for each possible patient or study attribute.

Adenosine↗