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.

Measurement of the acoustic reflectance function based on Lamb wave using high f-number transducers.

Ultrasonic reflectivity using a V(z) technique is a powerful characterization method in acoustic microscopy to measure the elastic properties of materials. Conventional techniques generally use a low f-number with high frequency; however, to measure the reflectance function of the highly attenuative material, a low frequency is essential. In this study, the transducer-pair method based on Lamb waves is used to measure the reflectance function of a highly attenuative material. The results demonstrate the feasibility of the proposed method using a commercial ultrasound transducer with high f-number.

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.

Increasing the transmission efficiency of transcranial ultrasound using a dual-mode conversion technique based on Lamb waves.

Transcranial focused ultrasound (FUS) is a noninvasive treatment for brain tumors and neuromodulation. Based on normal incidence, conventional FUS techniques use a focused or an array of ultrasonic transducers to overcome the attenuation and absorption of ultrasound in the skull; however, this remains the main limitation of using FUS. A dual-mode conversion technique based on Lamb waves is proposed to achieve high transmission efficiency. This concept was validated using the finite element analysis (FEA) and experiments based on changes in the incident angle. Aluminum, plexiglass, and a human skull were used as materials with different attenuations. The transmission loss was calculated for each material, and the results were compared with the reflectance function of the Lamb waves. Oblique incidence based on dual-mode conversion exhibited a better transmission efficiency than that of a normal incidence for all of the specimens. The total transmission losses for the materials were 13.7, 15.46, and 3.91 dB less than those associated with the normal incidence. A wedge transducer was designed and fabricated to implement the proposed method. The results demonstrated the potential applicability of the dual-mode conversion technique for the human skull.

Patterned Interference Radiation Force for Transcranial Neuromodulation.

Compared with the conventional method of transcranial focused ultrasound stimulation using a single transducer or a focused beam, the compression and tensile forces are generated from the high-pressure gradient of a standing wave that can generate increased stimulation. We experimentally verified a neuromodulation system using patterned interference radiation force (PIRF) and propose a method for obtaining the magnitude of the radiation force, which is considered the main factor influencing ultrasound neuromodulation. The radiation forces generated using a single focused transducer and a standing wave created via two focused transducers were compared using simulations. Radiation force was calculated based on the relationship between the acoustic pressure, radiation force and time-averaged second-order pressure obtained using an acoustic streaming simulation. The presence of the radiation force was verified by measuring the time-averaged second-order pressure generated due to the radiation force, by using a glass tube.

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.

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.

Radiation Force as a Physical Mechanism for Ultrasonic Neurostimulation of the Ex Vivo Retina.

Focused ultrasound has been shown to be effective at stimulating neurons in many animal models, both in vivo and ex vivo Ultrasonic neuromodulation is the only noninvasive method of stimulation that could reach deep in the brain with high spatial-temporal resolution, and thus has potential for use in clinical applications and basic studies of the nervous system. Understanding the physical mechanism by which energy in a high acoustic frequency wave is delivered to stimulate neurons will be important to optimize this technology. We imaged the isolated salamander retina of either sex during ultrasonic stimuli that drive ganglion cell activity and observed micron scale displacements, consistent with radiation force, the nonlinear delivery of momentum by a propagating wave. We recorded ganglion cell spiking activity and changed the acoustic carrier frequency across a broad range (0.5-43 MHz), finding that increased stimulation occurs at higher acoustic frequencies, ruling out cavitation as an alternative possible mechanism. A quantitative radiation force model can explain retinal responses and could potentially explain previous in vivo results in the mouse, suggesting a new hypothesis to be tested in vivo Finally, we found that neural activity was strongly modulated by the distance between the transducer and the electrode array showing the influence of standing waves on the response. We conclude that radiation force is the dominant physical mechanism underlying ultrasonic neurostimulation in the ex vivo retina and propose that the control of standing waves is a new potential method to modulate these effects.SIGNIFICANCE STATEMENT Ultrasonic neurostimulation is a promising noninvasive technology that has potential for both basic research and clinical applications. The mechanisms of ultrasonic neurostimulation are unknown, making it difficult to optimize in any given application. We studied the physical mechanism by which ultrasound is converted into an effective energy form to cause neurostimulation in the retina and find that ultrasound acts via radiation force leading to a mechanical displacement of tissue. We further show that standing waves have a strong modulatory effect on activity. Our quantitative model by which ultrasound generates radiation force and leads to neural activity will be important in optimizing ultrasonic neurostimulation across a wide range of applications.

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.

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.

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.