High-spatial-resolution transcranial focused ultrasound neuromodulation using frequency-modulated pattern interference radiation force.

Stimulating the brain in a precise location is crucial in ultrasound neuromodulation. However, improving the resolution proves a challenge owing to the characteristics of transcranial focused ultrasound. In this paper, we present a new neuromodulation system that overcomes the existing limitations based on an acoustic radiation force with a frequency-modulated waveform and standing waves. By using the frequency-modulated pattern interference radiation force (FM-PIRF), the axial spatial resolution can be reduced to a single wavelength level and the target location can be controlled in axial direction electronically. A linear frequency-modulated chirp waveform used in the experiment was designed based on the simulation results. The displacement of the polydimethylsiloxane (PDMS) cantilever was measured at intervals of 0.1 mm to visualize the distribution of radiation force. These results and methods experimentally show that FM-PIRF has improved spatial resolution and capability of electrical movement.

Acoustic radiation force for analyzing the mechanical stress in ultrasound neuromodulation.

Objective. Although recent studies have shown that mechanical stress plays an important role in ultrasound neuromodulation, the magnitude and distribution of the mechanical stress generated in tissues by focused ultrasound transducers have not been adequately examined. Various acoustic radiation force (ARF) equations used in previous studies have been evaluated based on the tissue displacement results and are suitable for estimating the displacement. However, it is unclear whether mechanical stress can be accurately determined. This study evaluates the mechanical stress predicted by various AFR equations and suggests the optimal equation for estimating the mechanical stress in the brain tissue.Approach. In this paper, brain tissue responses are compared through numerical finite element simulations by applying the three most used ARF equations-Reynolds stress force ((RSF)), momentum flux density tensor force, and attenuation force. Three ARF fields obtained from the same pressure field were applied to the linear elastic model to calculate the displacement, mechanical stress, and mean pressure generated inside the tissue. Both the simple pressure field using a single transducer and the complex standing wave pressure field using two transducers were simulated.Main results. For the case using a single transducer, all three ARFs showed similar displacement. However, when comparing the mechanical stress results, only the results using the RSF showed a strong stress tensor at the focal point. For the case of using two transducers, the displacement and stress tensor field of the pattern related to the standing wave were calculated only from the results using the RSF.Significance. The model using RSF equation allows accurate analysis on stress tensor inside the tissue for ultrasound neuromodulation.

Combining Acoustic Bioprinting with AI-Assisted Raman Spectroscopy for High-Throughput Identification of Bacteria in Blood.

Identifying pathogens in complex samples such as blood, urine, and wastewater is critical to detect infection and inform optimal treatment. Surface-enhanced Raman spectroscopy (SERS) and machine learning (ML) can distinguish among multiple pathogen species, but processing complex fluid samples to sensitively and specifically detect pathogens remains an outstanding challenge. Here, we develop an acoustic bioprinter to digitize samples into millions of droplets, each containing just a few cells, which are identified with SERS and ML. We demonstrate rapid printing of 2 pL droplets from solutions containing S. epidermidis, E. coli, and blood; when they are mixed with gold nanorods (GNRs), SERS enhancements of up to 1500× are achieved.We then train a ML model and achieve ≥99% classification accuracy from cellularly pure samples and ≥87% accuracy from cellularly mixed samples. We also obtain ≥90% accuracy from droplets with pathogen:blood cell ratios <1. Our combined bioprinting and SERS platform could accelerate rapid, sensitive pathogen detection in clinical, environmental, and industrial settings.

A tool for monitoring cell type-specific focused ultrasound neuromodulation and control of chronic epilepsy.

Focused ultrasound (FUS) is a powerful tool for noninvasive modulation of deep brain activity with promising therapeutic potential for refractory epilepsy; however, tools for examining FUS effects on specific cell types within the deep brain do not yet exist. Consequently, how cell types within heterogeneous networks can be modulated and whether parameters can be identified to bias these networks in the context of complex behaviors remains unknown. To address this, we developed a fiber Photometry Coupled focused Ultrasound System (PhoCUS) for simultaneously monitoring FUS effects on neural activity of subcortical genetically targeted cell types in freely behaving animals. We identified a parameter set that selectively increases activity of parvalbumin interneurons while suppressing excitatory neurons in the hippocampus. A net inhibitory effect localized to the hippocampus was further confirmed through whole brain metabolic imaging. Finally, these inhibitory selective parameters achieved significant spike suppression in the kainate model of chronic temporal lobe epilepsy, opening the door for future noninvasive therapies.

Spike frequency-dependent inhibition and excitation of neural activity by high-frequency ultrasound.

