Imaging Methods for Ultrasound Contrast Agents.

Microbubble contrast agents were introduced more than 25 years ago with the objective of enhancing blood echoes and enabling diagnostic ultrasound to image the microcirculation. Cardiology and oncology waited anxiously for the fulfillment of that objective with one clinical application each: myocardial perfusion, tumor perfusion and angiogenesis imaging. What was necessary though at first was the scientific understanding of microbubble behavior in vivo and the development of imaging technology to deliver the original objective. And indeed, for more than 25 years bubble science and imaging technology have evolved methodically to deliver contrast-enhanced ultrasound. Realization of the basic bubbles properties, non-linear response and ultrasound-induced destruction, has led to a plethora of methods; algorithms and techniques for contrast-enhanced ultrasound (CEUS) and imaging modes such as harmonic imaging, harmonic power Doppler, pulse inversion, amplitude modulation, maximum intensity projection and many others were invented, developed and validated. Today, CEUS is used everywhere in the world with clinical indications both in cardiology and in radiology, and it continues to mature and evolve and has become a basic clinical tool that transforms diagnostic ultrasound into a functional imaging modality. In this review article, we present and explain in detail bubble imaging methods and associated artifacts, perfusion quantification approaches, and implementation considerations and regulatory aspects.

Diagnostic Ultrasound High Mechanical Index Impulses Restore Microvascular Flow in Peripheral Arterial Thromboembolism.

We sought to explore mechanistically how intermittent high-mechanical-index (MI) diagnostic ultrasound impulses restore microvascular flow. Thrombotic microvascular obstruction was created in the rat hindlimb muscle of 36 rats. A diagnostic transducer confirmed occlusion with low-MI imaging during an intravenous microbubble infusion. This same transducer was used to intermittently apply ultrasound with an MI that produced stable or inertial cavitation (IC) for 10 min through a tissue-mimicking phantom. A nitric oxide inhibitor, L-Nω-nitroarginine methyl ester (L-NAME), was pre-administered to six rats. Plateau microvascular contrast intensity quantified skeletal microvascular blood volume, and postmortem staining was used to detect perivascular hemorrhage. Intermittent IC impulses produced the greatest recovery of microvascular blood volume (p < 0.0001, analysis of variance). Nitric oxide inhibition did not affect the skeletal microvascular blood volume improvement, but did result in more perivascular hemorrhage. IC inducing pulses from a diagnostic transducer can reverse microvascular obstruction after acute arterial thromboembolism. Nitric oxide may prevent unwanted bio-effects of these IC pulses.

Improvements in cerebral blood flow and recanalization rates with transcranial diagnostic ultrasound and intravenous microbubbles after acute cerebral emboli.

OBJECTIVES: Intravenous microbubbles (MBs) and transcutaneous ultrasound have been used to recanalize intra-arterial thrombi without the use of tissue plasminogen activator. In the setting of acute ischemic stroke, it was our objective to determine whether skull attenuation would limit the ability of ultrasound alone to induce the type and level of cavitation required to dissolve thrombi and improve cerebral blood flow (CBF) in acute ischemic stroke. MATERIALS AND METHODS: In 40 pigs, bilateral internal carotid artery occlusions were created with 4-hour-old thrombi. Pigs were then randomized to high-mechanical index (MI = 2.4) short-pulse (5 microseconds) transcranial ultrasound (TUS) alone or a systemic MB infusion (3% Definity) with customized cavitation detection and imaging system transmitting either high-MI (2.4) short pulses (5 microseconds) or intermediate-MI (1.7) long pulses (20 microseconds). Angiographic recanalization rates of both internal carotids were compared in 24 of the pigs (8 per group), and quantitative analysis of CBF with perfusion magnetic resonance imaging was measured before, immediately after, and at 24 hours using T2* intensity versus time curves in 16 pigs. RESULTS: Complete angiographic recanalization was achieved in 100% (8/8) of pigs treated with image-guided high-MI TUS and MBs, but in only 4 of 8 treated with high-MI TUS alone or 3 of 8 pigs treated with image-guided intermediate-MI TUS and MBs (both P < 0.05). Ipsilateral and contralateral CBF improved at 24 hours only after 2.4-MI 5-microsecond pulse treatments in the presence of MB (P < 0.005). There was no evidence of microvascular or macrovascular hemorrhage with any treatment. CONCLUSIONS: Guided high-MI impulses from an ultrasound imaging system produce sustained improvements in ipsilateral and contralateral CBF after acute cerebral emboli.

Microbubble cavitation imaging.

Ultrasound cavitation of microbubble contrast agents has a potential for therapeutic applications such as sonothrombolysis (STL) in acute ischemic stroke. For safety, efficacy, and reproducibility of treatment, it is critical to evaluate the cavitation state (moderate oscillations, stable cavitation, and inertial cavitation) and activity level in and around a treatment area. Acoustic passive cavitation detectors (PCDs) have been used to this end but do not provide spatial information. This paper presents a prototype of a 2-D cavitation imager capable of producing images of the dominant cavitation state and activity level in a region of interest. Similar to PCDs, the cavitation imaging described here is based on the spectral analysis of the acoustic signal radiated by the cavitating microbubbles: ultraharmonics of the excitation frequency indicate stable cavitation, whereas elevated noise bands indicate inertial cavitation; the absence of both indicates moderate oscillations. The prototype system is a modified commercially available ultrasound scanner with a sector imaging probe. The lateral resolution of the system is 1.5 mm at a focal depth of 3 cm, and the axial resolution is 3 cm for a therapy pulse length of 20 µs. The maximum frame rate of the prototype is 2 Hz. The system has been used for assessing and mapping the relative importance of the different cavitation states of a microbubble contrast agent. In vitro (tissue-mimicking flow phantom) and in vivo (heart, liver, and brain of two swine) results for cavitation states and their changes as a function of acoustic amplitude are presented.

The stripe artifact in transcranial ultrasound imaging.

OBJECTIVE: Transcranial images are affected by a "stripe artifact" (also known as a "streak artifact"): two dark stripes stem radially from the apex to the base of the scan. The stripes limit the effective field of view even on patients with good temporal windows. This study investigated the angle dependency of ultrasound transmission through the skull to elucidate this artifact. METHODS: In vivo transcranial images were obtained to illustrate the artifact. In vitro hydrophone measurements were performed in water to evaluate transcranial wavefronts at different incidence angles of the ultrasound beam. Both a thin acrylic plate, as a simple bone model, and a human temporal bone sample were used. RESULTS: The imaging wavefront splits into two after crossing the solid layer (acrylic model or skull sample) at an oblique angle. An early-arrival wavefront originates from the direct longitudinal wave transmission through water-bone interfaces, while a late-arrival wavefront results from longitudinal-to-transverse mode conversion at the water-bone interface, propagation of the transverse wave through the skull, and transverse-to-longitudinal conversion at the bone-water interface. At normal incidence, only the direct wavefront (without mode conversion) is observed. As the incidence angle increases, the additional "mode conversion" wavefront appears. The amplitude of the transcranial wavefront decreases and reaches a minimum at an incidence angle of about 27°. Beyond that critical angle, only the mode conversion wavefront is transmitted. CONCLUSIONS: The stripes are a consequence of the angle-dependent ultrasound transmission and mode conversion at fluid-solid interfaces such as between the skull and the surrounding fluidlike soft tissues.