Preliminary study in differential contrast echography

Microbubble-based contrast agents have backscattering properties that differ greatly from those of soft tissues. These agents exhibit nonlinear scattering properties in response to incident acoustic energy, causing harmonic components in reflected energy. Even in linear scattering conditions, an important difference is observed in the frequency dependence of their backscatter coefficient, when compared to that of tissues. In this situation, any such differential behaviour can be exploited by imaging instrumentation to enhance the detection of agent-containing vessels against background tissue. The resulting B-mode image brightness (or pixel level) can thus be the representation of a local parameter computed from radio frequency (rf) signal processing of the raw echoes. The object of this article is to report on parametric imaging studies performed with Sonovue (formerly code named BR1, Bracco Research SA), aimed at assessing the contrast-enhancing potential of spectral rf signal processing. The technique used, termed here "differential contrast echography" (DCE), is applicable in real-time B-mode imaging. It is based on an on-line subtractive approach, using dual-channel signal processing to implement differential filtering and demodulation. In this preliminary work, DCE was implemented off-line, on rf echo signals digitised from commercial B-mode scanners. Data acquisition, DCE processing and complete B-mode image reconstruction were programmed on a personal computer. The images presented were produced from test phantoms as well as animal phased array scanning. The phantom included a flow channel, background scattering material, fixed echogenic targets and echo-free regions. Animal scanning was performed on rabbit liver. The results obtained from DCE show promising contrast-enhancing properties. The regions containing no contrast agent are significantly suppressed from the image, preferentially leaving the regions perfused by the contrast agent. This property was favourable to experimenting with image-overlay presentations, superimposing colour-coded DCE imaging with standard log-compressed grey-scale B-mode, in a way analogous to duplex imaging combining colour Doppler and B-mode.     

Harmonic imaging

Microbubbles undergoing resonant oscillation in a diagnostic ultrasound field can be induced to exhibit nonlinear motion. The ultrasound signals emitted by such microbubbles contain strong harmonics at twice the frequency of the transmitted ultrasound beam. Second harmonic imaging improves tissue-agent contrast. The usefulness of second harmonic imaging was evaluated in vivo experiments. The hepatic parenchyma was clearly enhanced in dogs. Second harmonic imaging can be expected to expand the capabilities of diagnostic ultrasound systems in visualizing tissue perfusion.     

Tissue harmonic imaging: why does it work?

The recent utilization of harmonic frequencies in the imaging of both tissue and contrast agents has dramatically improved echocardiographic image quality. In contrast harmonics, the harmonic frequency energy is generated on reflection from the microbubble contrast agent. In tissue harmonics, the harmonic frequency energy is generated gradually as the ultrasonic wave propagates through the tissue. Critical to the utility of tissue-generated harmonic frequencies is their origin beyond the chest wall and their nonlinear relation to the fundamental frequency energy strength. These two characteristics of tissue-generated harmonics ensure that the echoes most likely to produce artifact are least likely to produce harmonic waves. Armed with an understanding of how these images are produced and with data emerging as to their clinical utility, we anticipate that harmonic imaging will become the standard for assessing regional and global left ventricular function in technically difficult studies.     

Dynamic Coupling Effects in Frictional Geomaterials—Stochastic Resonance

Nonlinear, dynamic coupling effects and the manifestation of stochastic resonance are explored in the context of frictional geomaterials. The first experiment is designed to study a single interface between two mineral surfaces. Results demonstrate that as the amplitude of the driving signal approaches the threshold of static frictional resistance, the noise level required to cause slippage decreases and the peak output signal-to-noise ratio increases, inducing stochastic resonance. The second experimental study is conducted with sand specimens. While the classical signature of stochastic resonance is not observed in these multiinterface systems, nonlinear energy coupling effects appear. The effect of signal interaction through the nonlinear behavior of the medium is further studied by simultaneously exciting the specimen with two sinusoidal signals of different frequencies. The output response at the frequency of the primary driving signal increases as the amplitude of the secondary “noise” signal increases. Coupling increases as the driving signal brings the specimen to its nonlinear regime. The results highlight the interaction between friction and vibration in geomaterials, and suggest potential implications to experimental studies, construction operations, and dynamic phenomena such as seismic response and landslides.     

