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Significance: Changes in lipid, water, and collagen (LWC) content in tissue are associated with numerous medical abnormalities (cancer, atherosclerosis, and Alzheimer's disease). Standard imaging modalities are limited in resolution, specificity, and/or penetration for quantifying these changes. Short-wave infrared (SWIR) photoacoustic imaging (PAI) has the potential to overcome these challenges by exploiting the unique optical absorption properties of LWC > 1000    nm ., Aim: This study's aim is to harness SWIR PAI for mapping LWC changes in tissue. The focus lies in devising a reflection-mode PAI technique that surmounts current limitations related to SWIR light delivery., Approach: To enhance light delivery for reflection-mode SWIR PAI, we designed a deuterium oxide ( D 2 O , "heavy water") gelatin (HWG) interface for opto-acoustic coupling, intended to significantly improve light transmission above 1200 nm., Results: HWG permits light delivery > 1    mJ up to 1850 nm, which was not possible with water-based coupling ( > 1    mJ light delivery up to 1350 nm). PAI using the HWG interface and the Visualsonics Vevo LAZR-X reveals a signal increase up to 24 dB at 1720 nm in lipid-rich regions., Conclusions: By overcoming barriers related to light penetration, the HWG coupling interface enables accurate quantification/monitoring of biomarkers like LWC using reflection-mode PAI. This technological stride offers potential for tracking changes in chronic diseases ( in vivo ) and evaluating their responses to therapeutic interventions., (© 2023 The Authors.)

Acoustoelectric imaging (AEI) is a technique that combines ultrasound (US) with radio frequency recording to detect and map local current source densities. This study demonstrates a new method called acoustoelectric time reversal (AETR), which uses AEI of a small current source to correct for phase aberrations through a skull or other US-aberrating layers with applications to brain imaging and therapy. Simulations conducted at three different US frequencies (0.5, 1.5, and 2.5 MHz) were performed through media layered with different sound speeds and geometries to induce aberrations of the US beam. Time delays of the acoustoelectric (AE) signal from a monopole within the medium were calculated for each element to enable corrections using AETR. Uncorrected aberrated beam profiles were compared with those after applying AETR corrections, which demonstrated a strong recovery (29%-100%) of lateral resolution and increases in focal pressure up to 283%. To further demonstrate the practical feasibility of AETR, we further conducted bench-top experiments using a 2.5 MHz linear US array to perform AETR through 3-D-printed aberrating objects. These experiments restored lost lateral restoration up to 100% for the different aberrators and increased focal pressure up to 230% after applying AETR corrections. Cumulatively, these results highlight AETR as a powerful tool for correcting focal aberrations in the presence of a local current source with applications to AEI, US imaging, neuromodulation, and therapy.

Background and Purpose: Cerebrovascular dynamics and pathomechanisms that evolve in the minutes and hours following traumatic vascular injury in the brain remain largely unknown. We investigated the pathophysiology evolution in mice within the first 3 hours after closed-head traumatic brain injury (TBI) and subarachnoid hemorrhage (SAH), two significant traumatic vascular injuries., Methods: We took a multimodal imaging approach using photoacoustic imaging, color Doppler ultrasound, and MRI to track injury outcomes using a variety of metrics., Results: Brain oxygenation and velocity-weighted volume of blood flow (VVF) values significantly decreased from baseline to 15 minutes after both TBI and SAH. TBI resulted in 19.2% and 41.0% ipsilateral oxygenation and VVF reductions 15 minutes postinjury, while SAH resulted in 43.9% and 85.0% ipsilateral oxygenation and VVF reduction (p < .001). We found partial recovery of oxygenation from 15 minutes to 3 hours after injury for TBI but not SAH. Hemorrhage, edema, reduced perfusion, and altered diffusivity were evident from MRI scans acquired 90-150 minutes after injury in both injury models, although the spatial distribution was mostly focal for TBI and diffuse for SAH., Conclusions: The results reveal that the cerebral oxygenation deficits immediately following injuries are reversible for TBI and irreversible for SAH. Our findings can inform future studies on mitigating these early responses to improve long-term recovery., (© 2023 The Authors. Journal of Neuroimaging published by Wiley Periodicals LLC on behalf of American Society of Neuroimaging.)

