Brooks D. Lindsey

The Ultrasound Brain Helmet: Feasibility Study of Multiple Simultaneous 3D Scans of Cerebral Vasculature

We describe early stage experiments to test the feasibility of an ultrasound brain helmet to produce multiple simultaneous real-time three-dimensional (3D) scans of the cerebral vasculature from temporal and suboccipital acoustic windows of the skull. The transducer hardware and software of the Volumetrics Medical Imaging (Durham, NC, USA) real-time 3D scanner were modified to support dual 2.5 MHz matrix arrays of 256 transmit elements and 128 receive elements which produce two simultaneous 64 degrees pyramidal scans. The real-time display format consists of two coronal B-mode images merged into a 128 degrees sector, two simultaneous parasagittal images merged into a 128 degrees x 64 degrees C-mode plane and a simultaneous 64 degrees axial image. Real-time 3D color Doppler scans from a skull phantom with latex blood vessel were obtained after contrast agent injection as a proof of concept. The long-term goal is to produce real-time 3D ultrasound images of the cerebral vasculature from a portable unit capable of internet transmission thus enabling interactive 3D imaging, remote diagnosis and earlier therapeutic intervention. We are motivated by the urgency for rapid diagnosis of stroke due to the short time window of effective therapeutic intervention.

Dual-frequency piezoelectric transducers for contrast enhanced ultrasound imaging

For many years, ultrasound has provided clinicians with an affordable and effective imaging tool for applications ranging from cardiology to obstetrics. Development of microbubble contrast agents over the past several decades has enabled ultrasound to distinguish between blood flow and surrounding tissue. Current clinical practices using microbubble contrast agents rely heavily on user training to evaluate degree of localized perfusion. Advances in separating the signals produced from contrast agents versus surrounding tissue backscatter provide unique opportunities for specialized sensors designed to image microbubbles with higher signal to noise and resolution than previously possible. In this review article, we describe the background principles and recent developments of ultrasound transducer technology for receiving signals produced by contrast agents while rejecting signals arising from soft tissue. This approach relies on transmitting at a low-frequency and receiving microbubble harmonic signals at frequencies many times higher than the transmitted frequency. Design and fabrication of dual-frequency transducers and the extension of recent developments in transducer technology for dual-frequency harmonic imaging are discussed.

Acoustic characterization of contrast-to-tissue ratio and axial resolution for dual-frequency contrast-specific acoustic angiography imaging

Recently, dual-frequency transducers have enabled high-spatial-resolution and high-contrast imaging of vasculature with minimal tissue artifacts by transmitting at a low frequency and receiving broadband superharmonic echoes scattered by microbubble contrast agents. In this work, we examine the imaging parameters for optimizing contrast-totissue ratio (CTR) for dual-frequency imaging and the relationship with spatial resolution. Confocal piston transducers are used in a water bath setup to measure the SNR, CTR, and axial resolution for ultrasound imaging of nonlinear scattering of microbubble contrast agents when transmitting at a lower frequency (1.5 to 8 MHz) and receiving at a higher frequency (7.5 to 25 MHz). Parameters varied include the frequency and peak negative pressure of transmitted waves, center frequency of the receiving transducer, microbubble concentration, and microbubble size. CTR is maximized at the lowest transmission frequencies but would be acceptable for imaging in the 1.5 to 3.5 MHz range. At these frequencies, CTR is optimized when a receiving transducer with a center frequency of 10 MHz is used, with the maximum CTR of 25.5 dB occurring when transmitting at 1.5 MHz with a peak negative pressure of 1600 kPa and receiving with a center frequency of 10 MHz. Axial resolution is influenced more heavily by the receiving center frequency, with a weak decrease in measured pulse lengths associated with increasing transmit frequency. A microbubble population containing predominately 4-μm-diameter bubbles yielded the greatest CTR, followed by 1- and then 2-μm bubbles. Varying concentration showed little effect over the tested parameters. CTR dependence on transmit frequency and peak pressure were confirmed through in vivo imaging in two rodents. These findings may lead to improved imaging of vascular remodeling in superficial or luminal cancers such as those of the breast, prostate, and colon.

