Russell S Witte

Interests

Teaching

• Ultrasound imaging• Functional Brain Imaging • Neural engineering• Bioelectricity ("The Body Electric")• Electromedicine/Vibrational Medicine

Research

• Hybrid modalities that combine ultrasound with light, microwaves and other forms of energy for novel contrast in biomedical imaging• Acoustoelectric Imaging for dynamic mapping of current densities in the heart and brain• Remote temperature mapping during thermal therapy• High resolution functional brain imaging • Photoacoustic imaging and spectroscopy for lymphatic imaging and tumor monitoring• Ultrasound elasticity imaging of human muscle and tendon• Novel acoustic sensors for medical applications

Courses

Scholarly Contributions

Journals/Publications

• Wang, X., Qin, T., Witte, R. S., & Xin, H. (2017). Microwave-Induced Thermoacoustic Communications. IEEE Transactions on Microwave Theory and Techniques, 65(9), 3369-78.
• Chinyere, I., Weigand, K., Moukabary, T., Witte, R. S., Lancaster, J., Goldman, S., & Juneman, E. B. (2016). Model of Induced Ventricular Tachycardia and Cardiac Electrophysiological Mapping. Circulation Research, 119(Supl 1), A 71.
• Gao, L., Schmitz, H. A., Zuniga, A. A., Klewer, J. A., Szivek, J. A., Taljanovic, M. S., Latt, L. D., & Witte, R. S. (2016). Minimizing strain error for in vivo ultra-sound elasticity imaging of human tendon. 2016 IEEE INTERNATIONAL ULTRASONICS SYMPOSIUM (IUS).
• Gimber, L. H., Melville, D. M., Klauser, A. S., Witte, R. S., Arif-Tiwari, H., & Taljanovic, M. S. (2016). Artifacts at Musculoskeletal US: Resident and Fellow Education Feature. Radiographics : a review publication of the Radiological Society of North America, Inc, 36(2), 479-80.
• Klewer, J., Gao, L., Guerra, J., Szivek, J., Taljanovic, M., Latt, L., & Witte, R. (2016). IN VIVO ULTRASOUND ELASTICITY IMAGING CLASSIFIES HEALTHY AND DISEASED POSTERIOR TIBIAL TENDONS. JOURNAL OF INVESTIGATIVE MEDICINE, 64(1), 324-324.
• Marshalek, J. P., Sheeran, P. S., Ingram, P., Dayton, P. A., Witte, R. S., & Matsunaga, T. O. (2016). Intracellular delivery and ultrasonic activation of folate receptor-targeted phase-change contrast agents in breast cancer cells in vitro. Journal of controlled release : official journal of the Controlled Release Society, 243, 69-77.
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  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
• Peyman, G. A., Ingram, C. P., Montilla, L. G., & Witte, R. S. (2016). A high-resolution 3D ultrasonic system for rapid evaluation of the anterior and posterior segment. Ophthalmic surgery, lasers & imaging : the official journal of the International Society for Imaging in the Eye, 43(2), 143-51.
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  Traditional ultrasound imaging systems for ophthalmology employ slow, mechanical scanning of a single-element ultrasound transducer. The goal was to demonstrate rapid examination of the anterior and posterior segment with a three-dimensional (3D) commercial ultrasound system incorporating high-resolution linear probe arrays.
• Qin, Y., Ingram, P., Burton, A., & Witte, R. S. (2016). 4D Acoustoelectric Imaging of Current Sources in a Human Head Phantom. 2016 IEEE INTERNATIONAL ULTRASONICS SYMPOSIUM (IUS).
• Wang, X., Witte, R. S., & Xin, H. (2016). Thermoacoustic and photoacoustic characterizations of few-layer graphene by pulsed excitations. APPLIED PHYSICS LETTERS, 108(14).
• Wang, Z., Challoo, R., Peng, H., Leung, C. S., & Witte, R. S. (2016). Complementary Detection of Multiple Electrical Sources in Tissue Using Acoustoelectric Effects. Ultrasound in medicine & biology, 42(9), 2323-33.
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  Accurate 3-D mapping of multiple bioelectric sources in nerve fibers with high spatial resolution is challenging for the diagnosis and treatment of a variety of neural abnormalities. Ultrasound current source density imaging exploits the acoustoelectric (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) for mapping electrical current flow in tissue. Ultrasound current source density imaging and two complementary Wheatstone bridge circuits were used to simultaneously detect two separate current flows induced in tissue phantoms. It has been found that the addition and subtraction of AE signals acquired by two circuits are independent components, regardless of whether the two sources are positioned at the same or different depths. In the ultrasound field, the AE signal from the bridge circuits is stronger, with a higher signal-to-noise ratio, than without a bridge circuit. Both experimental and simulated AE images depend 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 (2.25-MHz transducer). The experimental results are consistent with simulations consisting of multiple current sources. Real-time 3-D ultrasound current source density images of multiple current flows co-registered with convention pulse echo ultrasound potentially facilitate monitoring of neurologic disorders.
• Bauer, D. R., Wang, X., Vollin, J., Xin, H., & Witte, R. S. (2015). Broadband Spectroscopic Thermoacoustic Characterization of Single-Walled Carbon Nanotubes. JOURNAL OF SPECTROSCOPY.
• Gao, L., Yuan, J. S., Heden, G. J., Szivek, J. A., Taljanovic, M. S., Latt, L. D., & Witte, R. S. (2015). Ultrasound elasticity imaging for determining the mechanical properties of human posterior tibial tendon: a cadaveric study. IEEE transactions on bio-medical engineering, 62(4), 1179-84.
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  Posterior tibial tendon dysfunction (PTTD) is a common degenerative condition leading to a severe impairment of gait. There is currently no effective method to determine whether a patient with advanced PTTD would benefit from several months of bracing and physical therapy or ultimately require surgery. Tendon degeneration is closely associated with irreversible degradation of its collagen structure, leading to changes to its mechanical properties. If these properties could be monitored in vivo, they could be used to quantify the severity of tendonosis and help determine the appropriate treatment. The goal of this cadaveric study was, therefore, to develop and validate ultrasound elasticity imaging (UEI) as a potentially noninvasive technique for quantifying tendon mechanical properties. Five human cadaver feet were mounted in a materials testing system (MTS), while the posterior tibial tendon (PTT) was attached to a force actuator. A portable ultrasound scanner collected 2-D data during loading cycles. Young's modulus was calculated from the strain, loading force, and cross-sectional area of the PTT. Average Young's modulus for the five tendons was (0.45 ± 0.16 GPa) using UEI, which was consistent with simultaneous measurements made by the MTS across the whole tendon (0.52 ± 0.18 GPa). We also calculated the scaling factor (0.12 ± 0.01) between the load on the PTT and the inversion force at the forefoot, a measurable quantity in vivo. This study suggests that UEI could be a reliable in vivo technique for estimating the mechanical properties of the PTT, and as a clinical tool, help guide treatment decisions for advanced PTTD and other tendinopathies.
• Goyal, U., Kim, Y., Tiwari, H. A., Witte, R., & Stea, B. (2015). A pilot study of ultrasound-guided electronic brachytherapy for skin cancer. Journal of contemporary brachytherapy, 7(5), 374-80.
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  Electronic brachytherapy (eBT) has gained acceptance over the past 5 years for the treatment of non-melanomatous skin cancer (NMSC). Although the prescription depth and radial margins can be chosen using clinical judgment based on visual and biopsy-derived information, we sought a more objective modality of measurement for eBT planning by using ultrasound (US) to measure superficial (< 5 mm depth) lesions.
• Goyal, U., Kim, Y., Tiwari, H. A., Witte, R., & Stea, B. (2015). A pilot study of ultrasound-guided electronic brachytheropy for skin cancer. JOURNAL OF CONTEMPORARY BRACHYTHERAPY, 7(5), 374-380.
• Qin, T., Wang, X., Qin, Y., Ingram, P., Wan, G., Witte, R. S., & Xin, H. (2015). Experimental Validation of a Numerical Model for Thermoacoustic Imaging Applications. IEEE ANTENNAS AND WIRELESS PROPAGATION LETTERS, 14, 1235-1238.
• Qin, Y., Li, Q., Ingram, P., Barber, C., Liu, Z., & Witte, R. S. (2015). Ultrasound Current Source Density Imaging of the Cardiac Activation Wave Using a Clinical Cardiac Catheter. IEEE TRANSACTIONS ON BIOMEDICAL ENGINEERING, 62(1), 241-247.
• Qin, Y., Li, Q., Ingram, P., Barber, C., Liu, Z., & Witte, R. S. (2015). Ultrasound current source density imaging of the cardiac activation wave using a clinical cardiac catheter. IEEE transactions on bio-medical engineering, 62(1), 241-7.
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  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 real-time 3-D cardiac activation wave mapping, which would greatly facilitate ablation procedures for treatment of arrhythmias.
• Wang, X., Liang, M., Witte, R. S., & Xin, H. (2015). Fabrication of a Realistic Breast Phantom Based on 3D Printing Technology for Thermoacoustic Imaging Application in Breast Cancer Detection. 2015 USNC-URSI RADIO SCIENCE MEETING (JOINT WITH AP-S SYMPOSIUM) PROCEEDINGS, 17-17.
• Wang, X., Qin, T., Witte, R. S., & Xin, H. (2015). Compressive Sensing Based Contrast-Enhanced Thermoacoustic Imaging for Breast Cancer Detection. 2015 31st International Review of Progress in Applied Computational Electromagnetics (ACES) Vol 31.
• Wang, X., Qin, T., Witte, R. S., & Xin, H. (2015). Computational Feasibility Study of Contrast-Enhanced Thermoacoustic Imaging for Breast Cancer Detection Using Realistic Numerical Breast Phantoms. IEEE TRANSACTIONS ON MICROWAVE THEORY AND TECHNIQUES, 63(5), 1489-1501.
• Wang, X., Qin, Y., Witte, R. S., & Xin, H. (2015). Modeling of Non-contact Thermoacoustic Imaging. 2015 USNC-URSI RADIO SCIENCE MEETING (JOINT WITH AP-S SYMPOSIUM) PROCEEDINGS, 314-314.
• Wang, X., Witte, R. S., & Xin, H. (2015). Thermoacoustic Applications in Breast Cancer Imaging, Non-contact Explosive Detection and Communications. 2015 ASIA-PACIFIC MICROWAVE CONFERENCE (APMC), VOLS 1-3.
• Witte, R. S., Taljanovic, M. S., Scalcione, L. R., Gimber, L. H., & EJ Lorenz, E. J. (2015). Advances in Lower Extremity Ultrasound. Current Radiology Reports, 3, 19.
• Keyes, J. T., Montilla, L. G., Witte, R. S., & Vande, G. (2014). RETENTION AND TRANSPORT OF HYDROPHOBIC AND HYDROPHILIC DRUG SURROGATE MOLECULES IN CORONARY ARTERIES MEASURED NONDESTRUCTIVELY WITH PHOTOACOUSTIC ULTRASOUND. PROCEEDINGS OF THE ASME SUMMER BIOENGINEERING CONFERENCE - 2013, PT A.
• Lancaster, J. J., Juneman, E., Arnce, S. A., Johnson, N. M., Qin, Y., Witte, R., Thai, H., Kellar, R. S., Ek Vitorin, J., Burt, J., Gaballa, M. A., Bahl, J. J., & Goldman, S. (2014). An electrically coupled tissue-engineered cardiomyocyte scaffold improves cardiac function in rats with chronic heart failure. The Journal of heart and lung transplantation : the official publication of the International Society for Heart Transplantation, 33(4), 438-45.
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  Varying strategies are currently being evaluated to develop tissue-engineered constructs for the treatment of ischemic heart disease. This study examines an angiogenic and biodegradable cardiac construct seeded with neonatal cardiomyocytes for the treatment of chronic heart failure (CHF).
• Lancaster, J. J., Juneman, E., Lahood, N., Weigand, K., Witte, R., Bahl, J., & Goldman, S. (2013). Implantation of an Electrically Coupled Cardiomyocyte Scaffold Improves Left Ventricular Ejection Fraction in Rats 18 Weeks after Implantation. JOURNAL OF CARDIAC FAILURE, 19(8), Supplement, Page S60. doi:dx.doi.org/10.1016
• Taljanovic, M. S., Melville, D. M., Scalcione, L. R., Gimber, L. H., Lorenz, E. J., & Witte, R. S. (2014). Artifacts in Musculoskeletal Ultrasonography. SEMINARS IN MUSCULOSKELETAL RADIOLOGY, 18(1), 3-11.
• Taljanovic, M. S., Melville, D. M., Scalcione, L. R., Gimber, L. H., Lorenz, E. J., & Witte, R. S. (2014). Artifacts in musculoskeletal ultrasonography. Seminars in musculoskeletal radiology, 18(1), 3-11.
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  During the past 2 decades, high-resolution ultrasonography (US) has been increasingly utilized in the diagnosis of musculoskeletal trauma and diseases with results comparable with MR imaging. US has an advantage over other cross-sectional modalities in many circumstances due to its superior spatial resolution and ability to allow dynamic assessment. When performing musculoskeletal US, the examiner has to be knowledgeable in the complex anatomy of the musculoskeletal system and US imaging technique. Additionally, he or she must be familiar with several common imaging artifacts in musculoskeletal US that may be mistaken for pathology, as well as several artifacts that frequently accompany pathologic conditions. These artifacts may occur with both B-mode gray-scale and Doppler imaging. In this article, we discuss common artifacts seen in musculoskeletal US and techniques to avoid or minimize these artifacts during clinical US examinations.
• Wang, Z., & Witte, R. S. (2014). Simulation-based validation for four- dimensional multi-channel ultrasound current source density imaging. IEEE transactions on ultrasonics, ferroelectrics, and frequency control, 61(3), 420-7.