Objective: Phase-change contrast agents (PCCAs) are perfluorocarbon nanodroplets (NDs) that have been widely studied for ultrasound imaging in vitro, pre-clinical studies, and most recently incorporated a variant of PCCAs, namely a microbubble-conjugated microdroplet emulsion, into the first clinical studies. Their properties also make them attractive candidates for a variety of diagnostic and therapeutic applications including drug-delivery, diagnosis and treatment of cancerous and inflammatory diseases, as well as tumor-growth tracking. However, control over the thermal and acoustic stability of PCCAs both in vivo and in vitro has remained a challenge for expanding the potential utility of these agents in novel clinical applications. As such, our objective was to determine the stabilizing effects of layer-by-layer assemblies and its effect on both thermal and acoustic stability., Methods: We utilized layer-by-layer (LBL) assemblies to coat the outer PCCA membrane and characterized layering by measuring zeta potential and particle size. Stability studies were conducted by; 1) incubating the LBL-PCCAs at atmospheric pressure at 37 ∘ C and 45 ∘ C followed by; 2) ultrasound-mediated activation at 7.24 MHz and peak-negative pressures ranging from 0.71 - 5.48 MPa to ascertain nanodroplet activation and resultant microbubble persistence. The thermal and acoustic properties of decafluorobutane gas-condensed nanodroplets (DFB-NDs) layered with 6 and 10 layers of charge-alternating biopolymers, (LBL 6 NDs and LBL 10 NDs) respectively, were studied and compared to non-layered DFB-NDs. Half-life determinations were conducted at both 37 ∘ C and 45 ∘ C with acoustic droplet vaporization (ADV) measurements occurring at 23 ∘ C., Discussion: Successful application of up to 10 layers of alternating positive and negatively charged biopolymers onto the surface membrane of DFB-NDs was demonstrated. Two major claims were substantiated in this study; namely, (1) biopolymeric layering of DFB-NDs imparts a thermal stability up to an extent; and, (2) both LBL 6 NDs and LBL 10 NDs did not appear to alter particle acoustic vaporization thresholds, suggesting that the thermal stability of the particle may not necessarily be coupled with particle acoustic vaporization thresholds., Conclusion: Results demonstrate that the layered PCCAs had higher thermal stability, where the half-lifes of the LBL x NDs are significantly increased after incubation at 37 ∘ C and 45 ∘ C. Furthermore, the acoustic vaporization profiles the DFB-NDs, LBL 6 NDs, and LBL 10 NDs show that there is no statistically significant difference between the acoustic vaporization energy required to initiate acoustic droplet vaporization., (Copyright © 2022 World Federation for Ultrasound in Medicine & Biology. Published by Elsevier Inc. All rights reserved.)

Acoustoelectric (AE) imaging can potentially image biological currents at high spatial (~mm) and temporal (~ms) resolution. However, it does not directly map the current field distribution due to signal modulation by the acoustic field and electric lead fields. Here we present a new method for current source density (CSD) imaging. The fundamental AE equation is inverted using truncated singular value decomposition (TSVD) combined with Tikhonov regularization, where the optimal regularization parameter is found based on a modified L-curve criterion with TSVD. After deconvolution of acoustic fields, the current field can be directly reconstructed from lead field projections and the CSD image computed from the divergence of that field. A cube phantom model with a single dipole source was used for both simulation and bench-top phantom studies, where 2D AE signals generated by a 0.6 MHz 1.5D array transducer were recorded by orthogonal leads in a 3D Cartesian coordinate system. In simulations, the CSD reconstruction had significantly improved image quality and current source localization compared to AE images, and performance further improved as the fractional bandwidth (BW) increased. Similar results were obtained in the phantom with a time-varying current injected. Finally, a feasibility study using an in vivo swine heart model showed that optimally reconstructed CSD images better localized the current source than AE images over the cardiac cycle.