Changes in Fos-like immunoreactivity evoked by maturation of the sneeze reflex triggered by nasal air puff stimulation in kittens

The contrast-enhanced magnetic resonance imaging (MRI) signal is rarely a direct measure of contrast concentration; rather it depends on the effect that the contrast agent has on the tissue water magnetization. To correctly interpret such studies, an understanding of the effects of water movement on the magnetic resonance (MR) signal is critical. In this review, we discuss how water diffusion within biological compartments and water exchange between these compartments affect MR signal enhancement and therefore our ability to extract physiologic information. The two primary ways by which contrast agents affect water magnetization are discussed: (1) direct relaxivity and (2) indirect susceptibility effects. For relaxivity agents, for which T1 effects usually dominate, the theory of relaxation enhancement is presented, along with a review of the relevant physiologic time constants for water movement affecting this relaxation enhancement. Experimental issues that impact accurate measurement of the relaxation enhancement are discussed. Finally, the impact of these effects on extracting physiologic information is presented. Susceptibility effects depend on the size and shape of the contrast agent, the size and shape of the compartment in which it resides, as well as the characteristics of the water movement through the resulting magnetic field inhomogeneity. Therefore, modeling of this effect is complex and is the subject of active study. However, since susceptibility effects can be much stronger than relaxivity effects in certain situations, they may be useful even without full quantitation.     

Effect of gas-containing microspheres and echo contrast agents on free radical formation by ultrasound

Stabilized microbubbles (microspheres) are widely used to enhance the contrast of ultrasound imaging. Our data provide direct evidence that the contrast agents, Levovist, PVC-AN (polyvinylidene chloride-acrylonitryl copolymer), and Albunex (compared to 5% human albumin), at concentrations comparable to those used for ultrasound imaging, enhance H2O2 production (through the superoxide-dependent pathway) in air-saturated aqueous solutions exposed to 47 kHz ultrasound above the cavitation threshold. These agents also act as scavengers of .H atoms and .OH radicals, thus lowering H2O2 formation (by recombination of .OH radicals) in argon-saturated solutions. EPR spin trapping also reveals that secondary radicals derived from the contrast agents are produced by reactions with .H and .OH which are formed by pyrolysis of water inside cavitation bubbles. In addition, the contrast agents themselves undergo pyrolysis reactions in the cavitation bubbles as demonstrated by formation of methyl radicals. Possible deleterious consequences of the formation of sonochemical intermediates may have to be assessed, particularly since some of the echo contrast agents have been shown to lower the cavitation threshold of diagnostic ultrasound. Unlike the microspheres formed from organic molecules, inorganic microspheres, Eccospheres, because of their stability and inert nature with respect to participation in free radical processes, appear to be suitable tools for enhancing the yields of aqueous sonochemical reactions.     

Neonatal intensive care: decision making in the face of prognostic uncertainty

Liver-specific MR imaging contrast agents consist of iron oxide particles or specially designed paramagnetic complexes targeting either the reticulo-endothelial system of the liver or the hepatocytes. These agents enhance the relaxation of water molecules in normal liver tissue and are excluded from abnormal tissue, such as metastases. Relaxation enhancement provides a map of normal liver function, increasing conspicuity of focal abnormalities. Understanding the indications and use of these agents is a central challenge for radiologists practicing liver MR imaging.     

Pitfalls in quantitative contrast echocardiography: the steps to quantitation of perfusion