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  Ultrasound current source density imaging (UCSDI), which has application to the heart and brain, exploits the acoustoelectric (AE) effect and Ohm's law to detect and map an electrical current distribution. In this study, we describe 4-D UCSDI simulations of a dipole field for comparison and validation with bench-top experiments. The simulations consider the properties of the ultrasound pulse as it passes through a conductive medium, the electric field of the injected dipole, and the lead field of the detectors. In the simulation, the lead fields of detectors and electric field of the dipole were calculated by the finite element (FE) method, and the convolution and correlation in the computation of the detected AE voltage signal were accelerated using 3-D fast Fourier transforms. In the bench-top experiment, an electric dipole was produced in a bath of 0.9% NaCl solution containing two electrodes, which injected an ac pulse (200 Hz, 3 cycles) ranging from 0 to 140 mA. Stimulating and recording electrodes were placed in a custom electrode chamber made on a rapid prototype printer. Each electrode could be positioned anywhere on an x-y grid (5 mm spacing) and individually adjusted in the depth direction for precise control of the geometry of the current sources and detecting electrodes. A 1-MHz ultrasound beam was pulsed and focused through a plastic film to modulate the current distribution inside the saline-filled tank. AE signals were simultaneously detected at a sampling frequency of 15 MHz on multiple recording electrodes. A single recording electrode is sufficient to form volume images of the current flow and electric potentials. The AE potential is sensitive to the distance from the dipole, but is less sensitive to the angle between the detector and the dipole. Multi-channel UCSDI potentially improves 4-D mapping of bioelectric sources in the body at high spatial resolution, which is especially important for diagnosing and guiding treatment of cardiac and neurologic disorders, including arrhythmia and epilepsy.
• Keyes, J. T., Lockwood, D. R., Utzinger, U., Montilla, L. G., Witte, R. S., & Vande Geest, J. P. (2013). Comparisons of planar and tubular biaxial tensile testing protocols of the same porcine coronary arteries. Annals of biomedical engineering, 41(7), 1579-91.
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  To identify the orthotropic biomechanical behavior of arteries, researchers typically perform stretch-pressure-inflation tests on tube-form arteries or planar biaxial testing of splayed sections. We examined variations in finite element simulations (FESs) driven from planar or tubular testing of the same coronary arteries to determine what differences exist when picking one testing technique vs. another. Arteries were tested in tube-form first, then tested in planar-form, and fit to a Fung-type strain energy density function. Afterwards, arteries were modeled via finite element analysis looking at stress and displacement behavior in different scenarios (e.g., tube FESs with tube- or planar-driven constitutive models). When performing FESs of tube inflation from a planar-driven constitutive model, pressure-diameter results had an error of 12.3% compared to pressure-inflation data. Circumferential stresses were different between tube- and planar-driven pressure-inflation models by 50.4% with the planar-driven model having higher stresses. This reduced to 3.9% when rolling the sample to a tube first with planar-driven properties, then inflating with tubular-driven properties. Microstructure showed primarily axial orientation in the tubular and opening-angle configurations. There was a shift towards the circumferential direction upon flattening of 8.0°. There was also noticeable collagen uncrimping in the flattened tissue.
• Wang, Z., & Witte, R. S. (2013). Simulation-Based Validation for Four-Dimensional Multi-Channel Ultrasound Current Source Density Imaging. IEEE TRANSACTIONS ON ULTRASONICS FERROELECTRICS AND FREQUENCY CONTROL, 61(3), 420-427.
• Wang, Z., Ingram, P., Greenlee, C. L., Olafsson, R., Norwood, R. A., & Witte, R. S. (2013). Design considerations and performance of MEMS acoustoelectric ultrasound detectors. IEEE transactions on ultrasonics, ferroelectrics, and frequency control, 60(9), 1906-16.
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  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.
• Witte, R., Montilla, L. G., Olafsson, R., Bauer, D. R., & Witte, R. S. (2013). Real-time photoacoustic and ultrasound imaging: a simple solution for clinical ultrasound systems with linear arrays. Physics in medicine and biology, 58(1).
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  Recent clinical studies have demonstrated that photoacoustic imaging (PAI) provides important diagnostic information during a routine breast exam for cancer. PAI enhances contrast between blood vessels and background tissue, which can help characterize suspicious lesions. However, most PAI systems are either not compatible with commercial ultrasound systems or inefficiently deliver light to the region of interest, effectively reducing the sensitivity of the technique. To address and potentially overcome these limitations, we developed an accessory for a standard linear ultrasound array that optimizes light delivery for PAI. The photoacoustic enabling device (PED) exploits an optically transparent acoustic reflector to help direct laser illumination to the region of interest. This study compares the PED with standard fiber bundle illumination in scattering and non-scattering media. In scattering media with the same incident fluence, the PED enhanced the photoacoustic signal by 18 dB at a depth of 5 mm and 6 dB at a depth of 20 mm. To demonstrate in vivo feasibility, we also used the device to image a mouse with a pancreatic tumor. The PED identified blood vessels at the periphery of the tumor, suggesting that PAI provides complementary contrast to standard pulse echo ultrasound. The PED is a simple and inexpensive solution that facilitates the translation of PAI technology to the clinic for routine screening of breast cancer.
• Banerjee, B., McKeown, K. R., Skovan, B., Ogram, E., Ingram, P., Ignatenko, N., Paine-Murrieta, G., Witte, R., & Matsunaga, T. O. (2012). Ultrasound Imaging of the Mouse Pancreatic Duct using Lipid Microbubbles.. MEDICAL IMAGING 2012: ULTRASONIC IMAGING, TOMOGRAPHY, AND THERAPY, 8320.
• Bauer, D. R., Olafsson, R., Montilla, L. G., & Witte, R. S. (2012). 3-D photoacoustic and pulse echo imaging of prostate tumor progression in the mouse window chamber. JOURNAL OF BIOMEDICAL OPTICS, 16(2).
• Olafsson, R., Witte, R. S., Jia, C., Huang, S., Kim, K., & O'Donnell, M. (2012). Cardiac Activation Mapping Using Ultrasound Current Source Density Imaging (UCSDI). IEEE TRANSACTIONS ON ULTRASONICS FERROELECTRICS AND FREQUENCY CONTROL, 56(3), 565-574.
• Peyman, G. A., Ingram, C. P., Montilla, L. G., & Witte, R. S. (2012). A High-Resolution 3D Ultrasonic System for Rapid Evaluation of the Anterior and Posterior Segment. OPHTHALMIC SURGERY LASERS & IMAGING, 43(2), 143-151.
• Qin, Y., Li, Q., Ingram, P., & Witte, R. S. (2012). Mapping the ECG in the live rabbit heart using Ultrasound Current Source Density Imaging with coded excitation. IEEE network, 2012, 910-913.
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  Ultrasound current source density imaging (UCSDI) is a noninvasive technique for mapping electric current fields in 4D (space + time) with the resolution of ultrasound imaging. This approach can potentially overcome limitations of conventional electrical mapping procedures often used during treatment of cardiac arrhythmia or epilepsy. However, at physiologic currents, the detected acoustoelectric (AE) interaction signal in tissue is very weak. In this work, we evaluated coded ultrasound excitation (chirps) for improving the sensitivity of UCSDI for mapping the electrocardiogram (ECG) in a live rabbit heart preparation. Results confirmed that chirps improved detection of the AE signal by as much as 6.1 dB compared to a square pulse. We further demonstrated mapping the ECG using a clinical intracardiac catheter, 1 MHz ultrasound transducer and coded excitation. B-mode pulse echo and UCSDI revealed regions of high current flow in the heart wall during the peak of the ECG. These improvements to UCSDI are important steps towards translation of this new technology to the clinic for rapidly mapping the cardiac activation wave.
• Qin, Y., Wang, Z., Ingram, P., Li, Q., & Witte, R. S. (2012). Optimizing Frequency and Pulse Shape for Ultrasound Current Source Density Imaging. IEEE TRANSACTIONS ON ULTRASONICS FERROELECTRICS AND FREQUENCY CONTROL, 59(10), 2149-2155.
• Roach, M., Alberini, J., Pecking, A. P., Testori, A., Verrecchia, F., Soteldo, J., Ganswindt, U., Joyal, J. L., Babich, J. W., Witte, R. S., Unger, E., & Gottlieb, R. (2012). Diagnostic and Therapeutic Imaging for Cancer: Therapeutic Considerations and Future Directions. JOURNAL OF SURGICAL ONCOLOGY, 103(6), 587-601.
• Wang, X., Bauer, D. R., Vollin, J. L., Manzi, D. G., Witte, R. S., & Xin, H. (2012). Impact of Microwave Pulses on Thermoacoustic Imaging Applications. IEEE ANTENNAS AND WIRELESS PROPAGATION LETTERS, 11, 1634-1637.
• Wang, X., Bauer, D. R., Witte, R., & Xin, H. (2012). Microwave-induced thermoacoustic imaging model for potential breast cancer detection. IEEE transactions on bio-medical engineering, 59(10), 2782-91.
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  In this study, we develop a complete microwave-induced thermoacoustic imaging (TAI) model for potential breast cancer imaging application. Acoustic pressures generated by different breast tissue targets are investigated by finite-difference time-domain simulations of the entire TAI process including the feeding antenna, matching mechanism, fluidic environment, 3-D breast model, and acoustic transducer. Simulation results achieve quantitative relationships between the input microwave peak power and the resulting specific absorption rate as well as the output acoustic pressure. Microwave frequency dependence of the acoustic signals due to different breast tissues is established across a broadband frequency range (2.3-12 GHz), suggesting key advantages of spectroscopic TAI compare to TAI at a single frequency. Reconstructed thermoacoustic images are consistent with the modeling results. This model will contribute to design, optimization, and safety evaluation of microwave-induced TAI and spectroscopy.
• Witte, R., Li, Q., Olafsson, R., Ingram, P., Wang, Z., & Witte, R. S. (2012). Measuring the acoustoelectric interaction constant using ultrasound current source density imaging. Physics in medicine and biology, 57(19).
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  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.
• Witte, R., Qin, Y., Wang, Z., Ingram, P., Li, Q., & Witte, R. S. (2012). Optimizing frequency and pulse shape for ultrasound current source density imaging. IEEE transactions on ultrasonics, ferroelectrics, and frequency control, 59(10).
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  Electric field mapping is commonly used to identify irregular conduction pathways in the heart (e.g., arrhythmia) and brain (e.g., epilepsy). Ultrasound current source density imaging (UCSDI), based on the acoustoelectric (AE) effect, is a promising new technique for mapping electrical current in four dimensions with enhanced resolution. The frequency and pulse shape of the ultrasound beam affect the sensitivity and spatial resolution of UCSDI. In this study, we explore the effects of ultrasound transducer frequency bandwidth and coded excitation pulses for UCSDI and the inherent tradeoff between sensitivity and spatial resolution. We used both simulations and bench-top experiments to image a time-varying electrical dipole in 0.9% NaCl solution. To study the effects of ultrasound bandwidth, we chose two ultrasound transducers with different center frequencies (1.0 and 2.25 MHz). For coded excitation, we measured the AE voltage signal with different chirp excitations. As expected, higher bandwidth correlated with improved spatial resolution at the cost of sensitivity. On the other hand, chirp excitation significantly improved sensitivity (3.5 μV/mA) compared with conventional square pulse excitation (1.6 μV/mA) at 1 MHz. Pulse compression achieved spatial resolution similar to that obtained using square pulse excitation, demonstrating enhanced detection sensitivity without loss of resolution. Optimization of the time duration of the chirp pulse and frequency sweep rate can be further used to improve the quality of UCSDI.
• Jia, C., Olafsson, R., Kim, K., Kolias, T. J., Rubin, J. M., Weitzel, W. F., Witte, R. S., Huang, S., Richards, M. S., Deng, C. X., & O'Donnell, M. (2011). TWO-DIMENSIONAL STRAIN IMAGING OF CONTROLLED RABBIT HEARTS. ULTRASOUND IN MEDICINE AND BIOLOGY, 35(9), 1488-1501.
• Roach, M., Alberini, J., Pecking, A. P., Testori, A., Verrecchia, F., Soteldo, J., Ganswindt, U., Joyal, J. L., Babich, J. W., Witte, R. S., Unger, E., & Gottlieb, R. (2011). Diagnostic and therapeutic imaging for cancer: therapeutic considerations and future directions. Journal of surgical oncology, 103(6), 587-601.
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  As cancer treatment cost soar and the mantra for "personalized medicine" grows louder, we will increasingly be searching for solutions to these diametrically opposed forces. In this review we highlight several exciting novel imaging strategies including MRI, CT, PET SPECT, sentinel node, and ultrasound imaging that hold great promise for improving outcomes through detection of lymph node involvement. We provide clinical data that demonstrate how these evolving strategies have the potential to transform treatment paradigms.
• Wang, X., Bauer, D. R., Witte, R., & Xin, H. (2011). Microwave-Induced Thermoacoustic Imaging Model for Potential Breast Cancer Detection. IEEE TRANSACTIONS ON BIOMEDICAL ENGINEERING, 59(10), 2782-2791.
• Wang, Z. H., Olafsson, R., Ingram, P., Li, Q., Qin, Y., & Witte, R. S. (2011). Four-dimensional ultrasound current source density imaging of a dipole field. APPLIED PHYSICS LETTERS, 99(11).
• Wang, Z. H., Olafsson, R., Ingram, P., Li, Q., Qin, Y., & Witte, R. S. (2011). Four-dimensional ultrasound current source density imaging of a dipole field. Applied physics letters, 99(11), 113701-1137013.
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  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.
• Witte, R., Bauer, D. R., Olafsson, R., Montilla, L. G., & Witte, R. S. (2011). 3-D photoacoustic and pulse echo imaging of prostate tumor progression in the mouse window chamber. Journal of biomedical optics, 16(2).