Injuries caused by surgical incisions or traumatic lacerations compromise the structural and functional integrity of skin. Immediate approximation and robust repair of skin are critical to minimize occurrences of dehiscence and infection that can lead to impaired healing and further complication. Light-activated skin sealing has emerged as an alternative to sutures, staples, and superficial adhesives, which do not integrate with tissues and are prone to scarring and infection. Here, we evaluate both shorter- and longer-term efficacy of tissue repair response following laser-activated sealing of full-thickness skin incisions in immunocompetent mice and compare them to the efficacy seen with sutures. Laser-activated sealants (LASEs) in which, indocyanine green was embedded within silk fibroin films, were used to form viscous pastes and applied over wound edges. A hand-held, near-infrared laser was applied over the incision, and conversion of the light energy to heat by the LASE facilitated rapid photothermal sealing of the wound in approximately 1 min. Tissue repair with LASEs was evaluated using functional recovery (transepidermal water loss), biomechanical recovery (tensile strength), tissue visualization (ultrasound [US] and photoacoustic imaging [PAI]), and histology, and compared with that seen in sutures. Our studies indicate that LASEs promoted earlier recovery of barrier and mechanical function of healed skin compared to suture-closed incisions. Visualization of sealed skin using US and PAI indicated integration of the LASE with the tissue. Histological analyses of LASE-sealed skin sections showed reduced neutrophil and increased proresolution macrophages on Days 2 and 7 postclosure of incisions, without an increase in scarring or fibrosis. Together, our studies show that simple fabrication and application methods combined with rapid sealing of wound edges with improved histological outcomes make LASE a promising alternative for management of incisional wounds and lacerations., Competing Interests: Kaushal Rege is affiliated with a start‐up company, Synergyan, LLC. Other authors declare no conflict of interest., (© 2022 The Authors. Bioengineering & Translational Medicine published by Wiley Periodicals LLC on behalf of American Institute of Chemical Engineers.)

In recent years, there has been a progressive trend towards less invasive technologies for detecting metastatic cancer and guiding therapy with the goal of lower morbidity, better outcomes, and superior cosmetic appearance than traditional methods. This mini-review examines three emerging noninvasive hybrid technologies for detecting primary cancer, metastasis and guiding thermal therapy. Real-time thermoacoustic imaging and thermometry potentially provides valuable and critical feedback for guiding focused microwave ablation therapy. Label-free photoacoustic monitoring of cancer cells is a promising clinical diagnostic and theranostic tool for detecting metastatic disease and monitoring the response to therapy. Finally, immunologically targeted gold nanoparticles combined with photoacoustic imaging is able to detect lymph node micrometastasis in mouse models of breast cancer. These emerging techniques have the potential to improve the decision to biopsy, provide more accurate prognosis, and enhance the efficacy of therapy for early and late stage cancers., (© 2021. The Author(s), under exclusive licence to Springer Nature B.V.)

Radiation therapy has long been known to be a very effective form of therapy in relieving symptoms and prolonging the life of patients with brain metastases. Novel developments in this field have allowed oncologists to improve on older forms of radiation therapy; these recent advances in radiotherapeutic techniques (stereotactic radiosurgery and hippocampal-avoidant whole brain radiation therapy) allow sparing of the healthy brain from receiving unnecessary radiation while delivering effective treatment to the metastases, thus improving the quality of life for surviving patients. Furthermore, multiple clinical trials have documented the increased loco-regional control in the brain when radiosurgery is interdigitated with immune check point inhibitors for treatment of melanoma brain metastases. Mild hyperthermia has been used for decades as an adjuvant to radiotherapy in the treatment of radiation resistant cancers; lately, however, thermal therapies, such as hyperthermia, cryoablation, radiofrequency ablation and high intensity focused ultrasound are being investigated to provide a new ablative approach to cancer while thermoacoustic imaging and thermometry have recently been proposed as new techniques for monitoring tissue temperature in the breast during ablation treatment. In addition, other hybrid techniques have emerged that combine ultrasounds with other forms of energy such as light to provide a more accurate diagnosis and enhance the efficacy of therapy for early and late stage cancers., (© 2021. The Author(s), under exclusive licence to Springer Nature B.V.)