Current methods used clinically to assess myocardial perfusion are invasive and expensive. As the technology of ultrasound imaging improves, CE may provide a relatively inexpensive, noninvasive means of quantitating myocardial perfusion. Issues regarding stability of microbubble contrast agents must be studied more closely under physiologic conditions. As such, encapsulated microbubbles may provide more stability under physiologic pressures than free gas microbubbles. Introducing high concentrations of contrast, either by hyperconcentrating the contrast agent or by increasing the injection rate, may provide greater stability under physiologic conditions. Further, before quantitative statement of tissue perfusion can be made, the relationship between tracer concentration and system response must be established. Further, a "linear" postprocessing ultrasound setting does not eliminate this requirement as data must still undergo nonlinear transformation during log compression and time-gain compensation. Additionally, issues regarding "electronic thresholding" must be explored more extensively in vivo. Commercial ultrasound scanners, in their present form, may not offer adequate sensitivity for absolute quantitative studies. Further development of modified ultrasound systems may provide sufficient sensitivity for quantitative perfusion imaging. CE offers a potentially powerful tool in the clinical management of patients with ischemic heart disease. Conventional coronary angiography provides information on the size of a lesion, but accompanying tissue perfusion distal to the lesion cannot be determined. Doppler ultrasonography determines velocity of blood flow in large vessels but does not offer the potential to quantitate tissue perfusion. Clearly, CE has a place in the future of diagnostic imaging. The recent work of Ito et al. demonstrated the qualitative potential of CE in the identification of "areas at risk" in patients who had undergone thrombolysis or percutaneous transluminal coronary angioplasty after an acute myocardial infarction. With further improvement in the ultrasound imaging techniques and microbubble stability, CE may offer an inexpensive, noninvasive means of assessing myocardial perfusion.     

Anaplastic large cell lymphoma of T-cell phenotype in acquired immunodeficiency syndrome

A variety of shortcomings are associated with most currently used gastrointestinal contrast agents for magnetic resonance imaging (MRI). Artifacts resulting from peristalsis and other motions in the abdominal region are produced by many positive contrast agents (which increase signal intensity). Although this is not a problem for negative contrast agents (which decrease signal intensity), some negative contrast agents produce magnetic susceptibility artifacts that are especially pronounced at high field strength and with gradient echo pulse sequences. These susceptibility artifacts are produced by both paramagnetic and diamagnetic agents. It has been demonstrated in phantoms, however, that susceptibility matching can be used to produce contrast agents with desirable relaxation and contrast properties but without deleterious susceptibility artifacts. We now report results of animal tests of such an oral contrast agent, consisting of a suspension of superparamagnetic iron oxide particles and diamagnetic barium sulfate particles, compared to individual suspensions of the iron oxide and of the barium sulfate. Iron oxide was the least effective and the matched susceptibility mixture was the most effective for the intestine, which has traditionally been the most difficult region of the GI tract to visualize clearly. Matched susceptibility mixtures, which are inherently able to yield images free of susceptibility artifacts without compromising contrast, show promise of being improved oral negative contrast agents for use in gastrointestinal MRI.     

Effect of molecular weight on the diffusion of contrast media into cartilage

STUDY DESIGN: A comparison of contrast enhancement in the intervertebral disc from two magnetic resonance imaging contrast media in experimental animals. OBJECTIVES: To test the effect of molecular weight on the diffusion of ionic contrast media into the intervertebral disc. SUMMARY OF BACKGROUND DATA: Intravenously administered gadopentetate diffuses similarly into the fibrocartilage of intervertebral discs and herniated disc fragments. Differentiation between recurrent disc fragments and scar tissue via magnetic resonance imaging is optimized by using contrast media, which result in different contrast enhancement of these two tissues. Contrast media of higher molecular weight diffuse more slowly into cartilage; hypothetically, therefore, such media will produce better contrast between scar tissue and recurrent disc fragments. METHODS: Gadopentetate (molecular weight 546) or gadolinium-polylysine (molecular weight 40,000) was injected intravenously into rabbits. The signal intensities of intervertebral disc and muscle tissue were recorded by magnetic resonance imaging at baseline and at pre-determined intervals for 2 hours after injection of the contrast medium. Contrast enhancement in these tissues was calculated in each animal for each contrast medium, and differences in enhancement were tested for significance by a growth-curve model. RESULTS: Contrast enhancement in the intervertebral disc was significantly less with gadolinium-polylysine than with gadopentetate. In muscle, no significant difference between the two media was observed. CONCLUSIONS: Molecular weight affects the diffusion of paramagnetic contrast media into the intervertebral disc. Contrast media of a high molecular weight may produce better contrast between recurrent herniated disc fragments and scar tissue than contrast media of lower molecular weight. This possibility should be rested in further studies.     

