Kai E. Thomenius

Subharmonic Imaging with Microbubble Contrast Agents: Initial Results

The subharmonic emission from insonified contrast microbubbles was used to create a new imaging modality called Subharmonic Imaging. The subharmonic response of contrast microbubbles to ultrasound pulses was first investigated for determining adequate acoustic transmit parameters. Subharmonic A-lines and gray scale images were then obtained using a laboratory pulse-echo system in vitro and a modified ultrasound scanner in vivo. Excellent suppression of all backscattered signals other than from contrast microbubbles was achieved for subharmonic A-lines in vitro while further optimization is required for in vivo gray scale subharmonic images.

Contrast-Enhanced Ultrasound Imaging of the Vasa Vasorum: From Early Atherosclerosis to the Identification of Unstable Plaques

Proliferation of the adventitial vasa vasorum (VV) is inherently linked with early atherosclerotic plaque development and vulnerability. Recently, direct visualization of arterial VV and intraplaque neovascularization has emerged as a new surrogate marker for the early detection of atherosclerotic disease. This clinical review focuses on contrast-enhanced ultrasound (CEUS) as a noninvasive application for identifying and quantifying carotid and coronary artery VV and intraplaque neovascularization. These novel approaches could potentially impact the clinicians ability to identify individuals with premature cardiovascular disease who are at high risk. Once clinically validated, the uses of CEUS may provide a method to noninvasively monitor therapeutic interventions. In the future, the therapeutic use of CEUS may include ultrasound-directed, site-specific therapies using microbubbles as vehicles for drug and gene delivery systems. The combined applications for diagnosis and therapy provide unique opportunities for clinicians to image and direct therapy for individuals with vulnerable lesions.

American Institute of Ultrasound in Medicine consensus report on potential bioeffects of diagnostic ultrasound: Executive summary

The continued examination of potential biological effects of ultrasound and their relationship to clinical practice is a key element in evaluating the safety of diagnostic ultrasound. Periodically, the American Institute of Ultrasound in Medicine (AIUM) sponsors conferences bringing experts together to examine the literature on ultrasound bioeffects and to develop conclusions and recommendations related to diagnostic ultrasound. The most recent effort included the examination of effects whose origins were thermal or nonthermal, with separate evaluations for potential effects related to fetal ultrasound. In addition, potential effects due to the introduction of ultrasound contrast agents were summarized. This information can be used to assess risks in comparison to the benefits of diagnostic ultrasound. The conclusions and recommendations are organized into 5 broad categories, with a comprehensive background and evaluation of each topic provided in the corresponding articles in this issue. The following summary is not meant as a substitute for the detailed examination of issues presented in each of the articles but rather as a means to facilitate further study of this consensus report and implementation of its recommendations. The conclusions and recommendations are the result of several rounds of deliberations at the consensus conference, subsequent review by the Bioeffects Committee of the AIUM, and approval by the AIUM Board of Governors.

Combination of digital mammography with semi-automated 3D breast ultrasound

This paper describes work aimed at combining 3D ultrasound with full-field digital mammography via a semi-automatic prototype ultrasound scanning mechanism attached to the digital mammography system gantry. Initial efforts to obtain high x-ray and ultrasound image quality through a compression paddle are proving successful. Registration between the x-ray mammogram and ultrasound image volumes is quite promising when the breast is stably compressed. This prototype system takes advantage of many synergies between the co-registered digital mammography and pulse-echo ultrasound image data used for breast cancer detection and diagnosis. In addition, innovative combinations of advanced US and X-ray applications are being implemented and tested along with the basic modes. The basic and advanced applications are those that should provide relatively independent information about the breast tissues. Advanced applications include x-ray tomosynthesis, for 3D delineation of mammographic structures, and non-linear elasticity and 3D color flow imaging by ultrasound, for mechanical and physiological information unavailable from conventional, non-contrast x-ray and ultrasound imaging.