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  Understanding the tumor microenvironment is critical to characterizing how cancers operate and predicting their response to treatment. We describe a novel, high-resolution coregistered photoacoustic (PA) and pulse echo (PE) ultrasound system used to image the tumor microenvironment. Compared to traditional optical systems, the platform provides complementary contrast and important depth information. Three mice are implanted with a dorsal skin flap window chamber and injected with PC-3 prostate tumor cells transfected with green fluorescent protein. The ensuing tumor invasion is mapped during three weeks or more using simultaneous PA and PE imaging at 25 MHz, combined with optical and fluorescent techniques. Pulse echo imaging provides details of tumor structure and the surrounding environment with 100-μm(3) resolution. Tumor size increases dramatically with an average volumetric growth rate of 5.35 mm(3)/day, correlating well with 2-D fluorescent imaging (R = 0.97, p < 0.01). Photoacoustic imaging is able to track the underlying vascular network and identify hemorrhaging, while PA spectroscopy helps classify blood vessels according to their optical absorption spectrum, suggesting variation in blood oxygen saturation. Photoacoustic and PE imaging are safe, translational modalities that provide enhanced depth resolution and complementary contrast to track the tumor microenvironment, evaluate new cancer therapies, and develop molecular contrast agents in vivo.
• Keyes, J. T., Lockwood, D. R., Utzinger, U., Montilla, L. G., Witte, R. S., & Vande Geest, J. P. (2010). Comparisons of Planar and Tubular Biaxial Tensile Testing Protocols of the Same Porcine Coronary Arteries. ANNALS OF BIOMEDICAL ENGINEERING, 41(7), 1579-1591.
• Li, Q., Olafsson, R., Ingram, P., Wang, Z., & Witte, R. (2010). Measuring the acoustoelectric interaction constant using ultrasound current source density imaging. PHYSICS IN MEDICINE AND BIOLOGY, 57(19), 5929-5941.
• Montilla, L. G., Olafsson, R., Bauer, D. R., & Witte, R. S. (2010). Real-time photoacoustic and ultrasound imaging: a simple solution for clinical ultrasound systems with linear arrays. PHYSICS IN MEDICINE AND BIOLOGY, 58(1), N1-N12.
• Wang, Z., Ingram, P., Greenlee, C. L., Olafsson, R., Norwood, R. A., & Witte, R. S. (2010). Design Considerations and Performance of MEMS Acoustoelectric Ultrasound Detectors. IEEE TRANSACTIONS ON ULTRASONICS FERROELECTRICS AND FREQUENCY CONTROL, 60(9), 1906-1916.
• Witte, R. S., Olafsson, R., Montilla, L. G., & Bauer, D. R. (2010). In vivo multi-modality photoacoustic and pulse echo tracking of prostate tumor growth using a window chamber. Bios, 7564(17). doi:10.1117/12.843875
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  Understanding the tumor microenvironment is critical to characterizing how cancers operate and predicting how they will eventually respond to treatment. The mouse window chamber model is an excellent tool for cancer research, because it enables high resolution tumor imaging and cross-validation using multiple modalities. We describe a novel multimodality imaging system that incorporates three dimensional (3D) photoacoustics with pulse echo ultrasound for imaging the tumor microenvironment and tracking tissue growth in mice. Three mice were implanted with a dorsal skin flap window chamber. PC-3 prostate tumor cells, expressing green fluorescent protein (GFP), were injected into the skin. The ensuing tumor invasion was mapped using photoacoustic and pulse echo imaging, as well as optical and fluorescent imaging for comparison and cross validation. The photoacoustic imaging and spectroscopy system, consisting of a tunable (680-1000nm) pulsed laser and 25 MHz ultrasound transducer, revealed near infrared absorbing regions, primarily blood vessels. Pulse echo images, obtained simultaneously, provided details of the tumor microstructure and growth with 100-μm3 resolution. The tumor size in all three mice increased between three and five fold during 3+ weeks of imaging. Results were consistent with the optical and fluorescent images. Photoacoustic imaging revealed detailed maps of the tumor vasculature, whereas photoacoustic spectroscopy identified regions of oxygenated and deoxygenated blood vessels. The 3D photoacoustic and pulse echo imaging system provided complementary information to track the tumor microenvironment, evaluate new cancer therapies, and develop molecular imaging agents in vivo. Finally, these safe and noninvasive techniques are potentially applicable for human cancer imaging.
• Witte, R. S., Wang, Z., Olafsson, R., Li, Q., & Ingram, P. (2010). Detection of multiple electrical sources in tissue using ultrasound current source density imaging. Proceedings of SPIE, 7629(39). doi:10.1117/12.844657
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  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/cm 2 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.
• Witte, R. S., Wang, Z., Olafsson, R., Norwood, R. A., Ingram, P., & Greenlee, C. L. (2010). Fabrication and characterization of an indium tin oxide acoustoelectric hydrophone. Proceedings of SPIE, 7629(39). doi:10.1117/12.845631
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  Clinical ultrasound (US) imaging and therapy require a precise knowledge of the intensity distribution of the acoustic field. Although piezoelectric hydrophones are most common, these devices are limited in terms of, for example, type of materials, cost, and performance at high frequency and pressure. As an alternative to conventional acoustic detectors, we describe acoustoelectric hydrophones, developed using photolithographic fabrication techniques, where the induced voltage (phase and amplitude) is proportional to both the US pressure and bias current injected through the device. In this study a number of different hydrophone designs were created using indium tin oxide (ITO). A constriction of the current path within the hydrophone created a localized "sensitivity zone" of high current density. The width of this zone ranged from 30 to 1000 μm, with a thickness of 100 nm. A raster scan of the US transducer produced a map of the acoustic field. Hydrophones were evaluated by mapping the pressure field of a 2.25 MHz single element transducer, and their performance was compared to a commercial capsule hydrophone. Focal spot sizes at -6 dB were as low as 1.75 mm, comparing well with the commercial hydrophone measurement of 1.80 mm. Maximum sensitivity was 2 nV/Pa and up to the 2nd harmonic was detected. We expect improved performance with future devices as we optimize the design. Acoustoelectric hydrophones are potentially cheaper and more robust than the piezoelectric models currently in clinical use, potentially providing more choice of materials and designs for monitoring therapy or producing arrays for imaging.
• Witte, R. S., Wang, Z., Olafsson, R., Norwood, R. A., Ingram, P., & Greenlee, C. L. (2010). Simulation-based optimization of the acoustoelectric hydrophone for mapping an ultrasound beam. Proceedings of SPIE, 7629(39). doi:10.1117/12.844651
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  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.
• Witte, R., Olafsson, R., Bauer, D. R., Montilla, L. G., & Witte, R. S. (2010). Real-time, contrast enhanced photoacoustic imaging of cancer in a mouse window chamber. Optics express, 18(18).
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  A clinical ultrasound scanner and 14 MHz linear array collected real-time photoacoustic images (PAI) during an injection of gold nanorods (GNRs) near the region of a mature PC-3 prostate tumor in mice implanted with a skin flap window chamber. Three dimensional spectroscopic PAI (690-900 nm) was also performed to investigate absorption changes near the tumor and enhance specific detection of GNRs. Whereas GNRs improved PAI contrast (+18 dB), the photoacoustic spectrum was consistent with the elevated near infrared absorption of GNRs. The versatile imaging platform potentially accelerates development of photoacoustic contrast agents and drug delivery for cancer imaging and therapy.
• Bauer, D. R., Wang, X., Vollin, J., Xin, H., & Witte, R. S. (2009). Spectroscopic thermoacoustic imaging of water and fat composition. APPLIED PHYSICS LETTERS, 101(3).
• Jia, C., Olafsson, R., Kim, K., Kolias, T. J., Rubin, J. M., Weitzel, W. F., Witte, R. S., Huang, S., Richards, M. S., Deng, C. X., & O'Donnell, M. (2009). Two-dimensional strain imaging of controlled rabbit hearts. Ultrasound in medicine & biology, 35(9), 1488-501.
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  Ultrasound strain imaging using 2-D speckle tracking has been proposed to quantitatively assess changes in myocardial contractility caused by ischemia. Its performance must be demonstrated in a controlled model system as a step toward routine clinical application. In this study, a well-controlled 2-D cardiac elasticity imaging technique was developed using two coplanar and orthogonal linear probes simultaneously imaging an isolated retroperfused rabbit heart. Acute ischemia was generated by left anterior descending (LAD) artery ligation. An excitation-contraction decoupler, 2,3-butanedione monoxime, was applied at a 4-mM concentration to reversibly reduce myocardial contractility. Results using a single probe demonstrate that directional changes in the in-plane principal deformation axes can help locate the bulging area as a result of LAD ligation, which matched well with corresponding Evans Blue staining, and strains or strain magnitude, based on principal stretches, can characterize heart muscle contractility. These two findings using asymmetric displacement accuracy (i.e., normal single-probe measurements with good axial but poor lateral estimates) were further validated using symmetric displacement accuracy (i.e., dual-probe measurements using only accurate axial tracking estimates from each). However, the accuracy of 2-D cardiac strain imaging using a single probe depends on the probe's orientation because of the large variance in lateral displacement estimates.
• Olafsson, R., Witte, R. S., Jia, C., Huang, S., Kim, K., & O'Donnell, M. (2009). Cardiac activation mapping using ultrasound current source density imaging (UCSDI). IEEE transactions on ultrasonics, ferroelectrics, and frequency control, 56(3), 565-74.
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  We describe the first mapping of biological current in a live heart using ultrasound current source density imaging (UCSDI). Ablation procedures that treat severe heart arrhythmias require detailed maps of the cardiac activation wave. The conventional procedure is time-consuming and limited by its poor spatial resolution (5-10 mm). UCSDI can potentially improve on existing mapping procedures. It is based on a pressure-induced change in resistivity known as the acousto-electric (AE) effect, which is spatially confined to the ultrasound focus. Data from 2 experiments are presented. A 540 kHz ultrasonic transducer (f/# = 1, focal length = 90 mm, pulse repetition frequency = 1600 Hz) was scanned over an isolated rabbit heart perfused with an excitation-contraction decoupler to reduce motion significantly while retaining electric function. Tungsten electrodes inserted in the left ventricle recorded simultaneously the AE signal and the low-frequency electrocardiogram (ECG). UCSDI displayed spatial and temporal patterns consistent with the spreading activation wave. The propagation velocity estimated from UCSDI was 0.25 +/- 0.05 mm/ms, comparable to the values obtained with the ECG signals. The maximum AE signal-to-noise ratio after filtering was 18 dB, with an equivalent detection threshold of 0.1 mA/ cm(2). This study demonstrates that UCSDI is a potentially powerful technique for mapping current flow and biopotentials in the heart.
• Witte, R., Olafsson, R., Huang, S., & O'Donnell, M. (2009). Imaging current flow in lobster nerve cord using the acoustoelectric effect. APPLIED PHYSICS LETTERS, 90(16).
• Hou, Y., Huang, S., Ashkenazi, S., Witte, R., & O'Donnell, M. (2008). Thin polymer etalon arrays for high-resolution photoacoustic imaging. JOURNAL OF BIOMEDICAL OPTICS, 13(6).
• Huang, S., Kim, K., Witte, R. S., Olafsson, R., & O'Donnell, M. (2008). Inducing and Imaging thermal strain using a single ultrasound linear array. IEEE TRANSACTIONS ON ULTRASONICS FERROELECTRICS AND FREQUENCY CONTROL, 54(9), 1718-1720.
• Huang, S., Rubin, J. M., Xie, H., Witte, R. S., Jia, C., Olafsson, R., & O'Donnell, M. (2008). Analysis of Correlation Coefficient Filtering in Elasticity Imaging. IEEE TRANSACTIONS ON ULTRASONICS FERROELECTRICS AND FREQUENCY CONTROL, 55(11), 2426-2441.
• Huang, S., Rubin, J. M., Xie, H., Witte, R. S., Jia, C., Olafsson, R., & O'Donnell, M. (2008). Analysis of correlation coefficient filtering in elasticity imaging. IEEE transactions on ultrasonics, ferroelectrics, and frequency control, 55(11), 2426-41.
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  Correlation-based speckle tracking methods are commonly used in elasticity imaging to estimate displacements. In the presence of local strain, a larger window size results in larger displacement error. To reduce tracking error, we proposed a short correlation window followed by a correlation coefficient filter. Although simulation and experimental results demonstrated the efficacy of the method, it was not clear why correlation coefficient filtering reduces tracking error since tracking error increases if normalization before filtering is not applied. In this paper, we analyzed tracking errors by estimating phase variances of the cross-correlation function and the correlation coefficient at the true time lag based on statistical properties of these functions' real and imaginary parts. The role of normalization is clarified by identifying the effect of the cross-correlation function's amplitude fluctuation on the function's imaginary part. Furthermore, we present analytic forms for predicting axial displacement error as a function of strain, system parameters (signal-to-noise ratio, center frequency, and signal and noise bandwidths), and tracking parameters (window and filter sizes) for cases with and without normalization before filtering. Simulation results correspond to theory well for both noise-free cases and general cases with an empirical correction term included for strains up to 4%.