Ultrasound can modulate action potential firing in vivo and in vitro, but the mechanistic basis of this phenomenon is not well understood. To address this problem, we used patch-clamp recording to quantify the effects of focused, high-frequency (43 MHz) ultrasound on evoked action potential firing in CA1 pyramidal neurons in acute rodent hippocampal brain slices. We find that ultrasound can either inhibit or potentiate firing in a spike frequency-dependent manner: at low (near-threshold) input currents and low firing frequencies, ultrasound inhibits firing, while at higher input currents and higher firing frequencies, ultrasound potentiates firing. The net result of these two competing effects is that ultrasound increases the threshold current for action potential firing, the slope of frequency-input curves, and the maximum firing frequency. In addition, ultrasound slightly hyperpolarizes the resting membrane potential, decreases action potential width, and increases the depth of the after-hyperpolarization. All of these results can be explained by the hypothesis that ultrasound activates a sustained potassium conductance. According to this hypothesis, increased outward potassium currents hyperpolarize the resting membrane potential and inhibit firing at near-threshold input currents but potentiate firing in response to higher-input currents by limiting inactivation of voltage-dependent sodium channels during the action potential. This latter effect is a consequence of faster action potential repolarization, which limits inactivation of voltage-dependent sodium channels, and deeper (more negative) after-hyperpolarization, which increases the rate of recovery from inactivation. Based on these results, we propose that ultrasound activates thermosensitive and mechanosensitive two-pore-domain potassium (K2P) channels through heating or mechanical effects of acoustic radiation force. Finite-element modeling of the effects of ultrasound on brain tissue suggests that the effects of ultrasound on firing frequency are caused by a small (<2°C) increase in temperature, with possible additional contributions from mechanical effects.

Toward rapid infectious disease diagnosis with advances in surface-enhanced Raman spectroscopy.

In a pandemic era, rapid infectious disease diagnosis is essential. Surface-enhanced Raman spectroscopy (SERS) promises sensitive and specific diagnosis including rapid point-of-care detection and drug susceptibility testing. SERS utilizes inelastic light scattering arising from the interaction of incident photons with molecular vibrations, enhanced by orders of magnitude with resonant metallic or dielectric nanostructures. While SERS provides a spectral fingerprint of the sample, clinical translation is lagged due to challenges in consistency of spectral enhancement, complexity in spectral interpretation, insufficient specificity and sensitivity, and inefficient workflow from patient sample collection to spectral acquisition. Here, we highlight the recent, complementary advances that address these shortcomings, including (1) design of label-free SERS substrates and data processing algorithms that improve spectral signal and interpretability, essential for broad pathogen screening assays; (2) development of new capture and affinity agents, such as aptamers and polymers, critical for determining the presence or absence of particular pathogens; and (3) microfluidic and bioprinting platforms for efficient clinical sample processing. We also describe the development of low-cost, point-of-care, optical SERS hardware. Our paper focuses on SERS for viral and bacterial detection, in hopes of accelerating infectious disease diagnosis, monitoring, and vaccine development. With advances in SERS substrates, machine learning, and microfluidics and bioprinting, the specificity, sensitivity, and speed of SERS can be readily translated from laboratory bench to patient bedside, accelerating point-of-care diagnosis, personalized medicine, and precision health.

Wide Bandwidth and Low Driving Voltage Vented CMUTs for Airborne Applications.

This paper presents a novel method to increase the bandwidth (BW) of airborne capacitive micromachined ultrasonic transducers (CMUTs). This method introduces a gaseous squeeze film as a damping mechanism, which induces a stiffening effect that lowers the pull-in voltage and improves the sensitivity. The optimal behavior of this stiffening effect versus the damping mechanism can be controlled by creating optimized fluidic trenches of various heights within the gap. The fractional BW can be controlled from 0.89% to 8.1% by adjusting the trench height while lowering the pull-in voltage to less than 54 V at the gap height of 1.0 [Formula: see text]. To achieve the largest sensitivity and lowest pull-in voltage at a given BW, we have developed a multi-parameter optimization method to adjust all combinations of design parameters. A novel multiple hard-mask process flow has been developed to enable fabrication of CMUTs with different cavity and trench heights on the same wafer. These devices provided an equivalent noise pressure level of 4.77 µ Pa/ √ Hz with 6.24-kHz BW for 7.6- [Formula: see text] deep fluidic trenches and 4.88 µ Pa/ √ Hz with 7.48-kHz BW for 14.3- [Formula: see text] deep fluidic trenches. This demonstration of the wide-BW CMUTs with high sensitivity and low pull-in voltage makes them applicable to medical and thermoacoustic imaging, nondestructive testing, and ultrasonic flow metering.

