Jeffry E. Powers

A new imaging technique based on the nonlinear properties of tissues

Finite amplitude sound propagating in a medium undergoes distortion due to the nonlinear properties of the medium. The nonlinear distortion produces harmonic (and subharmonic) energy in the propagating signal. The amplitudes used by commercial medical scanners during routine diagnostic scanning are in most cases finite and thus within the range that produces nonlinear distortion. Thermoviscous absorption of tissue which is frequency dependent rapidly dissipates this harmonic energy. This has led to the widely held assumption that nonlinear distortion was not a significant factor in medical diagnostic imaging. However, the wide dynamic range, digital architecture, and the signal processing capabilities of modern diagnostic ultrasound systems make it possible to utilize this tissue generated harmonic energy for image formation. These images often demonstrate reduced nearfield artifacts and improved tissue structure visualization. Previously, those images were believed to be the result of transmitted second harmonic energy. It is shown that the nonlinear properties of tissue are the major contribution of harmonic images.

Imaging instrumentation for ultrasound contrast agents

The past decade has seen dramatic improvements in ultrasound imaging system performance. The introduction of color Doppler imaging has added a new dimension to blood flow measurement, displaying blood flow as a real-time map over a two-dimensional image rather than as a spectrum from the single point of pulsed Doppler or the single line of continuous wave Doppler. The more recent refinement of power Doppler (also known as Color Power AngiographyTM) has increased the imaging sensitivity of color Doppler to the point where images such as that shown in Figure 1 have become common place. If the function of a contrast agent is to enhance the echo from blood, is such help needed with state of the art ultrasound instruments? We believe that it is. First, not all patients yield images like that shown in Figure 1, nor can such images be obtained in all anatomical locations. Contrast agents can extend the anatomical scope, and hence the clinical utility, of conventional ultrasound imaging. Second, as we shall see, contrast agents allow renegotiation of some of the fundamental compromises inherent in a blood flow image and allow system design changes which result in improvements that go far beyond Doppler signal enhancement.

Effects of Acoustic Radiation Force on the Binding Efficiency of BR55, a VEGFR2-Specific Ultrasound Contrast Agent

This work describes an in vivo study analyzing the effect of acoustic radiation force (ARF) on the binding of BR55 VEGFR2-specific contrast-agent microbubbles in a model of prostatic adenocarcinoma in rat. A commercial ultrasound system was modified by implementing high duty-cycle 3.5-MHz center frequency ARF bursts in a scanning configuration. This enabled comparing the effects of ARF on binding in tumor and healthy tissue effectively in the same field of view. Bubble binding was established by measuring late-phase enhancement in amplitude modulation (AM) contrast-specific imaging mode (4 MHz, 150 kPa) 10 min after agent injection when the unbound bubbles were cleared from the circulation. Optimal experimental conditions, such as agent concentration (0.4 × 10(8)-1.6 × 10(8) bubbles/kg), acoustic pressure amplitude (26-51 kPa) and duty-cycle (20%-95%) of the ARF bursts, were evaluated in their ability to enhance binding in tumor without significantly increasing binding in healthy tissue. Using the optimal conditions (38 kPa peak-negative pressure, 95% duty cycle), ARF-assisted binding of BR55 improved significantly in tumor (by a factor of 7) at a lower agent dose compared with binding without ARF, and it had an insignificant effect on binding in healthy tissue. Thus, the high binding specificity of BR55 microbubbles for targeting VEGFR2 present at sites of active angiogenesis was confirmed by this study. Therefore, it is believed that based on the results obtained in this work, ultrasound molecular imaging using target-specific contrast-agent microbubbles should preferably be performed in combination with ARF.

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.