• Kim, K., Agarwal, A., Mcdonald, A. M., Moore, R. M., Myers Jr., D. D., Witte, R. S., Huanga, S. -., Ashkenazi, S., Kaplan, M. J., Wakefield, T. W., O'Donnell, M., & Kotov, N. A. (2008). In vivo imaging of inflammatory responses by photoacoustics using cell-targeted gold nanorods (GNR) as contrast agent - art. no. 68560H. PHOTONS PLUS ULTRASOUND: IMAGING AND SENSING 2008: THE NINTH CONFERENCE ON BIOMEDICAL THERMOACOUSTICS, OPTOACOUSTICS, AND ACOUSTIC-OPTICS, 6856, H8560-H8560.
• Kim, K., Huang, S., Hall, T. L., Witte, R. S., Chenevert, T. L., & O'Donnell, M. (2008). Arterial vulnerable plaque characterization using ultrasound-induced thermal strain imaging (TSI). IEEE TRANSACTIONS ON BIOMEDICAL ENGINEERING, 55(1), 171-180.
• Kim, K., Huang, S., Hall, T. L., Witte, R. S., Chenevert, T. L., & O'Donnell, M. (2008). Arterial vulnerable plaque characterization using ultrasound-induced thermal strain imaging (TSI). IEEE transactions on bio-medical engineering, 55(1), 171-80.
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  Thermal strain imaging (TSI) is demonstrated in two model systems mimicking two potential clinical applications. First, a custom ultrasound (US) microscope produced high-resolution TSI images of an excised porcine coronary artery. Samples were placed in a temperature-controlled water chamber and scanned transversely and longitudinally. Phase-sensitive, correlation-based speckle tracking was applied to map the spatial distribution of temporal strain across the sample. TSI differentiated fatty tissue from water-based arterial wall and muscle with high contrast and a spatial resolution of 60 microm for a 50-MHz transducer. Both transverse and longitudinal TSI images compared well with B-scans of arterial wall structures, including intima, media, adventitia, and overlying fatty tissue. A second model system was used to test the hypothesis that US can produce the heating pattern required for TSI of internal structures. A 2-D phased array with independent drive electronics was combined with a conventional US scanner (iU22, Philips, Bothell, WA) for these studies. This 513-element array, originally designed for the US therapy, acted as the US heat source. To quantify the temporal strain induced by this system, TSI was performed on a homogeneous rubber phantom. TSI temperature estimates were within 3% error for a 3.2 degrees C temperature rise produced within 2 s using a specially designed beamformer and pulse sequencer. The system was then used to produce TSI scanning of an excised kidney containing an intact piece of fat below the collecting system. These images were validated using an magnetic resonance imaging (MRI) pulse sequence designed for lipid quantification. TSI scans matched well MRI scans and histology both anatomically and quantitatively. Finally, to test the potential of US-induced TSI for a significant clinical problem, images were obtained on an excised canine aorta with fatty tissue inside the lumen. Both longitudinal and transversal TSI agreed well with anatomy. These in vitro results demonstrate the potential of high-resolution US-induced TSI with a small temperature change (
• Kim, K., Witte, R. S., O'donnell, M., Kotov, N. A., Kopelman, R., Kipke, D. R., Kim, K., Fan, W., & Agarwal, A. (2008). Enhanced photoacoustic neuroimaging with gold nanorods and PEBBLEs. Proceedings of SPIE, 6856. doi:10.1117/12.764337
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  Photoacoustic (PA) imaging provides excellent optical contrast with decent penetration and high spatial resolution, making it attractive for a variety of neural applications. We evaluated optical contrast agents with high absorption in the near infrared (NIR) as potential enhancers for PA neuroimaging: optical dyes, gold nanorods (GNRs) and PEBBLEs loaded with indocyanine green. Two PA systems were developed to test these agents in excised neural tissue and in vivo mouse brain. Lobster nerves were stained with the agents for 30 minutes and placed in a hybrid nerve chamber capable of electrical stimulation and recording, optical spectroscopy and PA imaging. Contrast agents boosted the PA signal by at least 30 dB using NIR illumination from a tunable pulsed laser. Photobleaching may be a limiting factor for optical dyes-the PA signal decreased steadily with laser illumination. The second setup enabled in vivo transcranial imaging of the mouse brain. A custom clinical ultrasound scanner and a 10-MHz linear array provided near real-time images during and after an injection of 2 nM gold nanorods into the tail vein. The peak PA signal from the brain vasculature was enhanced by up to 2 dB at 710 nm. Temporal dynamics of the PA signal were also consistent with mixing of the GNRs in the blood. These studies provide a baseline for enhanced PA imaging in neural tissue. The smart contrast agents employed in this study can be further engineered for molecular targeting and controlled drug delivery with potential treatment for a myriad of neural disorders.
• Olafsson, R., Jia, C., Huang, S., Kim, K., Witte, R. S., & O'Donnell, M. (2008). Mapping Cardiac Currents using Ultrasound Current Source Density Imaging. 2008 IEEE ULTRASONICS SYMPOSIUM, VOLS 1-4 AND APPENDIX, 757-760.
• Olafsson, R., Witte, R. S., Huang, S., & O'Donnell, M. (2008). Ultrasound current source density imaging. IEEE TRANSACTIONS ON BIOMEDICAL ENGINEERING, 55(7), 1840-1848.
• Olafsson, R., Witte, R. S., Huang, S., & O'Donnell, M. (2008). Ultrasound current source density imaging. IEEE transactions on bio-medical engineering, 55(7), 1840-8.
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  Surgery to correct severe heart arrhythmias usually requires detailed maps of the cardiac activation wave prior to ablation. The pinpoint electrical mapping procedure is laborious and limited by its spatial resolution (5-10 mm). We propose ultrasound current source density imaging (UCSDI), a direct 3-D imaging technique that potentially facilitates existing mapping procedures with superior spatial resolution. The technique is based on a pressure-induced change in resistivity known as the acoustoelectric (AE) effect, which is spatially confined to the ultrasound focus. AE-modulated voltage recordings are used to map and reconstruct current densities. In this preliminary study, we tested UCSDI under controlled conditions and compared it with conventional electrical mapping techniques. A 2-D dipole field was produced by a pair of electrodes in a bath of 0.9% NaCl solution. Boundary electrodes detected the AE signal while a 7.5-MHz focused ultrasound transducer was scanned across the bath. UCSDI located the current source and sink to within 1 mm of their actual positions. A future UCSDI system potentially provides real-time 3-D images of the cardiac activation wave coregistered with anatomical ultrasound and would greatly facilitate corrective procedures for heart abnormalities.
• Witte, R. S., Hall, T., Olafsson, R., Huang, S., & O'Donnell, M. (2008). Inexpensive Acoustoelectric Hydrophone For Mapping High Intensity Ultrasonic Fields. Journal of applied physics, 104(5), 54701.
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  We describe an inexpensive alternative to conventional hydrophones for measuring ultrasonic fields. The hydrophone, composed of common laboratory supplies, depends on the acoustoelectric (AE) effect, a well-known interaction between electrical current and pressure. Beam patterns of a 540 kHz annular transducer captured using a bowtie graphite hydrophone were consistent with patterns obtained using conventional, more expensive hydrophones. The AE signal was proportional to both the applied bias current (1.83 µV/mA) and pressure (13.3 µV/MPa) with sensitivity better than 50 kPa. Disposable AE hydrophones may be an attractive alternative for clinical applications that require close monitoring of high intensity acoustic fields.
• Gao, L., Yuan, J. S., Heden, G. J., Szivek, J. A., Taljanovic, M. S., Latt, L. D., & Witte, R. S. (2007). Ultrasound Elasticity Imaging for Determining the Mechanical Properties of Human Posterior Tibial Tendon: A Cadaveric Study. IEEE TRANSACTIONS ON BIOMEDICAL ENGINEERING, 62(4), 1179-1184.
• Huang, S., Kim, K., Witte, R. S., Olafsson, R., & O'Donnell, M. (2007). Inducing and imaging thermal strain using a single ultrasound linear array. IEEE transactions on ultrasonics, ferroelectrics, and frequency control, 54(9), 1718-20.
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  For the first time, the feasibility of inducing and imaging thermal strain using an ultrasound imaging array is demonstrated. A commercial ultrasound scanner was used to heat and image a gelatin phantom with a cylindrical rubber inclusion. The inclusion was successfully characterized as an oil-bearing material using thermal strain imaging.
• Jia, C., Olafsson, R., Kim, K., Witte, R. S., Huang, S. -., Kolias, T. J., Rubin, J. M., Weitzel, W. F., Deng, C., & O'Donnell, M. (2007). Controlled 2D cardiac elasticity imaging on an isolated perfused rabbit heart. 2007 IEEE ULTRASONICS SYMPOSIUM PROCEEDINGS, VOLS 1-6, 745-748.
• Kim, K., Huang, S. -., Olafsson, R., Jia, C., Witte, R. S., & O'Donnell, M. (2007). Motion artifact reduction by ECG gating in ultrasound induced thermal strain imaging. 2007 IEEE ULTRASONICS SYMPOSIUM PROCEEDINGS, VOLS 1-6, 581-584.
• Kim, K., Witte, R. S., O'donnell, M., Kim, K., Huang, S., & Ashkenazi, S. (2007). Contrast-enhanced photoacoustic imaging of live lobster nerve cord. Proceedings of SPIE, 6437(14). doi:10.1117/12.701570
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  Photoacoustic imaging provides optical contrast with good penetration and high spatial resolution, making it an attractive tool for noninvasive neural applications. We chose a commercial dye (NK2761) commonly used for optical imaging of membrane potential to enhance photoacoustic images of the live lobster nerve cord. The abdominal segment of the nerve cord was excised, stained and positioned in a custom neural recording system, enabling electrical stimulation and recording of compound action potentials. Photoacoustic and pulse echo images were also collected using a commercial ultrasound scanner and a 10-MHz linear probe. A wavelength-tunable pulsed laser source (Surelite TM , 5 ns, ~15 mJ, 30 mJ/cm 2 ) operating at 20 Hz produced photoacoustic waves. Longitudinal photoacoustic scans of a 25-mm segment of the excised nerve cord, including ganglionic and axonal processes, were collected and displayed every 7 seconds. Without the contrast agent, an average of 10 scans produced a peak photoacoustic signal 6 dB over background noise. An additional 29 dB was obtained after the nerve was submerged in the dye for 20 minutes. The gain decreased to 23 dB and 14 dB at 810 nm and 910 nm, respectively - consistent with the dye's optical absorbance measured using a portable spectrometer. The contrast-enhanced photoacoustic signal had a broad spectrum peaking at 4 MHz, and, after high pass filtering, images approached 200-mm spatial resolution. The hybrid imaging system, which provided several hours of electrical stimulation and recording, represents a robust testbed to develop novel photoacoustic contrast for neural applications.
• Olafsson, R., Jia, C., Huang, S., Witte, R. S., & O'Donnell, M. (2007). Detection of electrical current in a live rabbit heart using ultrasound. 2007 IEEE ULTRASONICS SYMPOSIUM PROCEEDINGS, VOLS 1-6, 989-992.
• Witte, R. S., Hall, T., Olafsson, R., Huang, S., & O'Donnell, M. (2007). Inexpensive acoustoelectric hydrophone for mapping high intensity ultrasonic fields. JOURNAL OF APPLIED PHYSICS, 104(5).
• Witte, R. S., O'donnell, M., Huang, S. W., Hou, Y., & Ashkenazi, S. (2007). Toward fiber-based high-frequency 3D ultrasound imaging. Proceedings of SPIE, 6437(14). doi:10.1117/12.701305
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  We present a fiber-based optical detection system for high-frequency 3D ultrasound and photoacoustic imaging. Optically probing the surface of a thin polymer Fabry-Perot etalon defines the acoustic array geometry and element size. We have previously demonstrated wide bandwidth signal detection (>40 MHz) and element size on the order of 15 mm. By integrating an etalon into a photoacoustic imaging system, high-resolution 3D images were obtained. However, the previous system is limited for clinical applications because the etalon is rigidly attached to a free-space optical scanning system. To move etalon detector technology toward a practical clinical device, we designed a remote-probe system based on a fiber bundle. A fiber bundle, composed of 160,000 individual light guides of 8-mm diameter, delivers the optical probe to the etalon. Light coupled into a single guide creates an active element on the etalon surface. We successfully measured the ultrasound signals from 10 MHz and 50 MHz ultrasound transducers using a laser tunable around 1550 nm. With further progress on reducing the size of the etalon, it will be possible to build a practical device for in vivo high-frequency 3D ultrasound and photoacoustic imaging, especially for intravascular and endoscopic applications.
• Witte, R. S., Olafsson, R., O'donnell, M., & Huang, S. W. (2007). Imaging current flow in lobster nerve cord using the acoustoelectric effect. Applied Physics Letters, 90(16), 163902. doi:10.1063/1.2724901
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  Ultrasound traversing a biologic fluid or tissue generates a local change in electrical conductivity known as the acoustoelectric effect. The authors exploit this interaction to image ionic current injected into the abdominal segment of the lobster nerve cord. A pair of recording electrodes detected the acoustoelectric signal induced by pulses of focused ultrasound (1.4 or 7.5MHz). The signal was linear with injected current at 2MPa (0.7μV∕mAcm2) and pressure at 75mA∕cm2 (23μV∕MPa). Acoustoelectric imaging of biocurrents potentially enhances spatial resolution of traditional electrophysiology and merits further study as an imaging modality for neural applications.