Molecular Acoustic Angiography: A New Technique for High-resolution Superharmonic Ultrasound Molecular Imaging

Ultrasound molecular imaging utilizes targeted microbubbles to bind to vascular targets such as integrins, selectins and other extracellular binding domains. After binding, these microbubbles are typically imaged using low pressures and multi-pulse imaging sequences. In this article, we present an alternative approach for molecular imaging using ultrasound that relies on superharmonic signals produced by microbubble contrast agents. Bound bubbles were insonified near resonance using a low frequency (4 MHz) element and superharmonic echoes were received at high frequencies (25-30 MHz). Although this approach was observed to produce declining image intensity during repeated imaging in both in vitro and in vivo experiments because of bubble destruction, the feasibility of superharmonic molecular imaging was demonstrated for transmit pressures, which are sufficiently high to induce shell disruption in bound microbubbles. This approach was validated using microbubbles targeted to the αvβ3 integrin in a rat fibrosarcoma model (n = 5) and combined with superharmonic images of free microbubbles to produce high-contrast, high-resolution 3-D volumes of both microvascular anatomy and molecular targeting. Image intensity over repeated scans and the effect of microbubble diameter were also assessed in vivo, indicating that larger microbubbles yield increased persistence in image intensity. Using ultrasound-based acoustic angiography images rather than conventional B-mode ultrasound to provide the underlying anatomic information facilitates anatomic localization of molecular markers. Quantitative analysis of relationships between microvasculature and targeting information indicated that most targeting occurred within 50 μm of a resolvable vessel (>100 μm diameter). The combined information provided by these scans may present new opportunities for analyzing relationships between microvascular anatomy and vascular targets, subject only to limitations of the current mechanically scanned system and microbubble persistence to repeated imaging at moderate mechanical indices.

The ultrasound brain helmet: new transducers and volume registration for in vivo simultaneous multi-transducer 3-D transcranial imaging

Because stroke remains an important and time-sensitive health concern in developed nations, we present a system capable of fusing 3-D transcranial ultrasound volumes acquired from two sides of the head. This system uses custom sparse array transducers built on flexible multilayer circuits that can be positioned for simultaneous imaging through both temporal acoustic windows, allowing for potential registration of multiple real-time 3-D scans of cerebral vasculature. We examine hardware considerations for new matrix arrays-transducer design and interconnects-in this application. Specifically, it is proposed that SNR may be increased by reducing the length of probe cables. This claim is evaluated as part of the presented system through simulation, experimental data, and in vivo imaging. Ultimately, gains in SNR of 7 dB are realized by replacing a standard probe cable with a much shorter flex interconnect; higher gains may be possible using ribbon-based probe cables. In vivo images are presented, showing cerebral arteries with and without the use of microbubble contrast agent; they have been registered and fused using a simple algorithm which maximizes normalized cross-correlation.

Optimization of Contrast-to-Tissue Ratio Through Pulse Windowing in Dual-Frequency “Acoustic Angiography” Imaging

Early-stage tumors in many cancers are characterized by vascular remodeling, indicative of transformations in cell function. We have previously presented a high-resolution ultrasound imaging approach to detecting these changes that is based on microbubble contrast agents. In this technique, images are formed from only the higher harmonics of microbubble contrast agents, producing images of vasculature alone with 100- to 200-μm resolution. In this study, shaped transmit pulses were used to image the higher broadband harmonic echoes of microbubble contrast agents, and the effects of varying pulse window and phasing on microbubble and tissue harmonic echoes were evaluated using a dual-frequency transducer in vitro and in vivo. An increase in the contrast-to-tissue ratio of 6.8 ± 2.3 dB was observed in vitro using an inverted pulse with a cosine window relative to a non-inverted pulse with a rectangular window. The increase in mean image intensity resulting from contrast enhancement in vivo in five rodents was 13.9 ± 3.0 dB greater for an inverted cosine-windowed pulse and 17.8 ± 3.6 dB greater for a non-inverted Gaussian-windowed pulse relative to a non-inverted pulse with a rectangular window. Implications for pre-clinical and diagnostic imaging are discussed.

