Pier Ingram

Four-dimensional ultrasound current source density imaging of a dipole field.

Ultrasound current source density imaging (UCSDI) potentially transforms conventional electrical mapping of excitable organs, such as the brain and heart. For this study, we demonstrate volume imaging of a time-varying current field by scanning a focused ultrasound beam and detecting the acoustoelectric (AE) interaction signal. A pair of electrodes produced an alternating current distribution in a special imaging chamber filled with a 0.9% NaCl solution. A pulsed 1 MHz ultrasound beam was scanned near the source and sink, while the AE signal was detected on remote recording electrodes, resulting in time-lapsed volume movies of the alternating current distribution.

Measuring the acoustoelectric interaction constant using ultrasound current source density imaging

Ultrasound current source density imaging (UCSDI) exploits the acoustoelectric (AE) effect, an interaction between ultrasound pressure and electrical resistivity, to map electrical conduction in the heart. The conversion efficiency for UCSDI is determined by the AE interaction constant K, a fundamental property of all materials; K directly affects the magnitude of the detected voltage signal in UCSDI. This paper describes a technique for measuring K in biological tissue, and reports its value for the first time in cadaver hearts. A custom chamber was designed and fabricated to control the geometry for estimating K, which was measured in different ionic salt solutions and seven cadaver rabbit hearts. We found K to be strongly dependent on concentration for the divalent salt CuSO(4), but not for the monovalent salt NaCl, consistent with their different chemical properties. In the rabbit heart, K was determined to be 0.041 ± 0.012%/MPa, similar to the measurement of K in physiological saline (0.034 ± 0.003%/MPa). This study provides a baseline estimate of K for modeling and experimental studies that involve UCSDI to map cardiac conduction and reentry currents associated with arrhythmias.

Intracellular delivery and ultrasonic activation of folate receptor-targeted phase-change contrast agents in breast cancer cells in vitro

Breast cancer is a diverse and complex disease that remains one of the leading causes of death among women. Novel, outside-of-the-box imaging and treatment methods are needed to supplement currently available technologies. In this study, we present evidence for the intracellular delivery and ultrasound-stimulated activation of folate receptor (FR)-targeted phase-change contrast agents (PCCAs) in MDA-MB-231 and MCF-7 breast cancer cells in vitro. PCCAs are lipid-coated, perfluorocarbon-filled particles formulated as nanoscale liquid droplets capable of vaporization into gaseous microbubbles for imaging or therapy. Cells were incubated with 1:1 decafluorobutane (DFB)/octafluoropropane (OFP) PCCAs for 1h, imaged via confocal microscopy, exposed to ultrasound (9MHz, MI=1.0 or 1.5), and imaged again after insonation. FR-targeted PCCAs were observed intracellularly in both cell lines, but uptake was significantly greater (p<0.001) in MDA-MB-231 cells (93.0% internalization at MI=1.0, 79.5% at MI=1.5) than MCF-7 cells (42.4% internalization at MI=1.0, 35.7% at MI=1.5). Folate incorporation increased the frequency of intracellular PCCA detection 45-fold for MDA-MB-231 cells and 7-fold for MCF-7 cells, relative to untargeted PCCAs. Intracellularly activated PCCAs ranged from 500nm to 6μm (IQR=800nm-1.5μm) with a mean diameter of 1.15±0.59 (SD) microns. The work presented herein demonstrates the feasibility of PCCA intracellular delivery and activation using breast cancer cells, illuminating a new platform toward intracellular imaging or therapeutic delivery with ultrasound.

Optimizing frequency and pulse shape for ultrasound current source density imaging

Electric field mapping is commonly used to identify irregular conduction pathways in the heart (e.g., arrhythmia) and brain (e.g., epilepsy). A new technique, ultrasound current source density imaging (UCSDI) based on the acoustoelectric (AE) effect, provides an alternative method for current activity mapping in four-dimension with high resolution. The ultrasound transducer frequency and pulse shape significantly affect the sensitivity and spatial resolution of UCSDI. In this paper, we analyze the tradeoff between spatial resolution and sensitivity in UCSDI from two aspects: (1) ultrasound transducer frequency and (2) coded excitation pulses. For frequency dependence, we imaged an electric dipole using ultrasound transducers with different center frequencies (1 MHz and 2.25 MHz) and compared the sensitivity and resolution. For coded excitation, we measured AE signals with chirp excitation at 1 MHz and demonstrated improved sensitivity for chirps (3.5 μV/mA at 1 MHz) compared with square pulse excitation (1.6 μV/mA). Pulse compression was also applied to preserve spatial resolution, demonstrating enhanced detection while preserving spatial resolution.