• Witte, R. S., Rousche, P. J., & Kipke, D. R. (2007). Fast wave propagation in auditory cortex of an awake cat using a chronic microelectrode array. JOURNAL OF NEURAL ENGINEERING, 4(2), 68-78.
• Witte, R. S., Rousche, P. J., & Kipke, D. R. (2007). Fast wave propagation in auditory cortex of an awake cat using a chronic microelectrode array. Journal of neural engineering, 4(2), 68-78.
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  We investigated fast wave propagation in auditory cortex of an alert cat using a chronically implanted microelectrode array. A custom, real-time imaging template exhibited wave dynamics within the 33-microwire array (3 mm(2)) during ten recording sessions spanning 1 month post implant. Images were based on the spatial arrangement of peri-stimulus time histograms at each recording site in response to auditory stimuli consisting of tone pips between 1 and 10 kHz at 75 dB SPL. Functional images portray stimulus-locked spiking activity and exhibit waves of excitation and inhibition that evolve during the onset, sustained and offset period of the tones. In response to 5 kHz, for example, peak excitation occurred at 27 ms after onset and again at 15 ms following tone offset. Variability of the position of the centroid of excitation during ten recording sessions reached a minimum at 31 ms post onset (sigma = 125 microm) and 18 ms post offset (sigma = 145 microm), suggesting a fine place/time representation of the stimulus in the cortex. The dynamics of these fast waves also depended on stimulus frequency, likely reflecting the tonotopicity in auditory cortex projected from the cochlea. Peak wave velocities of 0.2 m s(-1) were also consistent with those purported across horizontal layers of cat visual cortex. The fine resolution offered by microimaging may be critical for delivering optimal coding strategies used with an auditory prosthesis. Based on the initial results, future studies seek to determine the relevance of these waves to sensory perception and behavior.
• Witte, R., & Kipke, D. (2007). Enhanced contrast sensitivity in auditory cortex as cats learn to discriminate sound frequencies. COGNITIVE BRAIN RESEARCH, 23(2-3), 171-184.
• Huang, S., Kim, K., Witte, R. S., Hall, T. L., Ashkenazi, S., Olafsson, R., & O'Donnell, M. (2006). Feasibility of Inducing and Imaging Thermal Strain for High-risk Plaque Identification in Peripheral Arteries Using Ultrasound Arrays. 2006 IEEE ULTRASONICS SYMPOSIUM, VOLS 1-5, PROCEEDINGS, 1333-1336.
• Qin, T., Wang, X., Qin, Y., Wan, G., Witte, R. S., & Xin, H. (2006). Quality Improvement of Thermoacoustic Imaging Based on Compressive Sensing. IEEE ANTENNAS AND WIRELESS PROPAGATION LETTERS, 14, 1200-1203.
• Witte, R. S., Kim, K., Martin, B. J., & O'Donnell, M. (2006). Effect of fatigue on muscle elasticity in the human forearm using ultrasound strain imaging. Conference proceedings : ... Annual International Conference of the IEEE Engineering in Medicine and Biology Society. IEEE Engineering in Medicine and Biology Society. Annual Conference, 1, 4490-3.
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  The etiology of skeletal muscle fatigue is not well understood partly because techniques portraying muscle performance in vivo are limited by either their invasiveness (e.g., needle electrodes) or poor spatial resolution (e.g., surface EMG). To better characterize effects of FES and muscle fatigue, we captured real-time high resolution dynamics of the human forearm before and after a fatigue exercise using ultrasound strain imaging. A 10 MHz linear ultrasound probe aligned with the fiber axis of the 3rd flexor digitorum superficialis (FDS) provided scans at 3-msec intervals during isometric twitch and tetanic contractions evoked by low and high frequency electrical stimuli (ES). Ultrasound images synchronized with traditional force and EMG were obtained for 5 healthy adults before and after a fatiguing exercise, induced by sustained maximal exertion of the middle finger pressed against a restraint until the initial force decreased by 75%. Immediately after fatigue, twitch and tetanic stimuli generated 55.1% and 19.5% less force, respectively, implying that low frequency fatigue dominated. The force deficit was associated with a decrease in several mechanical properties of the fatigued muscle during twitch contractions, such as transverse peak strain (34 +/- 15%) and half peak strain duration (32.3 +/- 12.5 msec). Changes were not uniform across the imaged section of the muscle, suggesting that boundary conditions or fiber heterogeneity affected the strain profile. Indeed, high stress zones appeared closer to the muscle-tendon junction during isometric contractions. This study provided new insight on the elastic behavior of muscle and potential mechanisms of injury, especially directed at prolonged stimulation and control of a neuromuscular prosthesis.
• Witte, R. S., Kim, K., Martin, B. J., & O'Donnell, M. (2006). Ultrasound elasticity Imaging of muscle fatigue in the human forearm: Implications for muscle injury and recovery. Proceedings of the 5th World Congress of Biomechanics, 101-106.
• Witte, R. S., O'donnell, M., Koh, I., Kim, K., & Ashkenazi, S. (2006). Early detection of dental caries using photoacoustics. Biomedical optics, 6086(9), 118-126. doi:10.1117/12.646455
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  For decades, visual, tactile and radiographic examinations have been the standard for diagnosing caries. Nonetheless, the extent of variation in the diagnosis of dental caries is substantial among dental practitioners using these traditional techniques. Therefore, a more reliable standard for detecting incipient caries would be desirable. Using photoacoustics, near-infrared (NIR) optical contrast between sound and carious dental tissues can be relatively easily and accurately detected at ultrasound resolution. In this paper, a pulsed laser (Nd:YAG, Quanta-Ray) was used to probe extracted human molars at different disease stages determined from periapical radiographs. Both fundamental (1064nm) and first harmonic (532nm) pulses (15ns pulse length, 100mJ at fundamental and 9mJ at first harmonic , 10Hz pulse repetition rate) were used to illuminate the occlusal surface of tooth samples placed in a water tank. The photoacoustic signal was recorded with an unfocused wideband single-element piezoelectric transducer (centered at 12 MHz, bandwidth 15 MHz) positioned at small angle (less than 30 degrees) to the laser beam close to the occlusal surface. At the fundamental wavelength, total photoacoustic energy increases from normal to incipient stage disease by as much as a factor of 10. Differences between photoacoustic energy at the fundamental and first harmonic wavelength further indicate spectral absorption changes of the underlying structure with disease progression. Using a focused laser beam, an extracted molar with suspected incipient caries was scanned along the occulusal surface to help localize the caries inside enamel and dentin. The significantly increasing photoacoustic signal at a specific scan line both at fundamental and first harmonic indicates the local development of the incipient caries. The photoacoustic results compare well with visual inspection after layer by layer dissection. Preliminary results demonstrate the feasibility of detecting incipient occlusal and proximal caries. This technique may ultimately allow for continuous monitoring of caries before and during treatment.
• Witte, R. S., Olafsson, R., & O'Donnell, M. (2006). Acoustoelectric Detection of Current Flow in a Neural Recording Chamber. 2006 IEEE ULTRASONICS SYMPOSIUM, VOLS 1-5, PROCEEDINGS, 5-8.
• van der Steen, A. F., Baldewsing, R. A., Levent Degertekin, F., Emelianov, S., Frijlink, M. E., Furukawa, Y., Goertz, D., Karaman, M., Khuri-Yakub, P. T., Kim, K., Mastik, F., Moriya, T., Oralkan, O., Saijo, Y., Schaar, J. A., Serruys, P. W., Sethuraman, S., Tanaka, A., Vos, H. J., , Witte, R., et al. (2006). IVUS beyond the horizon. EuroIntervention : journal of EuroPCR in collaboration with the Working Group on Interventional Cardiology of the European Society of Cardiology, 2(1), 132-42.
• Ashkenazi, S., Witte, R., & O'Donnell, M. (2005). High frequency ultrasound imaging using Fabry-Perot optical etalon. Medical Imaging 2005: Ultrasonic Imaging and Signal Processing, 5750, 289-297.
• Ashkenazi, S., Witte, R., & O'Donnell, M. (2005). High frequency ultrasound imaging using Fabry-Perot optical etalon. Photons Plus Ultrasound: Imaging and Sensing 2005, 5697, 243-250.
• Ashkenazi, S., Witte, R., Kim, K., Hou, Y., & O'Donnell, M. (2005). Tissue microscopy using optical generation and detection of ultrasound. 2005 IEEE Ultrasonics Symposium, Vols 1-4, 269-272.
• Olafsson, R., Bauer, D. R., Montilla, L. G., & Witte, R. S. (2005). Real-time, contrast enhanced photoacoustic imaging of cancer in a mouse window chamber. OPTICS EXPRESS, 18(18), 18625-18632.
• Shi, Y., Witte, R. S., & O'Donnell, M. (2005). Identification of vulnerable atherosclerotic plaque using IVUS-based thermal strain imaging. IEEE TRANSACTIONS ON ULTRASONICS FERROELECTRICS AND FREQUENCY CONTROL, 52(5), 844-850.
• Shi, Y., Witte, R. S., & O'Donnell, M. (2005). Identification of vulnerable atherosclerotic plaque using IVUS-based thermal strain imaging. IEEE transactions on ultrasonics, ferroelectrics, and frequency control, 52(5), 844-50.
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  Pathology and autopsy studies have demonstrated that sudden disruption of vulnerable atherosclerotic plaque is responsible for most acute coronary syndromes. These plaques are characterized by a lipid-rich core with abundant inflammatory cells and a thin fibrous cap. Thermal strain imaging (TSI) using intravascular ultrasound (IVUS) has been proposed for high-risk arterial plaque detection, in which image contrast results from the temperature dependence of sound speed. It has the potential to distinguish a lipid-laden lesion from the arterial vascular wall due to its strong contrast between water-bearing and lipid-bearing tissue. Initial simulations indicate plaque identification is possible for a 1 degrees C temperature rise. A phantom experiment using an IVUS imaging array further supports the concept, and results agree reasonably well with prediction.
• Witte, R. S., & Kipke, D. R. (2005). Enhanced contrast sensitivity in auditory cortex as cats learn to discriminate sound frequencies. Brain research. Cognitive brain research, 23(2-3), 171-84.
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  To better understand the nature and time course for learning-induced cortical reorganization, we examined frequency-specific changes in auditory cortex as cats gradually improved at a difficult sound frequency discrimination task. Three adult cats were trained to discriminate between a tone pip at a fixed target frequency (S-) and a higher deviant frequency (S+). An adaptive training schedule led to an efficient estimate of the frequency discrimination threshold (FDT), which was used to track daily performance. Each cat was also implanted with an array of microwires in auditory cortex. Tone pips with different frequency and amplitude were used to map receptive fields. Onset responses were correlated with training time and the cat's ability to discriminate frequencies. Although lifetime of the neural implants varied among cats, each provided sufficient neural recording to relate at least 3 weeks of learning to response changes in the cortex. An improved FDT was associated with a differential decrease in response strength between the S- frequency and S+ frequencies. Response to the training frequencies gradually located in a local minimum compared to adjacent frequencies (p < 0.001, Cohen's d=0.50). Cortical changes were consistent with a theory of bimodal generalization that enhances stimulus classification by reducing similarity between reinforced and nonreinforced stimuli. Such a strategy may be especially appropriate during an early stage of learning to discriminate similar sounds and differ from later strategies required for fine discrimination.
• Shi, Y., Witte, R. S., de Ana, F. J., Chen, X. C., Xie, H., & O'Donnell, M. (2004). Application of ultrasonic thermal imaging in IVUS systems. 2004 IEEE Ultrasonics Symposium, Vols 1-3, 1130-1133.
• Witte, R. S., Dow, D. E., Olafsson, R., Shi, Y., & O'Donnell, M. (2004). High resolution ultrasound imaging of skeletal muscle dynamics and effects of fatigue. 2004 IEEE Ultrasonics Symposium, Vols 1-3, 764-767.
• Shi, Y., Witte, R. S., Milas, S. M., Neiss, J. H., Chen, X. C., Cain, C. A., & O'Donnell, M. (2003). Microwave-induced thermal imaging of tissue dielectric properties. ULTRASONIC IMAGING, 25(2), 109-121.
• Shi, Y., Witte, R. S., Milas, S. M., Neiss, J. H., Chen, X. C., Cain, C. A., & O'Donnell, M. (2003). Microwave-induced thermal imaging of tissue dielectric properties. Ultrasonic imaging, 25(2), 109-21.
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  A new imaging method, microwave-induced thermal imaging (MITI), was developed to differentiate tissue based on thermal and dielectric properties. Image contrast depends on temporal strain in tissue, which was determined by one-dimensional speckle tracking using a phase-sensitive, correlation-based technique. The underlying mechanisms were analyzed and experimental results on biologic tissue agreed well with theoretical predictions. Because of its strong contrast between water-bearing and lipid-bearing tissue, the technique may enhance existing intravascular ultrasound (IVUS) imaging systems to identify vulnerable arterial plaque.
• Shi, Y., Witte, R. S., Milas, S. M., Neiss, J. H., Chen, X. C., Cain, C. A., & O'Donnell, M. (2003). Ultrasonic thermal imaging of microwave absorption. 2003 IEEE ULTRASONICS SYMPOSIUM PROCEEDINGS, VOLS 1 AND 2, 224-227.
• Clement, R. S., Witte, R. S., Rousche, P. J., & Kipke, D. R. (1999). Functional connectivity in auditory cortex using chronic, multichannel unit recordings. NEUROCOMPUTING, 26-7, 347-354.
• Witte, R. S., Otto, K. J., Williams, J. C., & Kipke, D. R. (1999). Pursuing dynamic reorganization in auditory cortex using chronic, multichannel unit recordings in awake, behaving cats. NEUROCOMPUTING, 26-7, 593-600.