A Suggested Roadmap for Cardiovascular Ultrasound Research for the Future

Sanjiv Kaul, MD, FASE,* James G. Miller, PhD,* Paul A. Grayburn, MD, Shinichi Hashimoto,Mark Hibberd, MD, PhD, Mark R. Holland, PhD, FASE, Helene C. Houle, BA, RDMS, RDCS, RVT, FASE,Allan L. Klein, MD, FASE, Peg Knoll, RDCS, FASE, Roberto M. Lang, MD, FASE,Jonathan R. Lindner, MD, FASE, Marti L. McCulloch, RDCS, FASE, Stephen Metz, PhD,Victor Mor-Avi, PhD, FASE, Alan S. Pearlman, MD, FASE, Patricia A. Pellikka, MD, FASE, Nancy DeMarsPlambeck,BS,RDMS,RDCS,RVT,DavidPrater,MS, ThomasR.Porter,MD,FASE,DavidJ.Sahn,MD,FASE,James D. Thomas, MD, FASE, Kai E. Thomenius, PhD, and Neil J. Weissman, MD, FASEINTRODUCTIONThe leadership at the American Society of Echocardiography (ASE)decided on a proactive role in defining selected areas of researchnecessary in this decade that will meet our future clinical needs.Consequently, ASE sponsored a Technology and ResearchSummit in the fall of 2010 in conjunction with the AmericanHeart Association Scientific Sessions in Chicago. In addition to theASE executive committee, in attendance were the editor, deputyeditor, and one of the associate editors of the Journal of theAmerican Society of Echocardiography. Also invited were physician-scientists active in the field of cardiovascular ultrasound, respectedultrasound physicists, and senior engineers from the various ultra-sound companies.The agenda for the full-day meeting covered a selected range ofsubjects including the assessment of global and regional left ventricu-lar function, regional myocardialperfusion, molecular imaging, thera-peutic ultrasound, and peripheral vascular imaging. Also addressedwere research necessary to determine the broad clinical utility ofhand held ultrasound devices and the impact of future technologicaldevelopments on the field of cardiovascular imaging.Because of time constraints, other important and worthy areas ofresearch were not discussed. There was an hour devoted to the dis-cussion of each subject that was initiated by the chairs and panelistsassigned to each of the topics. The discussion was robust, and at theend, the chairs and panelists for each topic were requested to sub-mit in writing a short synopsis of the discussion. These have beencompiled into a document that we believe will serve as a roadmapfor cardiovascular ultrasound research for this decade. At the endof each section a short list of references for selected reading isprovided.Although we have defined the areas that are ripe for future re-search, we also strongly believe that we havetotrain the future scien-tists who will implement this research agenda. ASE has historicallyawarded one or two fellowship training grants a year and also anaward for researchtraining of a sonographer. At some institutions fel-lowshavealsoreceivedtraininggrantsfromthelocalAmericanHeartAssociation, and very occasionally a training grant (F32) from theNational Institutes of Health. However, this is not enough. We needmore institutional training grants from the National Institutes ofHealth in order to train an adequate number of MD and PhD scien-tists in cardiovascular imaging. To our knowledge there are currentlyonlyahandfulofsuchtraininggrantsinthecountry,whichiswoefullyinadequate. We believe that we need at least 20–25 such traininggrants devoted to the general field of cardiovascular imaging so thatwithin a decade there will be enough physicians trained in scientificmethods and clinical research to address the subjects that havebeen discussed in this report.The field of cardiovascular ultrasound is very broad, ranging fromclinical validation of new technology to studies requiring knowledgeof physics, mathematics, organic chemistry, physiology, pharmacol-ogy, molecular and vascular biology, genetics, clinical trials, and out-come research. Cross-training of individuals in one or more of thesefields is essential for cardiovascular ultrasound to thrive and succeed.Ourhopeisthatthisreportwillencourageyoungpeopletorealizethescope of cardiac ultrasound research and make a career in this dy-namic field.Selected Reading

Automated Ultrasound Scanning on a Dual-Modality Breast Imaging System Coverage and Motion Issues and Solutions

We are developing an automated ultrasound imaging‐mammography system wherein a digital mammography unit has been augmented with a motorized ultrasound transducer carriage above a special compression paddle. Challenges of this system are acquiring complete coverage of the breast and minimizing motion. We assessed these problems and investigated methods to increase coverage and stabilize the compressed breast.

Subharmonic Contrast Microbubble Signals for Noninvasive Pressure Estimation under Static and Dynamic Flow Conditions

Our group has proposed the concept of subharmonic aided pressure estimation (SHAPE) utilizing microbubble-based ultrasound contrast agent signals for the noninvasive estimation of hydrostatic blood pressures. An experimental system for in vitro SHAPE was constructed based on two single-element transducers assembled confocally at a 60° angle to each other. Changes in the first, second and subharmonic amplitudes of five different ultrasound contrast agents were measured in vitro at static hydrostatic pressures from 0–186 mmHg, acoustic pressures from 0.35–0.60 MPa peak-to-peak and frequencies of 2.5–6.6 MHz. The most sensitive agent and optimal parameters for SHAPE were determined using linear regression analysis and implemented on a Logiq 9 scanner (GE Healthcare, Milwaukee, WI). This implementation of SHAPE was then tested under dynamic-flow conditions and compared to pressure-catheter measurements. Over the pressure range studied, the first and second harmonic amplitudes reduced approximately 2 dB for all contrast agents. Over the same pressure range, the subharmonic amplitudes decreased by 9–14 dB and excellent linear regressions were achieved with the hydrostatic pressure variations (r2 = 0.98, p < 0.001). Optimal sensitivity was achieved at a transmit frequency of 2.5 MHz and acoustic pressure of 0.35 MPa using Sonazoid (GE Healthcare, Oslo, Norway). A Logiq 9 scanner was modified to implement SHAPE on a convex transducer with a frequency range from 1.5–4.5 MHz and acoustic pressures from 0–3.34 MPa. Results matched the pressure catheter (r2 = 0.87). In conclusion, subharmonic contrast signals are a good indicator of hydrostatic pressure. Out of the five ultrasound contrast agents tested, Sonazoid was the most sensitive for subharmonic pressure estimation. Real-time SHAPE has been implemented on a commercial scanner and offers the possibility of allowing pressures in the heart and elsewhere to be obtained noninvasively.

