Laurence W. Hedlund

Mechanism of detection of acute cerebral ischemia in rats by diffusion-weighted magnetic resonance microscopy.

Background and Purpose The aim of this study was to measure apparent diffusion coefficients in rat brain tissue exposed to ouabain, glutamate, and N-methyl-D-aspartate and to compare them with apparent diffusion coefficients found in acute cerebral ischemia. Methods The apparent diffusion coefficient was measured using magnetic resonance microscopy in four groups of Sprague-Dawley rats after occlusion of the right middle cerebral artery and ipsilateral common carotid artery (n=7), after ouabain exposure (n=6), during glutamate exposure (n=7), or during N-methyl-D-aspartate exposure (n=3). Ouabain, glutamate, and N-methyl-D-aspartate were applied via an intracerebrally implanted microdialysis membrane. Results Three hours after the induction of focal cerebral ischemia, a 33% reduction in the apparent diffusion coefficient was observed in the right dorsolateral corpus striatum and olfactory cortex. After ouabain exposure, reductions in the apparent diffusion coefficient were observed within a 1,500 -μm radius of the microdialysis membrane. Quantitative analysis revealed that apparent diffusion coefficient values in ischemic and ouabain-exposed tissue fell within the same range. Glutamate and N-methyl-D-aspartate reduced the brain tissue apparent diffusion coefficient by 35% and 40%, respectively. Conclusions On the basis of these findings, we conclude that ischemia-induced apparent diffusion coefficient reductions are likely caused by a shift of extracellular to intraceUular water.

Spatially resolved measurements of hyperpolarized gas properties in the lung in vivo. Part I: Diffusion coefficient

In imaging of hyperpolarized noble gases, a knowledge of the diffusion coefficient (D) is important both as a contrast mechanism and in the design of pulse sequences. We have made diffusion coefficient maps of both hyperpolarized 3He and 129Xe in guinea pig lungs. Along the length of the trachea, 3He D values were on average 2.4 cm2/sec, closely reproducing calculated values for free gas (2.05 cm2/sec). The 3He D values measured perpendicular to the length of the trachea were approximately a factor of two less, indicating restriction to diffusion. Further evidence of restricted diffusion was seen in the distal pulmonary airspaces as the average 3He D was 0.16 cm2/sec. An additional cause for the smaller 3He D in the lung was due to the presence of air, which is composed of heavier and larger gases. The 129Xe results show similar trends, with the trachea D averaging 0.068 cm2/sec and the lung D averaging 0.021 cm2/sec. Magn Reson Med 42:721–728, 1999.

A liposomal nanoscale contrast agent for preclinical CT in mice

OBJECTIVE The goal of this study was to determine if an iodinated, liposomal contrast agent could be used for high-resolution, micro-CT of low-contrast, small-size vessels in a murine model. MATERIALS AND METHODS A second-generation, liposomal blood pool contrast agent encapsulating a high concentration of iodine (83-105 mg I/mL) was evaluated. A total of five mice weighing between 20 and 28 g were infused with equivalent volume doses (500 microL of contrast agent/25 g of mouse weight) and imaged with our micro-CT system for intervals of up to 240 min postinfusion. The animals were anesthetized, mechanically ventilated, and vital signs monitored allowing for simultaneous cardiac and respiratory gating of image acquisition. RESULTS Initial enhancement of about 900 H in the aorta was obtained, which decreased to a plateau level of approximately 800 H after 2 hr. Excellent contrast discrimination was shown between the myocardium and cardiac blood pool (650-700 H). No significant nephrogram was identified, indicating the absence of renal clearance of the agent. CONCLUSION The liposomal-based iodinated contrast agent shows long residence time in the blood pool, very high attenuation within submillimeter vessels, and no significant renal clearance rendering it an effective contrast agent for murine vascular imaging using a micro-CT scanner.