A Microwave-Induced Thermoacoustic Imaging System With Non-Contact Ultrasound Detection.

Portable and easy-to-use imaging systems are in high demand for medical, security screening, nondestructive testing, and sensing applications. We present a new microwave-induced thermoacoustic imaging system with non-contact, airborne ultrasound (US) detection. In this system, a 2.7 GHz microwave excitation causes differential heating at interfaces with dielectric contrast, and the resulting US signal via the thermoacoustic effect travels out of the sample to the detector in air at a standoff. The 65 dB interface loss due to the impedance mismatch at the air-sample boundary is overcome with high-sensitivity capacitive micromachined ultrasonic transducers with minimum detectable pressures (MDPs) as low as 278 µ Pa rms and we explore two different designs-one operating at a center frequency of 71 kHz and another at a center frequency of 910 kHz. We further demonstrate that the air-sample interface presents a tradeoff with the advantage of improved resolution, as the change in wave velocity at the interface creates a strong focusing effect alongside the attenuation, resulting in axial resolutions more than 10× smaller than that predicted by the traditional speed/bandwidth limit. A piecewise synthetic aperture radar (SAR) algorithm modified for US imaging and enhanced with signal processing techniques is used for image reconstruction, resulting in mm-scale lateral and axial image resolution. Finally, measurements are conducted to verify simulations and demonstrate successful system performance.

Advances in Capacitive Micromachined Ultrasonic Transducers.

Capacitive micromachined ultrasonic transducer (CMUT) technology has enjoyed rapid development in the last decade. Advancements both in fabrication and integration, coupled with improved modelling, has enabled CMUTs to make their way into mainstream ultrasound imaging systems and find commercial success. In this review paper, we touch upon recent advancements in CMUT technology at all levels of abstraction; modeling, fabrication, integration, and applications. Regarding applications, we discuss future trends for CMUTs and their impact within the broad field of biomedical imaging.

High-Efficiency Output Pressure Performance Using Capacitive Micromachined Ultrasonic Transducers with Substrate-Embedded Springs.

Capacitive micromachined ultrasonic transducers (CMUTs) with substrate-embedded springs offer highly efficient output pressure performance over conventional CMUTs, owing to their nonflexural parallel plate movement. The embedded silicon springs support thick Si piston plates, creating a large nonflexural average volume displacement efficiency in the operating frequency range from 1⁻3 MHz. Static and dynamic volume displacements of the nonflexural parallel plates were examined using white light interferometry and laser Doppler vibrometry. In addition, an output pressure measurement in immersion was performed using a hydrophone. The device showed a maximum transmission efficiency of 21 kPa/V, and an average volume displacement efficiency of 1.1 nm/V at 1.85 MHz with a low DC bias voltage of 55 V. The device element outperformed the lead zirconate titanate (PZT) ceramic HD3203, in the maximum transmission efficiency or the average volume displacement efficiency by 1.35 times. Furthermore, its average volume displacement efficiency reached almost 80% of the ideal state-of-the-art single-crystal relaxor ferroelectric materials PMN-0.33PT. Additionally, we confirmed that high-efficiency output pressure could be generated from the CMUT device, by quantitatively comparing the hydrophone measurement of a commercial PZT transducer.

A Column-Row-Parallel Ultrasound Imaging Architecture for 3D Plane-wave Imaging and Tx 2nd-Order Harmonic Distortion (HD2) Reduction.

We propose a Column-Row-Parallel imaging frontend architecture for integrated and low-power 3D medical ultrasound imaging. The Column-Row-Parallel architecture offers linear-scaling interconnection, acquisition and programming time with row-by-row or column-by-column operations, while supporting volumetric imaging functionality and fault-tolerance against possible transducer element defects with per-element controls. The combination of column-parallel selection logic, row-parallel selection logic, and per-element selection logic reaches a balance between flexible imaging aperture definition and manageable imaging data / control interface to a 2D array. A 16×16 CMUT-ASIC Column-Row-Parallel prototype is fabricated and assembled with a flip-chip bonding process. It facilitates the 3D plane-wave coherent compounding algorithm for volumetric imaging with a fast frame rate of 62.5 Hz and 46% improved lateral resolution with 10-angle compounding and a field of view volume of 2.3mm in both azimuth and elevation, 8.5mm in depth. At a hypothetically scaled up 64x64 array size, the frame rate can still be kept at 31.2 Hz for a volume of 40mm in both azimuth and elevation, 150mm in depth. An interleaved checker board pattern with in-phase (I) and quadrature (Q) excitations is also demonstrated for reducing CMUT second harmonic distortion (HD2) emission by up to 25 dB at the loss of 3 dB fundamental energy reduction. The method reduces nonlinear effects from both transducers and circuits and is a wide band technique that is applicable to arbitrary pulse shapes.