Noninvasive thermal therapies for the treatment of breast cancer depend on accurate monitoring of tissue temperature to optimize treatment and ensure safety. This work describes a real-time system for 3-D thermoacoustic imaging and thermometry (TAI-TAT) for tracking temperature in tissue samples during heating. The study combines a 2.7-GHz microwave pulse generator with a custom 1.5-D 0.6 MHz ultrasound array for generating and detecting TA signals. The system is tested and validated on slabs of biological tissue and saline gel during heating. Calibration curves for relating the TA signal to temperature were calculated in saline gel (3.40%/°C), muscle (1.73%/°C), and fat (1.15%/°C), respectively. The calibrations were used to produce real-time, volumetric temperature maps at ~3-s intervals with a spatial resolution of approximately 3 mm. TAT temperature changes within a region of interest were compared to adjacent thermocouples with a mean error of 17.3%, 13.2%, and 20.4% for muscle, gel, and fat, respectively. The TAT algorithm was also able to simultaneously track temperatures in different tissues. With further development, noninvasive TAI-TAT may prove to be a valuable method for accurate and real-time feedback during breast cancer ablation therapy.

Aim: To determine whether differences in joint and tendon stiffness as measured by ultrasound shear wave elastography are present in breast cancer patients with aromatase inhibitor-associated arthralgias compared to age-comparable healthy control women., Methods: Postmenopausal women with stage I-III breast cancer who were taking adjuvant aromatase inhibitors and complained of joint pain were enrolled ( n = 6). Postmenopausal women with no history of breast cancer, hormone treatment, or joint pain served as controls ( n = 7). All subjects had bilateral hands and wrists evaluated by gray-scale and power Doppler ultrasound, and shear wave elastography ultrasound., Results: Patients with AI-associated arthralgias had significantly stiffer tendons than controls in the 1 st extensor compartment (long axis; p = 0.001), 4 th extensor compartment (long axis; p = 0.014), 3 rd metacarpophalangeal joint ( p = 0.002), the pooled values of the extensor compartments, both long ( p = 0.044) and short axes ( p = 0.035), and the pooled values for the metacarpophalangeal joints ( p = 0.002). On ultrasound, the patients (but not controls) presented with hyperemia and increased tenosynovial fluid in the flexor and extensor tendon sheaths, and the median nerves were symptomatic and bifid; however, these differences were not statistically significant., Conclusions: This is the first study to identify increased tendon stiffness as a putative physiological characteristic of aromatase inhibitor-associated arthralgias. Future studies should determine whether increased tendon stiffness is a risk factor for the development of aromatase inhibitor-associated arthralgias, or a result of aromatase inhibitor treatment., Competing Interests: Conflict of interest Authors do not report any financial or personal connections with other persons or organizations, which might negatively affect the contents of this publication and/or claim authorship rights to this publication., (© Polish Ultrasound Society.)

Acoustoelectric cardiac imaging (ACI) is a hybrid modality that exploits the interaction of an ultrasonic pressure wave and the resistivity of tissue to map current densities in the heart. This study demonstrates for the first time in vivo ACI in a swine model. ACI measured beat-to-beat variability ( n =20) of the peak of the cardiac activation wave at one location of the left ventricle as 5.32±0.74µ V , 3.26±0.54 m m below the epicardial surface, and 2.67±0.56 m s before the peak of the local electrogram. Cross-sectional ACI images exhibited propagation velocities of 0.192±0.061 m / s along the epicardial-endocardial axis with an SNR of 24.9 dB. This study demonstrates beat-to-beat and multidimensional ACI, which might reveal important information to help guide electroanatomic mapping procedures during ablation therapy.

