Investigation of Physical Phenomena Underlying Temporal-Enhanced Ultrasound as a New Diagnostic Imaging Technique: Theory and Simulations.

Temporal-enhanced ultrasound (TeUS) is a novel noninvasive imaging paradigm that captures information from a temporal sequence of backscattered US radio frequency data obtained from a fixed tissue location. This technology has been shown to be effective for classification of various in vivo and ex vivo tissue types including prostate cancer from benign tissue. Our previous studies have indicated two primary phenomena that influence TeUS: 1) changes in tissue temperature due to acoustic absorption and 2) micro vibrations of tissue due to physiological vibration. In this paper, first, a theoretical formulation for TeUS is presented. Next, a series of simulations are carried out to investigate micro vibration as a source of tissue characterizing information in TeUS. The simulations include finite element modeling of micro vibration in synthetic phantoms, followed by US image generation during TeUS imaging. The simulations are performed on two media, a sparse array of scatterers and a medium with pathology mimicking scatterers that match nuclei distribution extracted from a prostate digital pathology data set. Statistical analysis of the simulated TeUS data shows its ability to accurately classify tissue types. Our experiments suggest that TeUS can capture the microstructural differences, including scatterer density, in tissues as they react to micro vibrations.

The Thrombolytic Effect of Diagnostic Ultrasound-Induced Microbubble Cavitation in Acute Carotid Thromboembolism.

BACKGROUND: Acute ischemic stroke is often due to thromboembolism forming over ruptured atherosclerotic plaque in the carotid artery (CA). The presence of intraluminal CA thrombus is associated with a high risk of thromboembolic cerebral ischemic events. The cavitation induced by diagnostic ultrasound high mechanical index (MI) impulses applied locally during a commercially available intravenous microbubble infusion has dissolved intravascular thrombi, especially when using longer pulse durations. The beneficial effects of this in acute carotid thromboembolism is not known. MATERIALS AND METHODS: An oversized balloon injury was created in the distal extracranial common CA of 38 porcine carotid arteries. After this, a 70% to 80% stenosis was created in the mid common CA proximal to the injury site using partial balloon inflation. Acute thrombotic CA occlusions were created just distal to the balloon catheter by injecting fresh autologous arterial thrombi. After angiographic documentation of occlusion, the common carotid thrombosis was treated with either diagnostic low MI imaging alone (0.2 MI; Philips S5-1) applied through a tissue mimicking phantom (TMP) or intermittent diagnostic high MI stable cavitation (SC)-inducing impulses with a longer pulse duration (0.8 MI; 20 microseconds' pulse duration) or inertial cavitation (IC) impulses (1.2 MI; 20 microseconds' pulse duration). All treatment times were for 30 minutes. Intravenous ultrasound contrast (2% Definity; Lantheus Medical) was infused during the treatment period. Angiographic recanalization in 4 intracranial and extracranial vessels downstream from the CA occlusion (auricular, ascending pharyngeal, buccinator, and maxillary) was assessed with both magnetic resonance 3-dimensional time-of-flight and phase contrast angiography. All magnetic resonance images were interpreted by an independent neuroradiologist using the thrombolysis in cerebral infarction (TICI) scoring system. RESULTS: By phase contrast angiography, at least mild recanalization (TICI 2a or higher) was seen in 64% of downstream vessels treated with SC impulses compared with 33% of IC treated and 29% of low MI alone treated downstream vessels (P = 0.001), whereas moderate or complete recanalization (TICI 2b or higher) was seen in 39% of SC treated vessels compared with 10% IC treated and 21% of low MI alone treated vessels (P = 0.001). CONCLUSIONS: High MI 20-microsecond pulse duration impulses during a commercial microbubble infusion can be used to recanalize acutely thrombosed carotid arteries and restore downstream flow without anticoagulants. However, this effect is only seen with SC-inducing impulses and not at higher mechanical indices, when a paradoxical reversal of the thrombolytic effect is observed. Diagnostic ultrasound-induced SC can be a nonsurgical method of dissolving CA thrombi and preventing thromboembolization.

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.

Using redundancy of round-trip ultrasound signal for non-continuous arrays: Application to gap and blockage compensation.

In ultrasound imaging, an array of elements is used to image a medium. If part of the array is blocked by an obstacle, or if the array is made from several sub-arrays separated by a gap, grating lobes appear and the image is degraded. The grating lobes are caused by missing spatial frequencies, corresponding to the blocked or non-existing elements. However, in an active imaging system, where elements are used both for transmitting and receiving, the round trip signal is redundant: different pairs of transmit and receive elements carry similar information. It is shown here that, if the gaps are smaller than the active sub-apertures, this redundancy can be used to compensate for the missing signals and recover full resolution. Three algorithms are proposed: one is based on a synthetic aperture method, a second one uses dual-apodization beamforming, and the third one is a radio frequency (RF) data based deconvolution. The algorithms are evaluated on simulated and experimental data sets. An application could be imaging through ribs with a large aperture.

A new sensor technology for 2D ultrasound-guided needle tracking.