A Column-Row-Parallel Ultrasound Imaging Architecture for 3-D Plane-Wave Imaging and Tx Second-Order Harmonic Distortion Reduction.

We propose a column-row-parallel imaging front-end architecture for integrated and low-power 3-D medical ultrasound imaging. The column-row-parallel architecture offers linear-scaling interconnection, acquisition, and programming time with row-by-row or column-by-column operations, while supporting volumetric imaging functionality and fault-tolerance against possible transducer element defects with per-element controls. The combination of column-parallel selection logic, row-parallel selection logic, and per-element selection logic reaches a balance between flexible imaging aperture definition and manageable imaging data/control interface to a 2-D array. A capacitive micromachined ultrasonic transducer (CMUT)-application-specific integrated circuit (ASIC) column-row-parallel prototype is fabricated and assembled with a flip-chip bonding process. It facilitates the 3-D plane-wave coherent compounding algorithm for volumetric imaging with a fast frame rate of 62.5 Hz and 46% improved lateral resolution with 10-angle compounding and a field of view volume of 2.3 mm in both azimuth and elevation, 8.5 mm in depth. At a hypothetically scaled up array size, the frame rate can still be kept at 31.2 Hz for a volume of 40 mm in both azimuth and elevation, 150 mm in depth. An interleaved checkerboard pattern with in-phase ( ) and quadrature ( ) excitations is also demonstrated for reducing CMUT second-harmonic distortion emission by up to 25 dB at the loss of 3-dB fundamental energy reduction. The method reduces nonlinear effects from both transducers and circuits and is a wide band technique that is applicable to arbitrary pulse shapes.

Activation of Piezo1 but Not NaV1.2 Channels by Ultrasound at 43 MHz.

Ultrasound (US) can modulate the electrical activity of the excitable tissues, but the mechanisms underlying this effect are not understood at the molecular level or in terms of the physical modality through which US exerts its effects. Here, we report an experimental system that allows for stable patch-clamp recording in the presence of US at 43 MHz, a frequency known to stimulate neural activity. We describe the effects of US on two ion channels proposed to be involved in the response of excitable cells to US: the mechanosensitive Piezo1 channel and the voltage-gated sodium channel NaV1.2. Our patch-clamp recordings, together with finite-element simulations of acoustic field parameters indicate that Piezo1 channels are activated by continuous wave US at 43 MHz and 50 or 90 W/cm2 through cell membrane stress caused by acoustic streaming. NaV1.2 channels were not affected through this mechanism at these intensities, but their kinetics could be accelerated by US-induced heating.

Localization of weak objects in reverberant fields using waveform inversion.

This paper presents an application of the Waveform inversion approach to localization of objects in reverberant fields and with limited spatial measurements. Reverberant fields in enclosures can potentially carry useful information, however, in an incoherent way. Incoherency comes from the consecutive reflections of the wave energy several times in the domain. This, along with diffraction and dispersion effects, can ultimately lead to mixing of the wave energy in a seemingly random way. However, spreading of the wave energy can lead to multiple interrogations of each point in the enclosure. Hence, any substructural changes in the enclosure can be sensed with sufficient information carried by the wave energy flow. Furthermore, the temporal information buried in the data makes it feasible to conduct only a few spatial measurements. The authors present a localization scheme that benefits from the reverberant field and can reduce the required number of spatial measurements.

Wireless Power Transfer to Millimeter-Sized Nodes Using Airborne Ultrasound.

We propose the use of airborne ultrasound for wireless power transfer to mm-sized nodes, with intended application in the next generation of the Internet of Things (IoT). We show through simulation that ultrasonic power transfer can deliver 50 [Formula: see text] to a mm-sized node 0.88 m away from a ~ 50-kHz, 25-cm2 transmitter array, with the peak pressure remaining below recommended limits in air, and with load power increasing with transmitter area. We report wireless power recovery measurements with a precharged capacitive micromachined ultrasonic transducer, demonstrating a load power of 5 [Formula: see text] at a simulated distance of 1.05 m. We present aperture efficiency, dynamic range, and bias-free operation as key metrics for the comparison of transducers meant for wireless power recovery. We also argue that long-range wireless charging at the watt level is extremely challenging with existing technology and regulations. Finally, we compare our acoustic powering system with cutting edge electromagnetically powered nodes and show that ultrasound has many advantages over RF as a vehicle for power delivery. Our work sets the foundation for further research into ultrasonic wireless power transfer for the IoT.