Objective: This study employs a human head model with real skull to demonstrate the feasibility of transcranial acoustoelectric brain imaging (tABI) as a new modality for electrical mapping of deep dipole sources during treatment of epilepsy with much better resolution and accuracy than conventional mapping methods., Approach: This technique exploits an interaction between a focused ultrasound (US) beam and tissue resistivity to localize current source densities as deep as 63 mm at high spatial resolution (1 to 4 mm) and resolve fast time-varying currents with sub-ms precision., Main Results: Detection thresholds through a thick segment of the human skull at biologically safe US intensities was below 0.5 mA and within range of strong currents generated by the human brain., Significance: This work suggests that 4D tABI may emerge as a revolutionary modality for real-time high-resolution mapping of neuronal currents for the purpose of monitoring, staging, and guiding treatment of epilepsy and other brain disorders characterized by abnormal rhythms.

Thermoacoustic (TA) imaging is a modality where pulsed microwaves are used to generate ultrasound waves in tissue, which are highly correlated with temperature. This study uses a self-calibration approach to improve the estimation of temperature using 3D real-time TA thermometry in porcine tissue during localized heating. The self-calibration method estimated temperatures at eight embedded thermocouple locations with a normalized root-mean-square error of 3.25±2.08 % . The results demonstrate that the method has the suitable accuracy and resolution to provide feedback control for breast cancer ablation therapy.

Objective: New innovations in deep brain stimulation (DBS) enable directional current steering-allowing more precise electrical stimulation of the targeted brain structures for Parkinson's disease, essential tremor and other neurological disorders. While intra-operative navigation through MRI or CT approaches millimeter accuracy for placing the DBS leads, no existing modality provides feedback of the currents as they spread from the contacts through the brain tissue. In this study, we investigate transcranial acoustoelectric imaging (tAEI) as a new modality to non-invasively image and characterize current produced from a directional DBS lead. tAEI uses ultrasound (US) to modulate tissue resistivity to generate detectable voltage signals proportional to the local currents., Approach: An 8-channel directional DBS lead (Infinity 6172ANS, Abbott Inc) was inserted inside three adult human skulls submerged in 0.9% NaCl. A 2.5 MHz linear array delivered US pulses through the transtemporal window and focused near the contacts on the lead, while a custom amplifier and acquisition system recorded the acoustoelectric (AE) interaction used to generate images., Main Results: tAEI detected monopolar current with stimulation pulses as short as 100 µs with an SNR ranging from 10-27 dB when using safe US pressure (mechanical indices  <0.78) and injected current of ~2 mA peak amplitude. Adjacent contacts were discernable along the length and within each ring of the lead with a mean radial separation between contacts of 2.10 and 1.34 mm, respectively., Significance: These results demonstrate the feasibility of tAEI for high resolution mapping of directional DBS currents using clinically-relevant stimulation parameters. This new modality may improve the accuracy for placing the DBS leads, guide calibration and programming, and monitor long-term performance of DBS for treatment of Parkinson's disease.

We describe a new application of acoustoelectric imaging for non-invasive mapping of the location, magnitude and polarity of current generated by a clinical deep brain stimulation (DBS) device. Ultrasound at 1MHz was focused near the DBS device as short current pulses were injected across different DBS leads. A recording electrode detected the high-frequency acoustoelectric interaction signal. Linear scans of the US beam produced time-varying images of the magnitude and polarity of the induced current, enabling precise localization of the DBS leads within 0.70mm, a detection threshold of 1.75mA at 1 MPa and a sensitivity of 0.52 ± 0.07 μV/(mA*MPa). Monopole and dipole configurations in saline were repeated through a human skullcap. Despite 13.8-dB ultrasound attenuation through bone, acoustoelectric imaging was still >10dB above background with a sensitivity of 0.56 ± 0.10 μV/(mA*MPa). This proof-of-concept study indicates that selective mapping of lead currents through a DBS device may be possible using non-invasive acoustoelectric imaging., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

This review describes emerging techniques within the last 5 years that employ ultrasound for detecting and staging malignancy, tracking metastasis, and guiding treatment. Ultrasound elastography quantifies soft tissue elastic properties that change as a tumor grows and proliferates. Hybrid imaging modalities that combine ultrasound with light or microwave energy provide novel contrast for mapping blood oxygen saturation, transport of particles through lymphatic vessels and nodes, and real-time feedback for guiding needle biopsies. Combining these methods with smart nanoparticles and contrast agents further promotes new paradigms for cancer imaging and therapy.