Improving MR quantification of regional blood volume with intravascular T1 contrast agents: accuracy, precision, and water exchange

The goal of this work was to develop a comprehensive understanding of the relationship between vascular proton exchange rates and the accuracy and precision of tissue blood volume estimates using intravascular T1 contrast agents. Using computer simulations, the effects of vascular proton exchange and experimental pulse sequence parameters on measurement accuracy were quantified. T1 and signal measurements made in a rat model implanted with R3230 mammary adenocarcinoma tumors demonstrated that the theoretical findings are biologically relevant; data demonstrated that over-simplified exchange models may result in measures of tumor, muscle, and liver blood volume fractions that depend on experimental parameters such as the vascular contrast concentration. As a solution to the measurement of blood volume in tissues with exchange that is unknown, methods that minimize exchange rate dependence were examined. Simulations that estimated both the accuracy and precision of such methods indicated that both the inversion recovery and the transverse-spoiled gradient echo methods using a "no-exchange" model provide the best trade-off between accuracy and precision.     

Hemostatic efficacy of a fibrin sealant dressing in an animal model of kidney injury

Arterial spin tagging techniques have been used to image tissue perfusion in MR without contrast injection or ionizing radiation. Currently, spin tagging studies are performed primarily using single-slice imaging sequences, which are time consuming. This note reports a multislice echo-planar arterial spin tagging technique (Simultaneous Multislice Acquisition with aRterial-flow Tagging, or "SMART"). Multiband RF encoding (Hadamard) is used to provide simultaneous multislice acquisition capability for spin tagging techniques (such as echo planar imaging signal targeting with alternating radio frequency and flow-sensitive alternative inversion recovery). The method is illustrated with a two-slice pulse sequence that was implemented using the FAIR technique to generate two perfusion weighted images simultaneously. Compared with single-slice sequences, this two-slice sequence provided similar image quality, signal-to-noise ratio, and twice the spatial coverage compared with the single-slice technique within the same scan time.     

Metabolites of ebrotidine, a new H2-receptor antagonist, in human urine

The clinical application of ultrasonographic contrast agents in colour Doppler flow imaging of hepatic tumours is receiving increasing attention. Levovist is a suspension of galactose microparticles that provides reproducible concentrations of stabilized air bubbles with transpulmonary stability. Its effect on colour Doppler imaging was assessed in 26 patients with colorectal cancer and histologically proven hepatic metastases. Colour Doppler flow imaging was performed before and after intravenous injection of 10 ml Levovist 300 mg/ml. At 5-10 s after injection there was significant enhancement of the hepatic lesions with colour Doppler signals in 23 patients, lasting for a mean(s.d.) of 180(45) s. A consistent pattern of colour Doppler signal was observed, with increased enhancement predominantly around the tumour periphery and little or no central enhancement. These data suggest that Levovist may increase the sensitivity and specificity of colour Doppler flow imaging of colorectal hepatic metastases.     

Suppression and the upward spread of masking

The purpose of this study is to clarify the role of suppression in the growth of masking when a signal is well above the masker in frequency (upward spread of masking). Classical psychophysical models assume that masking is primarily due to the spread of masker excitation, and that the nonlinear upward spread of masking reflects a differential growth in excitation between the masker and the signal at the signal frequency. In contrast, recent physiological studies have indicated that upward spread of masking in the auditory nerve is due to the increasing effect of suppression with increasing masker level. This study compares thresholds for signals between 2.4 and 5.6 kHz in simultaneous and nonsimultaneous masking for conditions in which the masker is either at or well below the signal frequency. Maximum differences between simultaneous and nonsimultaneous masking were small (< 6 dB) for the on-frequency conditions but larger for the off-frequency conditions (15-32 dB). The results suggest that suppression plays a major role in determining thresholds at high masker levels, when the masker is well below the signal in frequency. This is consistent with the conclusions of physiological studies. However, for signal levels higher than about 40 dB SPL, the growth of masking for signals above the masker frequency is nonlinear even in the nonsimultaneous-masking conditions, where suppression is not expected. This is consistent with an explanation based on the compressive response of the basilar membrane, and confirms that suppression is not necessary for nonlinear upward spread of masking.     