Detection of multiple electrical sources in tissue using ultrasound current source density imaging

Accurate three dimensional (3D) mapping of bioelectric sources in the body with high spatial resolution is important for the diagnosis and treatment of a variety of cardiac and neurological disorders. Ultrasound current source density imaging (UCSDI) is a new technique that maps electrical current flow in tissue. UCSDI is based on the acousto-electric (AE) effect, an interaction between electrical current and acoustic pressure waves propagating through a conducting material and has distinct advantages over conventional electrophysiology (i.e., without ultrasound). In this study, UCSDI was used to simultaneously image current flow induced in two tissue phantoms positioned at different depths. Software to simulate AE signal was developed in Matlab™ to complement the experimental model and further characterize the relationship between the ultrasound beam and electrical properties of the tissue. Both experimental and simulated images depended on the magnitude and direction of the current, as well as the geometry (shape and thickness) and location of the current sources in the ultrasound field (2.25MHz transducer). The AE signal was proportional to pressure and current with detection levels on the order of 1 mA/cm2 at 258kPa. We have imaged simultaneously two separate current sources in tissue slabs using UCSDI and two bridge circuits to accurately monitor current flow through each source. These results are consistent with UCSDI simulations of multiple current sources. Real-time 3D UCSD images of current flow automatically co-registered with pulse echo ultrasound potentially facilitates corrective procedures for cardiac and neural abnormalities.

Simulation-based optimization of the acoustoelectric hydrophone for mapping an ultrasound beam

Most single element hydrophones depend on a piezoelectric material that converts pressure changes to electricity. These devices, however, can be expensive, susceptible to damage at high pressure, and/or have limited bandwidth and sensitivity. The acousto-electric (AE) hydrophone is based on the AE effect, an interaction between electrical current and acoustic pressure generated when acoustic waves travel through a conducting material. As we have demonstrated previously, an AE hydrophone requires only a conductive material and can be constructed out of common laboratory supplies to generate images of an ultrasound beam pattern consistent with more expensive hydrophones. The sensitivity is controlled by the injected bias current, hydrophone shape, thickness and width. In this report we describe simulations aimed at optimizing the design of the AE hydrophone with experimental validation using new devices composed of a resistive element of indium tin oxide (ITO). Several shapes (e.g., bowtie and dumbbell) and resistivities were considered. The AE hydrophone with a dumbbell configuration achieved the best beam pattern of a 2.25MHz ultrasound transducer with lateral and axial resolutions consistent with images generated from a commercial hydrophone (Onda Inc.). The sensitivity of this device was ~2 nV/Pa. Our simulations and experimental results both indicate that designs using a combination of ITO and gold (ratio of resistivities = ~18) produce the best results. We hope that design optimization will lead to new devices for monitoring ultrasonic fields for biomedical imaging and therapy, including lithotripsy and focused ultrasound surgery.

Ultrasound Current Source Density Imaging of the Cardiac Activation Wave Using a Clinical Cardiac Catheter

Ultrasound current source density imaging (UCSDI), based on the acoustoelectric (AE) effect, is a noninvasive method for mapping electrical current in 4-D (space + time). This technique potentially overcomes limitations with conventional electrical mapping procedures typically used during treatment of sustained arrhythmias. However, the weak AE signal associated with the electrocardiogram is a major challenge for advancing this technology. In this study, we examined the effects of the electrode configuration and ultrasound frequency on the magnitude of the AE signal and quality of UCSDI using a rabbit Langendorff heart preparation. The AE signal was much stronger at 0.5 MHz (2.99 μV/MPa) than 1.0 MHz (0.42 μV/MPa). Also, a clinical lasso catheter placed on the epicardium exhibited excellent sensitivity without penetrating the tissue. We also present, for the first time, 3-D cardiac activation maps of the live rabbit heart using only one pair of recording electrodes. Activation maps were used to calculate the cardiac conduction velocity for atrial (1.31 m/s) and apical (0.67 m/s) pacing. This study demonstrated that UCSDI is potentially capable of realtime 3-D cardiac activation wave mapping, which would greatly facilitate ablation procedures for treatment of arrhythmias.