The acoustoelectric (AE) effect is a basic physical phenomenon, which underlies the changes made in the conductivity of a medium by the application of focused ultrasound. Recently, based on the AE effect, several biomedical imaging techniques have been widely studied, such as ultrasound-modulated electrical impedance tomography and ultrasound current source density imaging. To further investigate the mechanism of the AE effect in tissue and to provide guidance for such techniques, we have modeled the tissue AE effect using the theory of solid mechanics. Both bulk compression and thermal expansion of tissue are considered and discussed. Computation simulation shows that the muscle AE effect result, conductivity change rate, is 3.26×10 -3 with 4.3-MPa peak pressure, satisfying the theoretical value. Bulk compression plays the main role for muscle AE effect, while thermal expansion makes almost no contribution to it. In addition, the AE signals of porcine muscle are measured at different focal positions. With the same magnitude order and the same change trend, the experiment result confirms that the simulation result is effective. Both simulation and experimental results validate that tissue AE effect modeling using solid mechanics theory is feasible, which is of significance for the further development of related biomedical imaging techniques.

In the past 2 decades, sonoelastography has been progressively used as a tool to help evaluate soft-tissue elasticity and add to information obtained with conventional gray-scale and Doppler ultrasonographic techniques. Recently introduced on clinical scanners, shear-wave elastography (SWE) is considered to be more objective, quantitative, and reproducible than compression sonoelastography with increasing applications to the musculoskeletal system. SWE uses an acoustic radiation force pulse sequence to generate shear waves, which propagate perpendicular to the ultrasound beam, causing transient displacements. The distribution of shear-wave velocities at each pixel is directly related to the shear modulus, an absolute measure of the tissue's elastic properties. Shear-wave images are automatically coregistered with standard B-mode images to provide quantitative color elastograms with anatomic specificity. Shear waves propagate faster through stiffer contracted tissue, as well as along the long axis of tendon and muscle. SWE has a promising role in determining the severity of disease and treatment follow-up of various musculoskeletal tissues including tendons, muscles, nerves, and ligaments. This article describes the basic ultrasound physics of SWE and its applications in the evaluation of various traumatic and pathologic conditions of the musculoskeletal system. © RSNA, 2017.

We present a novel two-dimensional (2D) MAET scanner, with a rotating object of interest and two fixed pairs of electrodes. Such an acquisition scheme, with our novel reconstruction techniques, recovers the boundaries of the regions of constant conductivity uniformly well, regardless of their orientation. We also present a general image reconstruction algorithm for the 2D MAET in a circular chamber with point-like electrodes immersed into the saline surrounding the object. An alternative linearized reconstruction procedure is developed, suitable for recovering the material interfaces (boundaries) when a non-ideal piezoelectric transducer is used for acoustic excitation. The work of the scanner and the linearized reconstruction algorithm is demonstrated using several phantoms made of high-contrast materials and a biological sample.

Although the drug-eluting stent (DES) has dramatically reduced the rate of coronary restenosis, it still occurs in up to 20% of patients with a DES. Monitoring drug delivery could be one way to decrease restenosis rates. We demonstrate real-time photoacoustic imaging and spectroscopy (PAIS) using a wavelength-tunable visible laser and clinical ultrasound scanner to track cardiac drug delivery. The photoacoustic signal was initially calibrated using porcine myocardial samples soaked with a known concentration of a drug surrogate (DiI). Next, an in situ coronary artery was perfused with DiI for 20 min and imaged to monitor dye transport in the tissue. Finally, a partially DiI-coated stent was inserted into the porcine brachiocephalic trunk for imaging. The photoacoustic signal was proportional to the DiI concentration between 2.4 and 120 ?? ? g / ml , and the dye was detected over 1.5 mm from the targeted coronary vessel. Photoacoustic imaging was also able to differentiate the DiI-coated portion of the stent from the uncoated region. These results suggest that PAIS can track drug delivery to cardiac tissue and detect drugs loaded onto a stent with sub-mm precision. Future work using PAIS may help improve DES design and reduce the probability of restenosis.