Diagnostic Ultrasound Induced Inertial Cavitation to Non-Invasively Restore Coronary and Microvascular Flow in Acute Myocardial Infarction

Ultrasound induced cavitation has been explored as a method of dissolving intravascular and microvascular thrombi in acute myocardial infarction. The purpose of this study was to determine the type of cavitation required for success, and whether longer pulse duration therapeutic impulses (sustaining the duration of cavitation) could restore both microvascular and epicardial flow with this technique. Accordingly, in 36 hyperlipidemic atherosclerotic pigs, thrombotic occlusions were induced in the mid-left anterior descending artery. Pigs were then randomized to either a) ½ dose tissue plasminogen activator (0.5 mg/kg) alone; or same dose plasminogen activator and an intravenous microbubble infusion with either b) guided high mechanical index short pulse (2.0 MI; 5 usec) therapeutic ultrasound impulses; or c) guided 1.0 mechanical index long pulse (20 usec) impulses. Passive cavitation detectors indicated the high mechanical index impulses (both long and short pulse duration) induced inertial cavitation within the microvasculature. Epicardial recanalization rates following randomized treatments were highest in pigs treated with the long pulse duration therapeutic impulses (83% versus 59% for short pulse, and 49% for tissue plasminogen activator alone; p<0.05). Even without epicardial recanalization, however, early microvascular recovery occurred with both short and long pulse therapeutic impulses (p<0.005 compared to tissue plasminogen activator alone), and wall thickening improved within the risk area only in pigs treated with ultrasound and microbubbles. We conclude that although short pulse duration guided therapeutic impulses from a diagnostic transducer transiently improve microvascular flow, long pulse duration therapeutic impulses produce sustained epicardial and microvascular re-flow in acute myocardial infarction.

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.

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

ObjectivesIntravenous 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 MethodsIn 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. ResultsComplete 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. ConclusionsGuided high-MI impulses from an ultrasound imaging system produce sustained improvements in ipsilateral and contralateral CBF after acute cerebral emboli.

Nonlinear pulsing schemes for the detection of ultrasound contrast agents

Ultrasound contrast agents are used in cardiology for the assessment of myocardial perfusion and in radiology for the detection and characterization of tumors. One widely used approach of imaging contrast agents is to use a low Mechanical Index (MI) nonlinear imaging technique to avoid bubble destruction and image both the macro‐ and micro‐circulation in real‐time. Various pulsing schemes are employed for the detection of nonlinear echoes from contrast microbubbles. The objective of this paper is to evaluate the various pulsing schemes for low MI imaging of contrast microbubbles and better understand their similarities and differences. The pulsing schemes considered are pulse inversion, power modulation, and their combination. Emphasis is placed on identifying whether nonlinearity due to propagation in tissue may be discriminated from nonlinearity due to scattering from bubbles. Bubble destruction (use of high MI) and tissue motion were not considered in this work. The evaluation of the different pulsing ...

Real-Time Two-Dimensional Imaging of Microbubble Cavitation

Ultrasound cavitation of microbubble contrast agents has a potentialfor therapeutic applications, including sonothrombolysis in acute ischemic stroke. For safety, efficacy, and reproducibility of treatment, it is critical to evaluate the cavitation state (e.g. stable versus inertial forms of cavitation) and intensity in and around a treatment area. Acoustic Passive Cavitation Detectors (PCDs) have been used but lack spatial information. This paper presents a prototype ofa 2D cavitation imager capable of producing images of the dominantcavitation state and intensity in a region of interest at a frame rate of 0.6Hz. The system is based on a commercial ultrasound scannerand imaging probe (iE33 scanner with S5-1 probe, Philips). Cavitation imaging is based on the spectral analysis of acoustic signal radiated by the cavitating microbubbles: ultraharmonics of the excitationfrequency indicate stable cavitation, while noise bands indicate inertial cavitation. The system demonstrates the capability to robustly identify stable and inertial cavitation thresholds of Definity microbubbles (Lantheus) in a vessel phantom through 3 ex-vivo human temporal bones, as well as to spatially discriminate the location of cavitation activities.

Investigation of image-guided sonothrombolysis in a porcine acute ischemic stroke model

Image-guided sonothrombolysis was prototyped on a modified ultrasound imaging system iE33 and further evaluated using a porcine acute ischemic stroke model. After 20 to 40 minute sonothrombolysis treatment with systemic infusion of Definity microbubbles, contrast reperfusion and arterial recanalization were observed on low MI ultrasound contrast imaging and X-ray based angiography, respectively. The study indicates that a modified diagnostic imaging system can be utilized with systemic microbubble infusion to rapidly restore cerebral blood flow in acute ischemic stroke.