Experimental Validation of a Numerical Model for Thermoacoustic Imaging Applications

Owing to its intrinsic advantages of favorable contrast and spatial resolution, microwave-induced thermoacoustic imaging (TAI) has drawn great attention in biomedical imaging applications, such as breast cancer detection. Many experimental studies have demonstrated the promising potential of TAI. Several TAI modeling studies have also been published that facilitate the design and optimization of TAI systems. However, experimental validation of the modeling results is rarely seen; thus it is highly desirable to prove the effectiveness of the modeling approach. In this letter, the TAI modeling approach previously described by our group is validated by experiments. A three-dimensional printed polymer slab with featured structures is used as the sample to be investigated by both the model and the experiment. Images are obtained to reveal the featured structures in the slab from both the modeling and experimental results. Rigorous comparisons between the modeling and experimental imaging results are carried out. The achieved good agreement between the images corroborates the validity of the TAI modeling approach and thereby encourages more applications of it.

Design considerations and performance of MEMS acoustoelectric ultrasound detectors

Most single-element hydrophones depend on a piezoelectric material that converts pressure changes to electricity. These devices, however, can be expensive, susceptible to damage at high pressure, and/or have limited bandwidth and sensitivity. We have previously described the acoustoelectric (AE) hydrophone as an inexpensive alternative for mapping an ultrasound beam and monitoring acoustic exposure. The device exploits the AE effect, an interaction between electrical current flowing through a material and a propagating pressure wave. Previous designs required imprecise fabrication methods using common laboratory supplies, making it difficult to control basic features such as shape and size. This study describes a different approach based on microelectromechanical systems (MEMS) processing that allows for much finer control of several design features. In an effort to improve the performance of the AE hydrophone, we combine simulations with bench-top testing to evaluate key design features, such as thickness, shape, and conductivity of the active and passive elements. The devices were evaluated in terms of sensitivity, frequency response, and accuracy for reproducing the beam pattern. Our simulations and experimental results both indicated that designs using a combination of indium tin oxide (ITO) for the active element and gold for the passive electrodes (conductivity ratio = ~20) produced the best result for mapping the beam of a 2.25-MHz ultrasound transducer. Also, the AE hydrophone with a rectangular dumbbell configuration achieved a better beam pattern than other shape configurations. Lateral and axial resolutions were consistent with images generated from a commercial capsule hydrophone. Sensitivity of the best-performing device was 1.52 nV/Pa at 500 kPa using a bias voltage of 20 V. We expect a thicker AE hydrophone closer to half the acoustic wavelength to produce even better sensitivity, while maintaining high spectral bandwidth for characterizing medical ultrasound transducers. AE ultrasound detectors may also be useful for monitoring acoustic exposure during therapy or as receivers for photoacoustic imaging.

Multichannel ultrasound current source density imaging of a 3-D dipole field

Ultrasound Current Source Density Imaging (UCSDI) potentially improves 3-D mapping of bioelectric sources in the body at high spatial resolution, which is especially important for diagnosing and guiding treatment for cardiac and neurologic disorders, including arrhythmia and epilepsy. In this study, we report 4-D imaging of a time varying electric dipole in saline. A 3-D dipole field was produced in a bath of 0.9% NaCl solution by injected current ranging from 0 to 140 mA. On the electrode chamber made on a 3D printer, each electrode can be placed anywhere on an XY grid (5mm spacing) and individually adjusted in the depth direction for precise geometry of current sources and recording electrodes. A 1 MHz ultrasound beam was pulsed and focused through a plastic film to modulate the current distribution inside the tank filled with saline. Acoustoelectric (AE) signals were simultaneously detected at a sampling frequency of 15MHz on up to 6 recording electrodes simultaneously. One single recording electrode can effectively provide enough information to form volume images of the dipole. The full-width-half-maximum of the reconstructed current dipole is 3.93mm along x-y plane, and 4.93mm along fast time. The ANR for envelope detection of the current waveform was 46 dB at 500 KPa and a 133mA dipole. Real-time 3-D UCSDI of current flow simultaneously co-registered with anatomy (pulse echo ultrasound) and standard electrophysiology (e.g., ECG) potentially facilitates corrective procedures for cardiac and neural abnormalities.