Ultrasound modulated electrical impedance tomography (UMEIT) is a novel hybrid imaging technique, which utilizes coupling between electric and acoustic modalities. Based on the forward solver along different current directions, an instrumental electrode configuration is proposed for 3D UMEIT. The proposed electrode configuration can produce a similar longitudinal current, making the power density distribution on the x-y plane approximately consistent with the corresponding conductivity distribution. Then, this satisfying power density is adopted to reconstruct a higher-resolution conductivity distribution. Therefore, the proposed electrode configuration contributes to improving the image reconstruction quality of UMEIT. Also, to clearly demonstrate its meaning in theory, the forward solver results are analyzed from an electrical point of view. In addition, the nonlinear partial differential equation (PDE) relating the power density to the measured data is derived again with a more reasonable expression. Finally, simulation with realistic geometry model of human breast is done and feasibility verifying experiment is made. Both simulation and experimental results validate the feasibility of the proposed electrode configuration.

Breast cancer is a diverse and complex disease that remains one of the leading causes of death among women. Novel, outside-of-the-box imaging and treatment methods are needed to supplement currently available technologies. In this study, we present evidence for the intracellular delivery and ultrasound-stimulated activation of folate receptor (FR)-targeted phase-change contrast agents (PCCAs) in MDA-MB-231 and MCF-7 breast cancer cells in vitro. PCCAs are lipid-coated, perfluorocarbon-filled particles formulated as nanoscale liquid droplets capable of vaporization into gaseous microbubbles for imaging or therapy. Cells were incubated with 1:1 decafluorobutane (DFB)/octafluoropropane (OFP) PCCAs for 1h, imaged via confocal microscopy, exposed to ultrasound (9MHz, MI=1.0 or 1.5), and imaged again after insonation. FR-targeted PCCAs were observed intracellularly in both cell lines, but uptake was significantly greater (p<0.001) in MDA-MB-231 cells (93.0% internalization at MI=1.0, 79.5% at MI=1.5) than MCF-7 cells (42.4% internalization at MI=1.0, 35.7% at MI=1.5). Folate incorporation increased the frequency of intracellular PCCA detection 45-fold for MDA-MB-231 cells and 7-fold for MCF-7 cells, relative to untargeted PCCAs. Intracellularly activated PCCAs ranged from 500nm to 6μm (IQR=800nm-1.5μm) with a mean diameter of 1.15±0.59 (SD) microns. The work presented herein demonstrates the feasibility of PCCA intracellular delivery and activation using breast cancer cells, illuminating a new platform toward intracellular imaging or therapeutic delivery with ultrasound., (Copyright © 2016 Elsevier B.V. All rights reserved.)

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., (Copyright © 2016 World Federation for Ultrasound in Medicine & Biology. Published by Elsevier Inc. All rights reserved.)

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.

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.

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.

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., (Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.)

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.

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.

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.

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.

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.

Background and Objective: 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., Materials and Methods: The 3D images of the porcine eye were generated in approximately 10 seconds by scanning one of two commercial linear arrays (25- and 50-MHz). Healthy enucleated pig eyes were compared with those with induced injury or placement of a foreign material (eg, metal). Rapid, volumetric imaging was also demonstrated in one human eye in vivo., Results: The 50-MHz probe provided exquisite volumetric images of the anterior segment at a depth up to 15 mm and axial resolution of 30 μm. The 25-MHz probe provided a larger field of view (lateral X depth: 20 × 30 mm), sufficient for capturing the entire anterior and posterior segments of the pig eye, at a resolution of 60 μm. A 50-MHz scan through the human eyelid illustrated detailed structures of the Meibomian glands, cilia, cornea, and anterior segment back to the posterior capsule., Conclusion: The 3D system with its high-frequency ultrasound arrays, fast data acquisition, and volume rendering capability shows promise for investigating anterior and posterior structures of the eye., (Copyright 2012, SLACK Incorporated.)

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.

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., (Copyright © 2011 Wiley-Liss, Inc.)

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.

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.

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.

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.

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%.

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.

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.

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 (<1 degrees C) for plaque characterization.

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.

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.

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.

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.