2D Ultrasound (US) is becoming the preferred modality for image-guided interventions due to its low cost and portability. However, the main limitation is the limited visibility of surgical tools. We present a new sensor technology that can easily be embedded on needles that are used for US-guided interventions. Two different types of materials are proposed to be used as sensor--co-polymer and PZT. The co-polymer technology is particularly attractive due to its plasticity, allowing very thin depositions (10-20 µm) on a variety of needle shapes. Both sensors receive acoustic energy and convert it to an electrical signal. The precise location of the needle can then be estimated from this signal, to provide real-time feedback to the clinician. We evaluated the feasibility of this new technology using (i) a 4DOF robot in a water tank; (ii) extensive ex vivo experiments; and (iii) in vivo studies. Quantitative robotic studies indicated that the co-polymer is more robust and stable when compared to PZT. In quantitative experiments, the technology achieved a tracking accuracy of 0.14 ± 0.03mm, significantly superior to competing technologies. The technology also proved success in near-real clinical studies on tissue data. This sensor technology is non-disruptive of existing clinical workflows, highly accurate, and is cost-effective. Initial clinician feedback shows great potential for large scale clinical impact.

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.

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.

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.

A non-disruptive technology for robust 3D tool tracking for ultrasound-guided interventions.

In the past decade ultrasound (US) has become the preferred modality for a number of interventional procedures, offering excellent soft tissue visualization. The main limitation however is limited visualization of surgical tools. A new method is proposed for robust 3D tracking and US image enhancement of surgical tools under US guidance. Small US sensors are mounted on existing surgical tools. As the imager emits acoustic energy, the electrical signal from the sensor is analyzed to reconstruct its 3D coordinates. These coordinates can then be used for 3D surgical navigation, similar to current day tracking systems. A system with real-time 3D tool tracking and image enhancement was implemented on a commercial ultrasound scanner and 3D probe. Extensive water tank experiments with a tracked 0.2mm sensor show robust performance in a wide range of imaging conditions and tool position/orientations. The 3D tracking accuracy was 0.36 +/- 0.16mm throughout the imaging volume of 55 degrees x 27 degrees x 150mm. Additionally, the tool was successfully tracked inside a beating heart phantom. This paper proposes an image enhancement and tool tracking technology with sub-mm accuracy for US-guided interventions. The technology is non-disruptive, both in terms of existing clinical workflow and commercial considerations, showing promise for large scale clinical impact.

Effects of attenuation and thrombus age on the success of ultrasound and microbubble-mediated thrombus dissolution.

The purpose of this study was to examine the effects of applied mechanical index, incident angle, attenuation and thrombus age on the ability of 2-D vs. 3-D diagnostic ultrasound and microbubbles to dissolve thrombi. A total of 180 occlusive porcine arterial thrombi of varying age (3 or 6 h) were examined in a flow system. A tissue-mimicking phantom of varying thickness (5 to 10 cm) was placed over the thrombosed vessel and the 2-D or 3-D diagnostic transducer aligned with the thrombosed vessel using a positioning system. Diluted lipid-encapsulated microbubbles were infused during ultrasound application. Percent thrombus dissolution (%TD) was calculated by comparison of clot mass before and after treatment. Both 2-D and 3-D-guided ultrasound increased %TD compared with microbubbles alone, but %TD achieved with 6-h-old thrombi was significantly less than 3-h-old thrombi. Thrombus dissolution was achieved at 10 cm tissue-mimicking depths, even without inertial cavitation. In conclusion, diagnostic 2-D or 3-D ultrasound can dissolve thrombi with intravenous nontargeted microbubbles, even at tissue attenuation distances of up to 10 cm. This treatment modality is less effective, however, for older aged thrombi.

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.

Capon beamforming in medical ultrasound imaging with focused beams.

Medical ultrasound imaging is conventionally done by insonifying the imaged medium with focused beams. The backscattered echoes are beamformed using delay-and-sum operations that cannot completely eliminate the contribution of signals backscattered by structures off the imaging beam to the beamsum. It leads to images with limited resolution and contrast. This paper presents an adaptation of the Capon beamformer algorithm to ultrasound medical imaging with focused beams. The strategy is to apply data-dependent weight functions to the imaging aperture. These weights act as lateral spatial filters that filter out off-axis signals. The weights are computed for each point in the imaged medium, from the statistical analysis of the signals backscattered by that point to the different elements of the imaging probe when insonifying it with different focused beams. Phantom and in vivo images are presented to illustrate the benefits of the Capon algorithm over the conventional delay and-sum approach. On heart sector images, the clutter in the heart chambers is decreased. The endocardium border is better defined. On abdominal linear array images, significant contrast and resolution enhancement are observed.

Optimal adaptive focusing through heterogeneous media with the minimally invasive inverse filter.

The inverse filter is a technique used to adaptively focus waves through heterogeneous media. It is based on the inversion of the Green's functions matrix between the M transducers of a focusing array and N control points in the focal area. The inverse filter minimizes the pressure deposited around the focal point. However it is highly invasive, requiring the presence of N transducers or hydrophones in the focal area at the control points' locations to measure the Green's functions. This paper presents a way of reaching the inverse filter's focusing quality with a minimally invasive setup: only one transducer (at the desired focal location) is needed. This minimally invasive inverse filter takes advantage of the fact all the information about the propagation medium can be retrieved from the signals backscattered by the medium towards the focusing array, if the propagation medium is lossless. A numerical simulation is performed to test this minimally invasive inverse filter through a scattering, lossless medium. The focusing quality equals the conventional, highly invasive inverse filter's. The average spatial and temporal contrast is increased by up to 10 dB compared to the time reversal focusing.