Imaging alveolar–capillary gas transfer using hyperpolarized 129Xe MRI

Effective pulmonary gas exchange relies on the free diffusion of gases across the thin tissue barrier separating airspace from the capillary red blood cells (RBCs). Pulmonary pathologies, such as inflammation, fibrosis, and edema, which cause an increased blood–gas barrier thickness, impair the efficiency of this exchange. However, definitive assessment of such gas-exchange abnormalities is challenging, because no methods currently exist to directly image the gas transfer process. Here we exploit the solubility and chemical shift of 129Xe, the magnetic resonance signal of which has been enhanced by 105 with hyperpolarization, to differentially image its transfer from the airspaces into the tissue barrier spaces and RBCs in the gas exchange regions of the lung. Based on a simple diffusion model, we estimate that this MR imaging method for measuring 129Xe alveolar-capillary transfer is sensitive to changes in blood–gas barrier thickness of ≈5 μm. We validate the successful separation of tissue barrier and RBC images and show the utility of this method in a rat model of pulmonary fibrosis where 129Xe replenishment of the RBCs is severely impaired in regions of lung injury.

Micro‐CT with respiratory and cardiac gating

Cardiopulmonary imaging in rodents using micro-computed tomography (CT) is a challenging task due to both cardiac and pulmonary motion and the limited fluence rate available from micro-focus x-ray tubes of most commercial systems. Successful imaging in the mouse requires recognition of both the spatial and temporal scales and their impact on the required fluence rate. Smaller voxels require an increase in the total number of photons (integrated fluence) used in the reconstructed image for constant signal-to-noise ratio. The faster heart rates require shorter exposures to minimize cardiac motion blur imposing even higher demands on the fluence rate. We describe a system with fixed tube/detector and with a rotating specimen. A large focal spot x-ray tube capable of producing high fluence rates with short exposure times was used. The geometry is optimized to match focal spot blur with detector pitch and the resolution limits imposed by the reproducibility of gating. Thus, it is possible to achieve isotropic spatial resolution of 100 microm with a fluence rate at the detector 250 times that of a conventional cone beam micro-CT system with rotating detector and microfocal x-ray tube. Motion is minimized for any single projection with 10 ms exposures that are synchronized to both cardiac and breathing motion. System performance was validated in vivo by studies of the cardiopulmonary structures in C57BL/6 mice, demonstrating the value of motion integration with a bright x-ray source.

Magnetic resonance imaging of blood flow with a phase subtraction technique: In vitro and in vivo validation

RATIONALE AND OBJECTIVES.One promising approach to flow quantification uses the velocity-dependent phase change of moving protons. A velocity-encoding phase subtraction technique was used to measure the velocity and flow rate of fluid flow in a phantom and blood flow in volunteers. METHODS.In a model, the authors measured constant flow velocities from 0.1 to 270.0 cm/second with an accuracy (95% confidence intervals) of ±12.5 cm/second. There was a linear relationship between the magnetic resonance imaging (MRI) measurement and the actual value (r2 = .99; P = .0001). RESULTS.Measuring mean pulsatile flow from 125 to 1,900 mL/minute, the accuracy of the MRI pulsatile flow measurements (95% confidence intervals) was ±70 mL/minute. There was a linear relationship between the MRI pulsatile flow measurement and the actual value (r2 =.99;P = .0001). In 10 normal volunteers, the authors tested the technique in vivo, quantitating flow rates in the pulmonary artery and the aorta. The average difference between the two measurements was 5%. In vivo carotid flow waveforms obtained with MRI agreed well with the shape of corresponding ultrasound Doppler waveforms. CONCLUSIONS.Velocity-encoding phase subtraction MRI bears potential clinical use for the evaluation of blood flow. Potential applications would be in the determination of arterial blood flow to parenchymal organs, the detection and quantification of intra- and extra-cardiac shunts, and the rapid determination of cardiac output and stroke volume.

4-D Micro-CT of the Mouse Heart

Purpose: Demonstrate noninvasive imaging methods for in vivo characterization of cardiac structure and function in mice using a micro-CT system that provides high photon fluence rate and integrated motion control. Materials and Methods: Simultaneous cardiac- and respiratory-gated micro-CT was performed in C57BL/6 mice during constant intravenous infusion of a conventional iodinated contrast agent (Isovue-370), and after a single intravenous injection of a blood pool contrast agent (Fenestra VC). Multiple phases of the cardiac cycle were reconstructed with contrast to noise and spatial resolution sufficient for quantitative assessment of cardiac function. Results: Contrast enhancement with Isovue-370 increased over time with a maximum of ~500 HU (aorta) and 900 HU (kidney cortex). Fenestra VC provided more constant enhancement over 3 hr, with maximum enhancement of ~620 HU (aorta) and ~90 HU (kidney cortex). The maximum enhancement difference between blood and myocardium in the heart was ~250 HU for Isovue-370 and ~500 HU for Fenestra VC. In mice with Fenestra VC, volumetric measurements of the left ventricle were performed and cardiac function was estimated by ejection fraction, stroke volume, and cardiac output. Conclusion: Image quality with Fenestra VC was sufficient for morphological and functional studies required for a standardized method of cardiac phenotyping of the mouse.