A rapid interleaved method for measuring signal intensity curves in both blood and tissue during contrast agent administration

A method has been developed that uses dynamic MR imaging to measure simultaneously the changes in signal intensity due to paramagnetic contrast agent in blood and tissue, using interleaved single-angle projection and imaging sequences. The basic projection/image sequence has a projection time resolution of 50 ms and can measure rapid changes in the blood signal intensity. Variants with a tissue suppression slab have time resolutions of 57 or 75 ms. Orientation of the projection and image planes can be defined independently. This technique will facilitate functional measurements using MR contrast agents, allowing the blood input function to be determined with excellent time resolution.     

Clinical applications of ultrasound contrast agents

Within the last decade safe and practical ultrasound contrast agents have been introduced. Most of these are based on gas-filled microbubbles, which markedly enhance Doppler signals and, in some cases, also gray-scale images. The clinical improvements expected from ultrasound contrast is reviewed. Tissue-specific contrast agents constitute another area of potential clinical significance. One particular agent is taken up by the reticulo-endothelial system and produces so-called acoustic emission signals when imaged. An introduction to the unique clinical applications of acoustic emission is given. Harmonic imaging is a new contrast-specific imaging modality, which utilizes the nonlinear properties of some agents in an attempt to alleviate current limitations of ultrasound contrast studies. Examples of harmonic images are presented.     

Magnetic resonance imaging of microbubbles in a superheated emulsion chamber for brachytherapy dosimetry

This paper describes development of magnetic resonance imaging (MRI) techniques for three-dimensional (3D) imaging of a position-sensitive detector for brachytherapy dosimetry. The detector is a 0.5 l chamber containing an emulsion of halocarbon-115 droplets in a tissue-equivalent glycerin-based gel. The halocarbon droplets are highly superheated and expand into vapor microbubbles upon irradiation. Brachytherapy sources can be inserted into the superheated emulsion chamber to create distributions of bubbles. Three-dimensional MRI of the chamber is then performed. A 3D gradient-echo technique was optimized for spatial resolution and contrast between bubbles and gel. Susceptibility gradients at the interfaces between bubbles and gel are exploited to enhance contrast so microscopic bubbles can be imaged using relatively large voxel sizes. Three-dimensional gradient-echo images are obtained with an isotropic resolution of 300 microns over a 77 mm x 77 mm x 9.6 mm field-of-view in an imaging time of 14 min. A post-processing technique was developed to semi-automatically segment the bubbles from the images and to assess dose distributions based on the measured bubble densities. Relative dose distributions are computed from MR images for a 125I brachytherapy source and the results compare favorably to relative radial dose distributions calculated as recommended by Task Group 43 of the American Association of Physicists in Medicine.     

Magnetic relaxation contrast agents in magnetization transfer imaging

RATIONALE AND OBJECTIVES: The effects of magnetic relaxation agents are explored in the context of magnetization transfer pulse sequences using cross-linked protein gels as modeled tissue systems. METHODS: Magnetization transfer pulse sequences were used to study contrast agents that are designed to bind to rotationally immobilized protein targets. RESULTS: The dynamic range available from contrast agents, used in conjunction with magnetization transfer pulse sequences, is comparable with or better than that based on spin-echo imaging sequences with short repetition times. Furthermore, useful changes in the intensity of water resonances may be achieved by using this combined approach even though the paramagnetic metal center may not have a free coordination position in the chelate complex for water molecule exchange. CONCLUSIONS: The inclusion of magnetization transfer acquisition protocols in the context of magnetic imaging with contrast agents presents new opportunities for control of the information content of the image and for new classes of contrast agent structure and delivery.     

Variational learning in nonlinear gaussian belief networks

We view perceptual tasks such as vision and speech recognition as inference problems where the goal is to estimate the posterior distribution over latent variables (e.g., depth in stereo vision) given the sensory input. The recent flurry of research in independent component analysis exemplifies the importance of inferring the continuous-valued latent variables of input data. The latent variables found by this method are linearly related to the input, but perception requires nonlinear inferences such as classification and depth estimation. In this article, we present a unifying framework for stochastic neural networks with nonlinear latent variables. Nonlinear units are obtained by passing the outputs of linear gaussian units through various nonlinearities. We present a general variational method that maximizes a lower bound on the likelihood of a training set and give results on two visual feature extraction problems. We also show how the variational method can be used for pattern classification and compare the performance of these nonlinear networks with other methods on the problem of handwritten digit recognition.