Pitch-catch phase aberration correction of multiple isoplanatic patches for 3-D transcranial ultrasound imaging

Having previously presented the ultrasound brain helmet, a system for simultaneous 3-D ultrasound imaging via both temporal bone acoustic windows, the scanning geometry of this system is utilized to allow each matrix array to serve as a correction source for the opposing array. Aberration is estimated using cross-correlation of RF channel signals, followed by least mean squares solution of the resulting overdetermined system. Delay maps are updated and real-time 3-D scanning resumes. A first attempt is made at using multiple arrival time maps to correct multiple unique aberrators within a single transcranial imaging volume, i.e., several isoplanatic patches. This adaptive imaging technique, which uses steered unfocused waves transmitted by the opposing, or beacon, array, updates the transmit and receive delays of 5 isoplanatic patches within a 64° x 64° volume. In phantom experiments, color flow voxels above a common threshold have also increased by an average of 92%, whereas color flow variance decreased by an average of 10%. This approach has been applied to both temporal acoustic windows of two human subjects, yielding increases in echo brightness in 5 isoplanatic patches with a mean value of 24.3 ± 9.1%, suggesting that such a technique may be beneficial in the future for performing noninvasive 3-D color flow imaging of cerebrovascular disease, including stroke.

A 3 MHz/18 MHz dual-layer co-linear array for transrectal acoustic angiography

In this paper, a novel dual layer co-linear array ultrasound transducer was developed for transrectal dual-frequency superharmonic imaging. The KLM model and Field II were used for the acoustic stack design and simulation of the acoustic field of the array, respectively. The newly designed and fabricated probe consists of 50 transmit elements with a center frequency of 3 MHz and 100 receive elements with a center frequency of 18 MHz. The dimensions of the array are 15 mm in azimuth and 9 mm in elevation. The pitch is 270 μm for the transmitting elements and 135 μm for the receiving element. Pulse-echo testing of TX/RX elements corresponded with the simulation results. Real-time contrast imaging was tested using a multi-channel imaging system. The non-linear responses from microbubble contrast agents flowing through a 200 μm cellulose tube at a distance of 30 mm from the probe were clearly observed and displayed in the image. The axial beam width and CNR were calculated to be 200 μm and 18 dB, respectively. These results suggest that the prototyped co-linear array is capable of performing dual-frequency superharmonic imaging of microbubbles (“acoustic angiography”) for prostate cancer assessment.

The ultrasound brain helmet for 3D transcranial Doppler imaging

Transcranial Doppler imaging with contrast enhancement is a promising approach for visualizing a variety of cerebrovascular diseases requiring rapid treatment to minimize long-term effects. To address the time-sensitive nature of these diseases, we present a real-time 3D ultrasound scanner capable of simultaneously acquiring two trans-temporal volumes with color and spectral Doppler capabilities. To improve the clinical value of these scans, we also present fused, rendered 3D volumes and a rapid technique for registering these volumes. In an in vivo study, we were able to visualize blood flow in the internal carotid arteries, encouraging further development of this system. When combined with presented techniques for phase correction and instrumentation improvements, we envision these visualization techniques may potentially provide clinicians with a rapid, definitive tool to aid in diagnosis.

Intravascular forward-looking ultrasound transducers for microbubble-mediated sonothrombolysis.

Effective removal or dissolution of large blood clots remains a challenge in clinical treatment of acute thrombo-occlusive diseases. Here we report the development of an intravascular microbubble-mediated sonothrombolysis device for improving thrombolytic rate and thus minimizing the required dose of thrombolytic drugs. We hypothesize that a sub-megahertz, forward-looking ultrasound transducer with an integrated microbubble injection tube is more advantageous for efficient thrombolysis by enhancing cavitation-induced microstreaming than the conventional high-frequency, side-looking, catheter-mounted transducers. We developed custom miniaturized transducers and demonstrated that these transducers are able to generate sufficient pressure to induce cavitation of lipid-shelled microbubble contrast agents. Our technology demonstrates a thrombolysis rate of 0.7 ± 0.15 percent mass loss/min in vitro without any use of thrombolytic drugs.