Spatially resolved measurements of hyperpolarized gas properties in the lung in vivo. Part II: T *(2).

The transverse relaxation time, T∗︁2, of hyperpolarized (HP) gas in the lung in vivo is an important parameter for pulse sequence optimization and image contrast. We obtained T∗︁2 maps of HP 3He and 129Xe in guinea pig lungs (n = 17) and in human lungs. Eight different sets of 3He guinea pig studies were acquired, with variation of slice selection, tidal volume, and oxygen level. For example, for a 3He tidal volume of 3 cm3 and no slice selection, the average T∗︁2 in the trachea was 14.7 ms and 8.0 ms in the intrapulmonary airspaces. The equivalent 129Xe experiment yielded an average T∗︁2 of 40.8 ms in the trachea and 18.5 ms in the intrapulmonary airspaces. The average 3He T∗︁2 in the human intrapulmonary airspaces was 9.4 ms. The relaxation behavior was predicted by treating the lung as a porous medium, resulting in good agreement between estimated and measured T∗︁2 values in the intrapulmonary airspaces. Magn Reson Med 42:729–737, 1999.

Magnetic resonance histology for morphologic phenotyping.

Magnetic resonance histology (MRH) images of the whole mouse have been acquired at 100‐micron isotropic resolution at 2.0T with image arrays of 256 × 256 × 1024. Higher resolution (50 × 50 × 50 microns) of limited volumes has been acquired at 7.1T with image arrays of 512 × 512 × 512. Even higher resolution images (20 × 20 × 20 microns) of isolated organs have been acquired at 9.4T. The volume resolution represents an increase of 625,000× over conventional clinical MRI. The technological basis is summarized that will allow basic scientists to begin using MRH as a routine method for morphologcic phenotyping of the mouse. MRH promises four unique attributes over conventional histology: 1) MRH is non‐destructive; 2) MRH exploits the unique contrast mechanisms that have made MRI so successful clinically; 3) MRH is 3‐dimensional; and 4) the data are inherently digital. We demonstrate the utility in morphologic phenotyping a whole C57BL/6J mouse. J. Magn. Reson. Imaging 2002;16:423–429. Published 2002 Wiley‐Liss, Inc.

Effects of turbulence on signal intensity in gradient echo images.

Although the appearance of laminar vascular flow in magnetic resonance (MR) images has been characterized, there is no general agreement about the effect of turbulent flow on MR signal intensity. This study uses a fast scan gradient echo pulse sequence to evaluate nonpulsatile turbulent flow in two different models. The first model simulated flow in normal vascular structure. It generated nonpulsatile, laminar and turbulent flow in straight, smooth-walled Plexiglas tubes. The second model simulated flow through a vascular stenosis. It generated nonpulsatile, laminar, and turbulent flow through an orifice. Velocities and flow rates ranged from low physiologic to well above the physiologic range (velocity = .3 to 280 cm/second, flow rate from .15 to 40 L/minute). Transition from laminar to turbulent flow was observed with dye streams. Turbulent flow in straight, smooth-walled vessels was not associated with a decrease in MR signal intensity even at the highest velocities and flow rates studied. The transition from laminar to turbulent flow through an orifice is not associated with a decrease in gradient echo signal intensity. As the intensity of the turbulent flow increases, however, there is a threshold above which signal intensity decreases linearly as turbulence increases (r = .97). This study suggests that flow in normal vascular structures should not be associated with decreased signal intensity in gradient echo images. Turbulent flow through areas such as valves, valvular lesions or vascular stenoses, may be associated with a decrease in gradient echo signal intensity.