A learning method for localizing objects in reverberant domains with limited measurements.

This article presents a learning (training)-based method for localizing objects in enclosures. Wave propagation in enclosures can lead to mixing of the wave energy, ultimately leading to incoherent spreading of information. This makes the localization problem challenging. However, spreading of the wave energy can lead to multiple interrogations of each point in the enclosure, which is in essence reminiscent of an ergodic or a closely ergodic behavior. Hence, any substructural changes in the enclosure can be sensed with sufficient information carried by the wave energy flow. Furthermore, temporal information buried in data makes it feasible to conduct only a few spatial measurements. A localization scheme is presented that benefits from the reverberant field and can reduce the required number of spatial measurements.

A $k$ -Space Pseudospectral Method for Elastic Wave Propagation in Heterogeneous Anisotropic Media.

This paper presents the theory of the k -space method generalized to model elastic wave propagation in heterogeneous anisotropic media. The k -space methods are promising time integration techniques giving, in conjunction with collocation spectral methods, accurate and efficient numerical schemes for problems in heterogeneous media. In this paper, the k -space operator is derived in a spatially continuous form using the Fourier analysis of the displacement formalism of elastodynamics. An efficient numerical algorithm is then constructed by applying a Fourier collocation spectral method, leading to define the discrete k -space scheme. The proposed method is temporally exact for homogeneous media, unconditionally stable for heterogeneous media, and also allows larger time steps without loss of accuracy. Implementation of the method is discussed in detail. The method is validated through a set of numerical tests. The numerical results show the efficacy of the method compared with the conventional schemes.

Lamb Wave Multitouch Ultrasonic Touchscreen.

Touchscreen sensors are widely used in many devices such as smart phones, tablets, and laptops with diverse applications. We present the design, analysis, and implementation of an ultrasonic touchscreen system that utilizes the interaction of transient Lamb waves with objects in contact with the screen. It attempts to improve on the existing ultrasound technologies, with the potential of addressing some of the weaknesses of the dominant technologies, such as the capacitive or resistive ones. Compared with the existing ultrasonic and acoustic modalities, among other advantages, it provides the capability of detecting several simultaneous touch points and also a more robust performance. The localization algorithm, given the hardware design, can detect several touch points with a very limited number of measurements (one or two). This in turn can significantly reduce the manufacturing cost.

Ex Vivo HIFU Experiments Using a $32 \times 32$ -Element CMUT Array.

High-intensity focused ultrasound (HIFU) has been used as noninvasive treatment for various diseases. For these therapeutic applications, capacitive micromachined ultrasonic transducers (CMUTs) have advantages that make them potentially preferred transducers over traditional piezoelectric transducers. In this paper, we present the design and the fabrication process of an 8 ×8 -mm 2 32 ×32 -element 2-D CMUT array for HIFU applications. To reduce the system complexity for addressing the 1024 transducer elements, we propose to group the CMUT array elements into eight HIFU channels based on the phase delay from the CMUT element to the targeted focal point. Designed to focus at an 8-mm depth with a 5-MHz exciting frequency, this grouping scheme was realized using a custom application-specific integrated circuit. With a 40-V dc bias and a 60-V peak-to-peak ac excitation, the surface pressure was measured 1.2 MPa peak-to-peak and stayed stable for a long enough time to create a lesion. With this dc and ac voltage combination, the measured peak-to-peak output pressure at the focus was 8.5 MPa, which is expected to generate a lesion in a minute according to the temperature simulation. The following ex vivo tissue experiments successfully demonstrated its capability to make lesions in both bovine muscle and liver tissue.

Design of Tunable Ultrasonic Receivers for Efficient Powering of Implantable Medical Devices With Reconfigurable Power Loads.

Miniaturized ultrasonic receivers are designed for efficient powering of implantable medical devices with reconfigurable power loads. Design parameters that affect the efficiency of these receivers under highly variable load conditions, including piezoelectric material, geometry, and operation frequency, are investigated. Measurements were performed to characterize electrical impedance and acoustic-to-electrical efficiency of ultrasonic receivers for off-resonance operation. Finally, we propose, analyze, and demonstrate adaptive matching and frequency tuning techniques using two different reconfigurable matching networks for typical implant loads from 10 [Formula: see text] to 1 mW. Both simulations and measurements show a significant increase in total implant efficiency (up to 50 percentage points) over this load power range when operating off-resonance with the proposed matching networks.