Proceedings Publications

• Allard, M., Preston, C., Huang, C., Chen, N., & Witte, R. S. (2021). Neuronavigation with Skull Segmentation and Acoustic Modeling for Guiding Transcranial Acoustoelectric Brain Imaging. In 2021 IEEE International Ultrasonics Symposium (IUS).
• Gao, L., Schmitz, H. A., Zuniga, A. A., Klewer, J. A., Szivek, J. A., Taljanovic, M. S., Latt, L. D., & Witte, R. S. (2016). Neuronavigation with Skull Segmentation and Acoustic Modeling for Guiding Transcranial Acoustoelectric Brain Imaging. In 2016 IEEE INTERNATIONAL ULTRASONICS SYMPOSIUM (IUS).
• Huang, C., Alvarez, A., Preston, C., Kang, J., O'Donnell, M., & Witte, R. S. (2021). Current Density Mapping of the In Vivo Swine Heart using Multichannel Acoustoelectric Cardiac Imaging. In 2021 IEEE International Ultrasonics Symposium (IUS).
• Reichel, E., Tamimi, E., Curiel-Lewandrowski, C., & Witte, R. S. (2021). Real-Time Trimodal Ultrasound, Photoacoustic, and Thermoacoustic Imaging for Biomedical Applications. In 2021 IEEE International Ultrasonics Symposium (IUS).
• Salinas, C. M., Reichel, E., & Witte, R. S. (2021). Short-wave Infrared Photoacoustic Spectroscopy for Lipid and Water Detection. In 2021 IEEE International Ultrasonics Symposium (IUS).
• Witte, R. S., Tseng, H., Qin, Y., & O'donnell, M. (2017). Coded excitation with optimized inverse filter for improving sensitivity in acoustoelectric imaging. In 2017 IEEE International Ultrasonics Symposium (IUS).
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  Noninvasive imaging of physiologic currents in the body is limited by poor spatial resolution due to the ambiguous conductivity distribution between the current sources and recording electrodes. Acoustoelectric imaging (AEI), based on the interaction between pressure and resistivity, provides higher spatial resolution. Although we have demonstrated AEI of the cardiac activation wave in the live rabbit heart, weak physiologic currents (e.g., in the heart or brain < 1 μV) and ultrasound (US) pulses of balanced shape (zero mean) make detection especially challenging. This study investigates the use of standard US transducers with coded excitation with optimized inverse filter to produce quasi-unipolar pulses that amplify the AE signal.
• Furdella, K., Witte, R. S., & Vande Geest, J. (2015, Summer). Tracking Mass Transport of a Drug Surrogate in Porcine Coronary Tissue using Photoacoustic Imaging and Spectroscopy. In Biomechanics, Bioengineering and Biotransport Conference.
• Qin, Y., Ingram, P., Wang, X., Qin, T., Xin, H., & Witte, R. S. (2014, 2014). Non-contact thermoacoustic imaging based on laser and microwave vibrometry. In 2014 IEEE INTERNATIONAL ULTRASONICS SYMPOSIUM (IUS), 1033-1036.
• Wang, X., Bauer, D., Witte, R., Xin, H., & , . (2015, 2013). Impact of Microwave Pulses on Microwave-Induced Thermoacoustic Imaging Applications. In 2013 USNC-URSI RADIO SCIENCE MEETING (JOINT WITH AP-S SYMPOSIUM), 210-210.
• Wang, X., Liang, M., Witte, R. S., & Xin, H. (2015, Summer). Fabrication of a realistic breast phantom based on 3D printing technology for thermoacoustic imaging application in breast cancer detection. In USNC-URSI Radio Science Meeting (Joint with AP-S Symposium), 314.
• Wang, X., Witte, R. S., Liang, M., & Xin, H. (2015, Summer). Modeling of non-contact thermoacoustic imaging. In Proceedings IEEE, USNC-URSI Radio Science Meeting (Joint with AP-S Symposium), 17.
• Witte, R. S., Wang, X., Xin, H., & Qin, T. (2015, March). Compressive sensing based contrast-enhanced thermoacoustic imaging for breast cancer detection. In 2015 31st International Review of Progress in Applied Computational Electromagnetics (ACES), 1-2.
• Bauer, D. R., Wang, X., Vollin, J., Xin, H., Witte, R. S., & , . (2014, 2012). Thermoacoustic Imaging and Spectroscopy for Enhanced Breast Cancer Detection. In 2011 IEEE INTERNATIONAL ULTRASONICS SYMPOSIUM (IUS), 2364-2367.
• Huang, S., Rubin, J. M., Jia, C., Olafsson, R., Witte, R. S., O'Donnell, M., & , . (2014, 2007). Error analysis of axial displacement estimation in elasticity imaging. In 2007 IEEE ULTRASONICS SYMPOSIUM PROCEEDINGS, VOLS 1-6, 1969-1972.
• Panchangam, A., Witte, R. S., Claflin, D. R., O'Donnell, M., Faulkner, J. A., Farkas, D., Nicolau, D., & Leif, R. (2014, 2006). A novel optical imaging system for investigating sarcomere dynamics in single skeletal muscle fibers - art. no. 608808. In Imaging, Manipulation, and Analysis of Biomolecules, Cells, and Tissues IV, 6088, 8808-8808.
• Qin, T., Wang, X., Meng, H., Qin, Y., Wan, G., Witte, R. S., Xin, H., & , . (2014, 2014). Performance Improvement for Thermoacoustic Imaging Using Compressive Sensing. In 2014 IEEE ANTENNAS AND PROPAGATION SOCIETY INTERNATIONAL SYMPOSIUM (APSURSI), 1919-1920.
• Qin, Y., Wang, Z., Ingram, P., Li, Q., Witte, R. S., & , . (2014, 2012). Optimizing frequency and pulse shape for ultrasound current source density imaging. In 2011 IEEE INTERNATIONAL ULTRASONICS SYMPOSIUM (IUS), 2138-2141.
• Wang, X., Xin, H., Bauer, D. R., & Witte, R. S. (2014, 2013). Computational Study of Thermoacoustic Imaging for Breast Cancer Detection Using a Realistic Breast Model. In 2013 IEEE ANTENNAS AND PROPAGATION SOCIETY INTERNATIONAL SYMPOSIUM (APSURSI), 2040-2041.
• Witte, R. S., Hall, T., Olafsson, R., O'Donnell, M., & , . (2014, 2007). Inexpensive acoustoelectric hydrophone for measuring high intensity ultrasound fields. In 2007 IEEE ULTRASONICS SYMPOSIUM PROCEEDINGS, VOLS 1-6, 737-740.
• Witte, R. S., Kim, K., Martin, B. J., O'Donnell, M., & , . (2014, 2006). Effect of fatigue on muscle elasticity in the human forearm using ultrasound strain imaging. In 2006 28th Annual International Conference of the IEEE Engineering in Medicine and Biology Society, Vols 1-15, 6029-6032.
• Witte, R. S., Qin, Y., Liu, Z., Li, Q., Ingram, P., & Barber, C. (2014). Cardiac activation mapping with ultrasound current source density imaging. In 2014 IEEE International Ultrasonics Symposium, 699-702.
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  Ultrasound current source density imaging (UCSDI) is a noninvasive method for mapping electrical current based on the acoustoelectric (AE) effect. This technique can potentially overcome the limitations (i.e. poor resolution, inaccurate anatomical registration) of the conventional electrical mapping procedures typically used during treatment of sustained arrhythmias. In this study, UCSDI of the electrocardiogram (ECG) is demonstrated using a clinical electrophysiology catheter placed on the epicardium of the live rabbit heart. For the first time, 3-D cardiac activation maps are presented. Activation maps were used to calculate the cardiac conduction velocity for atrial pacing (1.31 m/s). We also demonstrated multi-electrode UCSDI for improving mapping accuracy by reducing the lied-field effect. This study indicates that UCSDI is potentially capable of real-time 3-D mapping of the cardiac activation wave, which would greatly facilitate ablation procedures for treatment of arrhythmias.
• Bauer, D. R., Olafsson, R., Montilla, L. G., Witte, R. S., Oraevsky, A., & Wang, L. (2013, 2010). In vivo multi-modality photoacoustic and pulse echo tracking of prostate tumor growth using a window chamber. In PHOTONS PLUS ULTRASOUND: IMAGING AND SENSING 2010, 7564.
• Olafsson, R., Witte, R. S., O'Donnell, M., Emelianov, S., & McAleavey, S. (2013, 2007). Measurement of a 2D electric dipole field using the acousto-electric effect - art. no. 65130S. In Medical Imaging 2007: Ultrasonic Imaging and Signal Processing, 6513, S5130-S5130.
• Wang, X., Xin, H., Bauer, D., Witte, R., & , . (2013, 2011). Microwave Induced Thermal Acoustic Imaging Modeling for Potential Breast Cancer Detection. In 2011 IEEE INTERNATIONAL SYMPOSIUM ON ANTENNAS AND PROPAGATION (APSURSI), 722-725.
• Witte, R. S., Huang, S., Ashkenazi, S., O'Donnell, M., & , . (2013, 2007). Hybrid imaging system for developing novel neural contrast agents. In 2007 3rd International IEEE/EMBS Conference on Neural Engineering, Vols 1 and 2, 229-232.
• Bauer, D. R., Montilla, L. G., Salek, M., Allen, N., Rege, K., Witte, R. S., & , . (2012, 2012). Simultaneous Detection of Multiple Contrast Agents with Photoacoustic Spectroscopy. In 2012 IEEE INTERNATIONAL ULTRASONICS SYMPOSIUM (IUS), 1421-1424.
• Bauer, D. R., Wang, X., Vollin, J., Xin, H., & Witte, R. S. (2012, 2012). Broadband Thermoacoustic Spectroscopy of Single Walled Carbon Nanotubes. In 2012 IEEE INTERNATIONAL ULTRASONICS SYMPOSIUM (IUS), 1204-1207.
• Ingram, P., Greenlee, C. L., Wang, Z., Olafsson, R., Norwood, R. A., Witte, R. S., D'hooge, J., & McAleavey, S. (2012, 2010). Fabrication and characterization of an indium tin oxide acoustoelectric hydrophone. In MEDICAL IMAGING 2010: ULTRASONIC IMAGING, TOMOGRAPHY, AND THERAPY, 7629.
• Li, Q., Qin, Y., Ingram, P., Witte, R., Wang, Z., & , . (2012, 2012). Ultrasound Current Source Density Imaging Using a Clinical Intracardiac Catheter. In 2011 IEEE INTERNATIONAL ULTRASONICS SYMPOSIUM (IUS), 704-707.
• Qin, Y., Li, Q., Ingram, P., Barber, C., Liu, Z., Witte, R. S., & , . (2012, 2014). Cardiac activation mapping with ultrasound current source density imaging. In 2014 IEEE INTERNATIONAL ULTRASONICS SYMPOSIUM (IUS), 699-702.
• Qin, Y., Li, Q., Ingram, P., Witte, R. S., & , . (2012, 2012). Mapping the ECG in the live rabbit heart using Ultrasound Current Source Density Imaging with coded excitation. In 2012 IEEE INTERNATIONAL ULTRASONICS SYMPOSIUM (IUS), 910-913.
• Wang, X., Bauer, D. R., Witte, R. S., Xin, H., & , . (2012, 2013). A Hybrid Microwave/Acoustic Communication Scheme - Thermoacoustic Communication. In 2013 IEEE MTT-S INTERNATIONAL MICROWAVE SYMPOSIUM DIGEST (IMS).
• Olafsson, R., Witte, R. S., Kim, K., Ashkenazi, S., O'Donnell, M., Emelianov, S., & Walker, W. (2011, 2006). Electric current mapping using the acousto-electric effect - art. no. 61470O. In Medical Imaging 2006: Ultrasonic Imaging and Signal Processing, 6147, O1470-O1470.
• Xin, H., Wang, X., Qin, T., Meng, H., Qin, Y., Witte, R. S., & , . (2011, 2014). Time-Efficient Contrast-Enhanced Thermoacoustic Imaging Modality for 3-D Breast Cancer Detection Using Compressive Sensing. In 2014 XXXITH URSI GENERAL ASSEMBLY AND SCIENTIFIC SYMPOSIUM (URSI GASS).
• Olafsson, R., Montilla, L., Ingram, P., Witte, R. S., Oraevsky, A., & Wang, L. (2010, 2009). Tracking contrast agents using real-time 2D photoacoustic imaging system for cardiac applications. In PHOTONS PLUS ULTRASOUND: IMAGING AND SENSING 2009, 7177.
• Wang, Z., Ingram, P., Olafsson, R., Greenlee, C. L., Norwood, R. A., Witte, R. S., D'hooge, J., & McAleavey, S. (2010, 2010). Simulation-Based Optimization of the Acoustoelectric Hydrophone for Mapping an Ultrasound Beam. In MEDICAL IMAGING 2010: ULTRASONIC IMAGING, TOMOGRAPHY, AND THERAPY, 7629.
• Witte, R. S., Olafsson, R., & Montilla, L. G. (2010). In vivo photoacoustic and pulse echo imaging of a pancreatic tumor using a hand held device. In 2010 IEEE International Ultrasonics Symposium, 2147-2150.
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  Ultrasonography and computed tomography are often used to diagnose pancreatic cancer. Using similar equipment as ultrasonography, photoacoustic (PA) imaging can provide vascular information over the same region of interest. Information about the vascularity in and around a lesion can be used to aid in the characterization and diagnosis of various cancers. Current PA imaging setups are restricted to bulky bench-top setups, limiting its practicality for clinical research. An ideal imaging platform would be non-invasive, real-time, portable, and inexpensive. We designed and fabricated an attachment to a clinical ultrasound probe which houses an optically transparent acoustic reflector in water. The design enables laser illumination in-line with the acoustic propagation path. The detector array simultaneously captures unbeamformed data on 64 elements at frequencies up to 10 MHz. We used the device to image in vivo a subcutaneous tumor in a SCID mouse implanted with Capan-2 pancreatic cancer cells and also a mouse pancreas embedded in a gel. Laser pulses (5 ns, 13 mJ/cm2) were transmitted through an optical window in the device, providing line illumination below the skin surface. Realtime 2D PA images between 700 nm and 960 nm were captured along with conventional pulse echo (PE) ultrasound to examine different sources of contrast in the tumor. The PE image identifies the acoustic window, skin surface, and variation in acoustic impedance within the tumor. PA images visualized areas of near infrared light absorption 4 mm deep within the tumor. Co-registered PE images provided an anatomical reference. This in vivo study demonstrates how a simple adapter to a clinical ultrasound array can be used for real-time simultaneous PE and PA imaging of cancer. With this efficient and practical design, cancer research can capitalize on noninvasive optical contrast below the tissue surface. With an optimized design, clinicians can incorporate PA imaging with routine ultrasound exams.
• Witte, R. S., Wang, Z., Olafsson, R., Li, Q., & Ingram, P. (2010). Measuring the acoustoelectric interaction constant in cardiac tissue using ultrasound current source density imaging. In 2010 IEEE International Ultrasonics Symposium, 245-248.
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  This paper demonstrates the first measurement of the acoustoelectric (AE) interaction constant in cardiac tissue. Radiofrequency catheter ablation is performed in clinics as a standard treatment for cardiac arrhythmia with a high success rate. The procedure requires a detailed map of the heart's activation wave prior to treatment. Conventional electrical mapping techniques are slow, prone to registration errors and have limited spatial resolution. We have developed Ultrasound Current Source Density Imaging (UCSDI) as a new modality to map reentry currents in the heart. UCSDI is based on the AE effect and Ohm's Law. The AE effect states that ultrasound pressure can be converted to a change in resistivity. The conversion efficiency is determined by the AE interaction constant K, a fundamental property of all materials; it directly affects the magnitude of the detected signals in UCSDI. In this study, K was measured in rabbit heart tissue, NaCl and CuSO 4 solution with UCSDI. A custom chamber was fabricated to control the geometry for estimating K. A 1 MHz transducer was pulsed at 200 Hz to induce a local and transient modulation of resistivity. K was calculated to be 0.043±0.013% /MPa in the heart based on the AE signal recorded with UCSDI. The value of K was in range of 0.9% NaCl. This provides a baseline estimate of K for mapping reentry currents in the heart with UCSDI.
• Witte, R. S., Wang, Z., Olafsson, R., Li, Q., & Ingram, P. (2010). Multichannel ultrasound current source density imaging of a 3-D dipole field. In 2010 IEEE International Ultrasonics Symposium, 253-256.
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  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.
• Witte, R. S., Huang, S., Ashkenazi, S., Kim, K., O'Donnell, M., Oraevsky, A., & Wang, L. (2009, 2007). Contrast-enhanced photoacoustic imaging of live lobster nerve cord - art. no. 64370J. In Photons Plus Ultrasound: Imaging and Sensing 2007, 6437, J4370-J4370.
• Witte, R. S., Olafsson, R., Montilla, L. G., & Ingram, P. (2009). Tracking contrast agents using real-time 2D photoacoustic imaging system for cardiac applications. In Photons Plus Ultrasound: Imaging and Sensing 2009, 7177.
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  Photoacoustic (PA) imaging is a rapidly developing imaging modality that can detect optical contrast agents with high sensitivity. While detectors in PA imaging have traditionally been single element ultrasound transducers, use of array systems is desirable because they potentially provide high frame rates to capture dynamic events, such as injection and distribution of contrast in clinical applications. We present preliminary data consisting of 40 second sequences of coregistered pulse-echo (PE) and PA images acquired simultaneously in real time using a clinical ultrasonic machine. Using a 7 MHz linear array, the scanner allowed simultaneous acquisition of inphase-quadrature (IQ) data on 64 elements at a rate limited by the illumination source (Q-switched laser at 20 Hz) with spatial resolution determined to be 0.6 mm (axial) and 0.4 mm (lateral). PA images had a signal-to-noise ratio of approximately 35 dB without averaging. The sequences captured the injection and distribution of an infrared-absorbing contrast agent into a cadaver rat heart. From these data, a perfusion time constant of 0.23 s -1 was estimated. After further refinement, the system will be tested in live animals. Ultimately, an integrated system in the clinic could facilitate inexpensive molecular screening for coronary artery disease.
• Witte, R. S., Wang, Z., Olafsson, R., Li, Q., & Ingram, P. (2009). Ultrasound Current Source Density Imaging of a time-varying current field in a multielectrode nerve chamber. In 2009 IEEE International Ultrasonics Symposium, 333-336.