Simultaneous grayscale and subharmonic ultrasound imaging on a modified commercial scanner

OBJECTIVE To demonstrate the feasibility of simultaneous dual fundamental grayscale and subharmonic imaging on a modified commercial scanner. MOTIVATION The ability to generate signals at half the insonation frequency is exclusive to ultrasound contrast agents (UCA). Thus, subharmonic imaging (SHI; transmitting at f(0) and receiving at f(0)/2) provides improved visualization of UCA within the vasculature via suppression of the surrounding tissue echoes. While this capability has proven useful in a variety of clinical applications, the SHI suppression of surrounding tissue landmarks (which are needed for sonographic navigation) also limits it use as a primary imaging modality. In this paper we present results using a commercial ultrasound scanner modified to allow imaging in both grayscale (f(0)=4.0 MHz) and SHI (f(0)=2.5 MHz, f(0)/2=1.25 MHz) modes in real time. METHODS A Logiq 9 ultrasound scanner (GE Healthcare, Milwaukee, WI) with a 4C curvilinear probe was modified to provide this capability. Four commercially available UCA (Definity, Lantheus Medical Imaging, North Billerica, MA; Optison, GE Healthcare, Princeton, NJ; SonoVue, Bracco Imaging, Milan, Italy; and Sonazoid, GE Healthcare, Oslo, Norway) were all investigated in vitro over an acoustic output range of 3.34 MPa. In vivo the subharmonic response of Sonazoid was investigated in the portal veins of four canines (open abdominal cavity) and four patients with suspected portal hypertension. RESULTS In vitro, the four UCA showed an average maximum subharmonic amplitude of 44.1±5.4 dB above the noise floor with a maximum subharmonic amplitude of 48.6±1.6 dB provided by Sonazoid. The average in vivo maximum signal above the noise floor from Sonazoid was 20.8±2.3 dB in canines and 33.9±5.2 dB in humans. Subharmonic amplitude as a function of acoustic output in both groups matched the S-curve behavior of the agent observed in vitro. The dual grayscale imaging provided easier sonographic navigation, while the degree of tissue suppression in SHI mode varied greatly on a case by case basis. CONCLUSIONS These results demonstrate the feasibility of dual grayscale and SHI on a modified commercial scanner. The ability to simultaneously visualize both imaging modes in real time should improve the applicability of SHI as a future primary clinical imaging modality.

Forward-looking volumetric intracardiac imaging using a fully integrated CMUT ring array

Atrial fibrillation is the most common type of cardiac arrhythmia that now affects over 2.2 million adults in the United States alone. Currently fluoroscopy is the most common method for guiding interventional electrophysiological procedures. We are developing a 9-F forward-looking intracardiac ultrasound catheter for real-time volumetric imaging. We designed and fabricated a 64-element 10-MHz CMUT ring array with through-wafer via interconnects. We also designed custom front-end electronics to be closely integrated with the CMUT array at the tip of the catheter for improved SNR. This integrated circuit (IC) is composed of preamplifiers and protection circuitry, and can directly interface a standard imaging system. This multi-channel IC is capable of passing up to ±50-V bipolar pulses. An 8-channel front-end IC was fabricated based on this circuit topology. Additionally, a flexible PCB was designed for the integration of ring array with front-end electronics. We have acquired a PC-based real-time imaging platform and demonstrated real-time imaging with the ring array. We have also shown volume images using off-line full synthetic aperture image reconstruction method. The presented experimental results demonstrate the performance of our forward-looking volumetric intracardiac imaging approach. We are currently working on the final catheter integration and further development of our real-time imaging methods.

Reconfigurable arrays for portable ultrasound

A collaborative effort is aimed at the development of reconfigurable array technology. The goal is to enable innovative medical ultrasound imagers ideally suited for portable ultrasound and applications such as remote emergency medicine and combat casualty care. Success depends on developing several technologies, the first of which is capacitive micromachined ultrasound transducers (cMUTs). The monolithic nature of cMUTs facilitates close connection with microelectronics. Thus a second technology under development is a switch matrix application specific integrated circuit (ASIC) that will enable the changing of interconnect between cMUT cells. The reconfigurable array concept arises from this ability to dynamically combine cMUT cells to form ideal apertures for a given imaging target (e.g. annular and phased apertures of various ring widths) and to move these apertures across the reconfigurable array plane [1-4]. Two central hypotheses are being tested: (1) the reconfigurable array can acquire acoustic pulse-echo data in a manner equivalent or superior to today’s 1D piezoceramic arrays (2) reconfigurable array technology will enable highly portable ultrasound platforms. Keywords-reconfigurable; annular; array; cMUT; ASIC; switch matrix; dynamic; phased; real-time