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  Drug resistant epilepsy can in some cases be treated with surgery. To minimize potentially crippling side effects of surgery, a detailed functional map of the brain is usually required prior to resection. Conventional mapping techniques rely on a coarse grid of electrodes with limited spatial resolution. Ultrasound Current Source Density Imaging (UCSDI) is new high resolution method to image electric current based on ultrasound. UCSDI potentially enhances conventional mapping procedures as it produces 4D (space and time) maps of current flow co-registered to ultrasound. In this paper, we describe a new system for studying UCSDI in peripheral nerves and neural tissue. This system allows multi-electrode detection of conventional electrophysiological signals simultaneous with UCSDI. UCSDI was used to map short bursts of current injected through the rat sciatic nerve. The amplitude of the current was varied to test the sensitivity of the system. The detection threshold was 0.1 mA/cm2 at ∼250 kPa, well within range for detecting bioelectric signals in neural tissue.
• Huang, S., Ashkenazi, S., Hou, Y., Witte, R. S., O'Donnell, M., Oraevsky, A., & Wang, L. (2007, 2008). Toward fiber-based high-frequency 3D ultrasound imaging - art. no. 643728. In Photons Plus Ultrasound: Imaging and Sensing 2007, 6437, 43728-43728.
• Montilla, L. G., Olafsson, R., Witte, R. S., Oraevsky, A., & Wang, L. (2008, 2010). Real-Time Pulse Echo and Photoacoustic Imaging Using an Ultrasound Array and In-line Reflective Illumination. In PHOTONS PLUS ULTRASOUND: IMAGING AND SENSING 2010, 7564.
• Wang, Z., Ingram, P., Olafsson, R., Li, Q., Witte, R. S., D'hooge, J., & McAleavey, S. (2008, 2010). Detection of Multiple Electrical Sources in Tissue Using Ultrasound Current Source Density Imaging. In MEDICAL IMAGING 2010: ULTRASONIC IMAGING, TOMOGRAPHY, AND THERAPY, 7629.
• Kim, K., Rubin, J. M., Witte, R. S., Weitzel, W. F., Rubin, J. M., Olafsson, R., O'donnell, M., Kolias, T. J., Kim, K., Jia, C., Huang, S. W., & Deng, C. X. (2007). 9A-2 Controlled 2D Cardiac Elasticity Imaging on an Isolated Perfused Rabbit Heart. In 2007 IEEE Ultrasonics Symposium Proceedings, 745-748.
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  Ultrasound strain and strain rate imaging have been proposed to detect myocardial muscle viability and contractility change. However, it's not easy to control experimental parameters and acquire high SNR data during in-vivo animal experiments. To address this, we performed 2D cardiac elasticity imaging on a well-controlled isolated retroperfused rabbit heart paced through the apex. The excitation-contraction decoupler, 2,3-butanedione monoxime (BDM) was used to optimize the maximum strain given frame acquisition rate, reducing the decorrelation due to excessive frame-to-frame strain. Under a local animal protocol, a heart was harvested from an anesthetized New Zealand White rabbit and prepared using a Langendorff preparation. Modified Oxygenated (95% 02 5% CO2) Krebs- Henseleit (K-H) buffer (PH 7.4, 37 degC) solution was retroperfused through the aorta. The heart was paced through the apex with electrodes at 3 Hz. The internal left ventricle (LV) pressure was recorded using a pressure meter connected to a water-filled latex balloon placed in the LV. The ECG signal was simultaneously recorded. Two linear array connected to a commercial US scanner (Sonix RP, Ultrasonix, Richmond, BC, Canada) were used to acquire RF data. The pacing signal, US RF, ECG and LV pressure data capturing were all synchronized using an field programmable gate array (FPGA) chip (ezFPGA-C6-6, Dallas Logic, Piano, TX, USA). All these data were acquired before administering, during perfusion and after flushing BDM without/with the ligation of left anterior decending (LAD) artery At each data acquisition point, US RF data were acquired over two heart cycles (41 frames/cycle). 2D speckle tracking was applied to estimate displacement and strain. In this experiment, principal stretches were also derived using tracking results from two probes with resolution about 1.25 mm along its own axial direction. The principal stretches were compared for the normal heart and heart with ischemia or MI produced by LAD ligation. The isolated rabbit heart combined with BDM (2 mM) provided a well-controlled experimental environment for cardiac strain imaging with a virtually high frame acquisition rate. By comparing the synchronized pacing signal, LV pressure, ECG signal, and principal stretch, we were able to monitor and verify the local cardiac contractility referenced to the electrical stimulation.
• Kim, K., Witte, R. S., Olafsson, R., O'donnell, M., Kim, K., Jia, C., & Huang, S. W. (2007). 7C-6 Motion Artifact Reduction by ECG Gating in Ultrasound Induced Thermal Strain Imaging. In 2007 IEEE Ultrasonics Symposium Proceedings, 581-584.
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  Cardiac motion related artifact in ultrasound induced thermal strain imaging (TSI) was reduced in-vitro and in-vivo using ECG gating. Tissue motion due to the heart beat is a major challenge for in-vivo TSI application, especially for cardiovascular systems. Temporal variation of the relative position between the transducer and the artery will induce decorrelation in speckle tracking. Tissue deformation produces mechanical strains directly. Thermal strains are equivalent to their motion-induced mechanical counterparts and are typically an order of magnitude smaller. Consequently, effective reduction of motion artifacts is critical for clinical use of TSI. Using ECG signals to trigger array firing, cardiac periodicity can be fully utilized to minimize motion artifacts, allowing thermal strains to accumulate over multiple cardiac cycles with little distortion. TSI gated by the lumen pressure signal on an artery phantom (rubber) connected to a pulsatile pumping system compares well with TSI when the phantom was immobile for the same heating/imaging sequences. An in-vivo test was performed on a rabbit femoral artery under local animal protocol. The animal's ECG gated a similar pulse sequence used for the phantom. The in-vivo temperature rise in the femoral arterial wall was also estimated. This estimation is well above the background noise in TSI due to speckle tracking error or/and any possible residual vibration. Breathing motion artifacts can be minimized in the clinic through a breath hold.
• Qin, T., Wang, X., Meng, H., Qin, Y., Webb, B., Wan, G., Witte, R. S., Xin, H., & , . (2007, 2014). Microwave-Induced Thermoacoustic Imaging for Embedded Explosives Detection. In 2014 IEEE ANTENNAS AND PROPAGATION SOCIETY INTERNATIONAL SYMPOSIUM (APSURSI), 1917-1918.
• Rubin, J. M., Witte, R. S., Rubin, J. M., Olafsson, R., O'donnell, M., Jia, C., & Huang, S. W. (2007). P4B-6 Error Analysis of Axial Displacement Estimation in Elasticity Imaging. In 2007 IEEE Ultrasonics Symposium Proceedings, 1969-1972.
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  Correlation-based speckle tracking methods are commonly used in elasticity imaging to estimate displacements. In the presence of local strain, a larger window size (in cross correlation calculation) results in larger displacement error. To reduce tracking error, we proposed using a short window followed by a correlation coefficient filter. Although simulation and experimental results demonstrated the efficacy of the method, it is not clear why correlation filtering reduces tracking error. In this study, we addressed this issue and analyzed the relationship between displacement error and tracking parameters such as window size and filter size. For simplicity, we focused on axial displacement estimation. Analytic forms for tracking without and with correlation filtering were derived to predict tracking error. For the former case, the expression shows increase of error with resolution. For the latter case, there exists one extra negative term so that tracking error decreases with resolution. Furthermore, given a fixed resolution, a smaller window together with a larger filter is preferred. Simulations were performed and the results match the theory well for strains up to 4%.
• Witte, R. S., Kim, K., Ashish, A., Fan, W., Kopelman, R., Kotov, N., Kipke, D., O'Donnell, M., Oraevsky, A., & Wang, L. (2007, 2008). Enhanced photoacoustic neuroimaging with gold nanorods and PEBBLEs - art. no. 685614. In PHOTONS PLUS ULTRASOUND: IMAGING AND SENSING 2008: THE NINTH CONFERENCE ON BIOMEDICAL THERMOACOUSTICS, OPTOACOUSTICS, AND ACOUSTIC-OPTICS, 6856, 85614-85614.
• Witte, R. S., O'donnell, M., Huang, S., & Ashkenazi, S. (2007). Hybrid Imaging System for Developing Novel Neural Contrast Agents. In 2007 3rd International IEEE/EMBS Conference on Neural Engineering, 229-232.
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  Neural contrast agents have a vast array of applications from molecular imaging to mapping membrane potential. We describe a hybrid neural recording system capable of ultrasonic, photoacoustic and optical imaging designed to develop and test the next-generation of neural contrast agents. Photoacoustic imaging (PA), in particular, provides optical contrast with good penetration and high spatial resolution, making it an attractive tool for noninvasive neural imaging. To demonstrate the system, we chose a commercial dye (NK2761) commonly used for optical imaging of neural tissue to enhance PA images of live lobster nerve cord. The abdominal segment was excised, stained and placed in a custom neural chamber. Photoacoustic and ultrasound images were collected using a clinical ultrasound scanner and a 10-MHz linear probe. A wavelength-tunable pulsed laser source (5 nsec, ~15 mJ) operating at 20 Hz produced PA waves. Longitudinal scans of the nerve cord were collected and displayed every 7 seconds. Without a contrast agent, the peak PA signal was 5 dB over noise. An additional 29 dB was achieved after the nerve was submerged in dye for 20 minutes. The contrast enhancement was consistent with the measured optical absorbance of the stained nerve. Photoacoustic images approached 200-mum spatial resolution. The hybrid system provided several hours of imaging, electrical stimulation and recording, serving as a robust testbed for developing novel contrast for neural applications.
• Witte, R. S., Olafsson, R., & O'donnell, M. (2007). Measurement of a 2D electric dipole field using the acousto-electric effect. In Medical Imaging 2007: Ultrasonic Imaging and Signal Processing, 6513.
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  Conventional methods for mapping cardiac current fields have either poor spatial resolution (e.g. ECG) or are time consuming (e.g., intra-cardiac catheter electrode mapping). We present a method based on the acousto-electric effect (AEE) and lead field theory for minimally-invasive mapping of 2D current distributions. The AEE is a pressure-induced conductivity modulation in which focused ultrasound can be used as a spatially-localized pressure source. As a proof of principle we generated a 2D dipole field in a thin bath of 0.9% NaCl solution by injecting 28 mA through a pair of electrodes. A 7.5 MHz transducer was focused on the bath from below. A recording electrode was rotated along the boundary of the bath in 20° steps. For each angle, the transducer was swept over the bath in a raster scan. A pulse-echo and an AEE voltage trace were acquired at each point. The AEE traces were combined in post-processing as if coming from a multi-electrode circular array. The direction and magnitude of the current field at each point in the plane was estimated from the AEE and compared to simulation. The potential field was independently mapped using a roving monopolar electrode. The correlation coefficient between this map and the simulated field was 0.9957. A current source density analysis located the current source and sink to within 1±2 mm of their true position. This method can be extended to 3 dimensions and has potential for use in rapid mapping of current fields in the heart with high spatial resolution.
• Witte, R. S., Olafsson, R., O'donnell, M., Huang, S. W., & Hall, T. L. (2007). 8F-6 Inexpensive Acoustoelectric Hydrophone For Measuring High Intensity Ultrasound Fields. In 2007 IEEE Ultrasonics Symposium Proceedings, 737-740.
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  We describe an inexpensive alternative to conventional hydrophones used to map an ultrasonic beam pattern. Instead of relying on piezo materials to detect pressure, these hydrophones depend on a bias current flowing through a conductive material. According to the well-described acoustoelectric (AE) effect, as a pressure wave interacts with a current field, a voltage is generated. We exploit this principal to design and test a variety of disposable hydrophones composed of common laboratory supplies. Designs varied primarily by the shape and material of their conductive layer, such as graphite or saline gel. The hydrophone was used to map the beam pattern of a 540-khz annular transducer and compared with a conventional fiber optic hydrophone. The detected AE signal was amplified, high-pass filtered and captured using a fast 12-bit acquisition board. The hydrophone in the form of a bowtie and composed of a thin layer of graphite on a paper substrate accurately reproduced the beam pattern and spectrum of the ultrasound transducer with decent sensitivity less than 50 kPa. The detected AE signal at 2 MPa was proportional to the applied bias current (2.90 muV/mA). The axial and lateral resolutions (5.2 and 4.1 mm, respectively) were both within 200 mum of the values obtained from a less sensitive fiber optic hydrophone. The disposable AE hydrophone may be an attractive alternative for clinical applications that require close monitoring of high intensity acoustic fields.
• O¿donnell, M., Witte, R. S., O�donnell, M., Olafsson, R., & O'donnell, M. (2006). 1A-4 Acoustoelectric Detection of Current Flow in a Neural Recording Chamber. In 2006 IEEE Ultrasonics Symposium, 5-8.
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  Acoustic pressure (P) traveling in a biologic fluid or tissue generates a local change in electrical conductivity. This acoustoelectric interaction (AE) induces a voltage modulation that depends on local current, resistance, and pressure. We explore the AE signal as a way to enhance traditional electrophysiology or surface recording of neural signals. A thin stretch tube mimicking an enlarged axon and an abdominal segment of a fresh lobster nerve cord were used as test structures for AE detection in a tri-compartment neural recording chamber. Stimulating electrodes passed low frequency current through the structures, while a pair of recording electrodes detected the high frequency AE signal. Ultrasound transducers from 0.5 to 7.5 MHz delivered P up to 2 MPa. The differentially-recorded AE signal was captured on a fast data acquisition board and saved for post processing. In the lobster nerve cord, the AE signal was linear between the tested range of current densities of 9 to 86 mA/cM2 [18 dB/log(J), r 2=0.96] and P of 0.5 to 2 MPa [21 dB/log(P), r 2 =0.96]. In addition, a transverse scan of the structures produced cross-sectional AE images of current flow with remote detection by the recording electrodes. Results were consistent with AE simulations. This study demonstrates that the AF signal can be used to detect and image current flow in a biologic environment with physiologically relevant current densities and acoustic pressures on par with clinical ultrasound imaging
• Witte, R. S., Olafsson, R., O'donnell, M., Kim, K., & Ashkenazi, S. (2006). Electric current mapping using the acousto-electric effect. In Medical Imaging 2006: Ultrasonic Imaging and Signal Processing, 6147, 213-223.
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  Conventional methods for mapping cardiac current fields lack either spatial resolution (e.g. ECG) or are time consuming (e.g., intra-cardiac catheter electrode mapping). We present a method based on the acousto-electric effect (AEE) with potential for rapid mapping of current fields in the heart with high spatial resolution. The AEE is a pressure-induced conductivity modulation, in which focused ultrasound can be used as a spatially localized pressure source. When an ultrasound beam is focused between a pair of recording electrodes in a homogeneous conductive medium, an induced voltage will be produced due to the pressure-modulated conductivity and local current density. The amplitude of the voltage change should be proportional to fluctuations in current density, such as those generated during the cardiac cycle, in the region of focused ultrasound. Preliminary experiments demonstrate the feasibility of this method. A 540 kHz ultrasound transducer is focused between two tin electrodes lying parallel to the beam axis. These electrodes inject current into a 0.9% saline solution. A pair of insulated stainless steel electrodes exposed at the tip is used to record voltage. To simulate a cardiac current, a low frequency current waveform is injected into the sample such that the peak current density (8 mA/cm 2 ) approximates cardiac currents. The transducer is pulsed at different delays after waveform initiation. Delays are chosen such that the low frequency waveform is adequately sampled. Using this approach an emulated ECG waveform has been successfully reconstructed from the ultrasound modulated voltage traces.

Presentations

• Witte, R. S., Pires, P., & Hutchinson, E. B. (2021, Feb.). Mouse Brain Photoacoustic Imaging to Detect Hyper-Acute Pathophysiology Following Traumatic Brain Injury, Ischemia and Hemorrhage.. VisualSonics Live Imaging Workshop: “From Brain to Belly”VisualSonics.
• Witte, R. S., Ingram, P. C., & Kunyansky, L. (2017, Spring). Lorentz force impedance tomography in 2D: Theory and Experiments. Quantitative Biology Colloquium. U of A.
• Witte, R. S., Ingram, P. C., & Kunyansky, L. (2017, Spring). Rotational Magneto-Acousto-Electric Tomography: Theory and Experiments.. 100 years of the Radon transform. Johannes Keppler University, Linz, Austria.
• Witte, R. S., Ingram, P. C., & Kunyansky, L. (2017, Spring). Rotational Magneto-Acousto-Electric Tomography: Theory and Experiments.. Inverse Problems Seminar. University College London..
• Witte, R. S., Ingram, P., & Kunyansky, L. (2017, January). Lorentz force impedance tomography in 2D: Theory and Experiments. Inverse Problems Seminar.. Texas A&M University.
• Latt, D. L., Gao, L., Taljanovic, M., Szivek, J. A., Guerra, J. D., Klewer, J. A., & Witte, R. S. (2016, March). In Vivo Ultrasound Elasticity Imaging Differentiates Healthy From Diseased Tendons. Orthopaedic Research Society 2016 Annual Meeting. Orlando, Florida.
• Taljanovic, M., Latt, D. L., Gao, L., & Witte, R. S. (2016, March). In Vivo Ultrasound Tension Elastography Differentiates Healthy From Diseased Posterior Tibialis tendon. 39th Annual Meeting of the Society of Skeletal Radiology (SSR). New Orleans, LA: Society of Skeletal Radiology.
• Witte, R. S., Latt, D. L., Gao, L., Klewer, J. A., Guerra, J. D., Taljanovic, M., Szivek, J. A., Szivek, J. A., Guerra, J. D., Taljanovic, M., Klewer, J. A., Gao, L., Latt, D. L., Witte, R. S., Witte, R. S., Klewer, J. A., Guerra, J. D., Szivek, J. A., Taljanovic, M., , Gao, L., et al. (2016, March). In Vivo Ultrasound Elasticity Imaging Differentiates Healthy From Diseased Tendons. ORS 2016 Annual Meeting. Orlando, Florida.

Poster Presentations

• Preston, C., Kasoff, W., & Witte, R. S. (2018, April). Non-invasively mapping deep brain stimulation currents in 4D using acoustoelectric imaging. Minnesota Neuromodulation Symposium. Minneapolis, MN.
• Ingram, P., Bera, T., Burton, A., Hill, D. F., Wilhite, C. A., Witte, R. S., & Cowen, S. L. (2017, November). Acoustoelectric brain imaging: preliminary results in anesthetized rats. UA COM Founder's Day Junior Investigator Poster Forum.
• Martinez, J. A., Chalasani, P., Witte, R. S., Kwoh, C. K., Hadden, A., & Taljanovic, M. (2016, April). Imaging Biomarkers of Aromatase-Inhibitor Induced Joint Pain. University of Arizona, Cancer Center Retreat. Banner University Medical Center, Tucson, AZ.
• Schmitz, H., Witte, R. S., Gao, L., Latt, D. L., Ingram, C. P., Taljanovic, M., Klewer, J., Szivek, J. A., Klewer, J., Szivek, J. A., Ingram, C. P., Taljanovic, M., Gao, L., Latt, D. L., Schmitz, H., & Witte, R. S. (2016, January). Ultrasound Elasticity Imaging of the Posterior Tibial Tendon using FOCUS Simulation Software. 27th Annual Undergraduate Biology Research Program Conference. Tucson, AZ.
• Witte, R. S., Qin, Y., Ingram, P., Burton, A., Tseng, H., Hill, D. F., Wilhite, C. A., Falk, T., Xu, Z., O'Donell, M., & Cowen, S. L. (2016, Fall). Acoustoelectric Brain Imaging of Deep Dipole Sources in a Human Head Phantom. 3rd Annual BRAIN Initiative® Investigators Meeting.

Others

• Martinez, J. A., Chalasani, P., Witte, R. S., Kwoh, C. K., Hadden, A., Taljanovic, M., Martinez, J. A., Chalasani, P., Witte, R. S., Kwoh, C. K., Hadden, A., & Taljanovic, M. (2016, April). Imaging Biomarkers of Aromatase-Inhibitor Induced Joint Pain. University of Arizona, Cancer Center Retreat.
• Juneman, E., Lancaster, J., Witte, R., Bahl, J., & Goldman, S. (2012, AUG). Electrical Coupling of a Biological Active Cardiomyocyte Patch. JOURNAL OF CARDIAC FAILURE.