Modulation of deep neural circuits with sonogenetics.

Noninvasive control of neuronal activity in the deep brain can be illuminating for probing brain function and treating dysfunctions. Here, we present a sonogenetic approach for controlling distinct mouse behavior with circuit specificity and subsecond temporal resolution. Targeted neurons in subcortical regions were made to express a mutant large conductance mechanosensitive ion channel (MscL-G22S), enabling ultrasound to trigger activity in MscL-expressing neurons in the dorsal striatum and increase locomotion in freely moving mice. Ultrasound stimulation of MscL-expressing neurons in the ventral tegmental area could activate the mesolimbic pathway to trigger dopamine release in the nucleus accumbens and modulate appetitive conditioning. Moreover, sonogenetic stimulation of the subthalamic nuclei of Parkinson's disease model mice improved their motor coordination and mobile time. Neuronal responses to ultrasound pulse trains were rapid, reversible, and repeatable. We also confirmed that the MscL-G22S mutant is more effective to sensitize neurons to ultrasound compared to the wild-type MscL. Altogether, we lay out a sonogenetic approach which can selectively manipulate targeted cells to activate defined neural pathways, affect specific behaviors, and relieve symptoms of neurodegenerative disease.

Low-Intensity Focused Ultrasound Ameliorates Ischemic Heart Failure Related to the Cholinergic Anti-Inflammatory Pathway.

OBJECTIVES: This study aims to determine the effect of low-intensity focused ultrasound (LIFU) in ischemic heart failure (IHF) and explore the potential neuroimmune mechanism. METHODS: Sprague-Dawley rats were subjected to ultrasound (US) with specific parameters, and electrocardiograms were recorded to analyze the effect of LIFU and/or vagal denervation on heart rate. Thereafter, myocardial infarction (MI) was induced by left anterior artery ligation, and LIFU was performed three times a day for 25 days after MI. Echocardiography, Masson staining, and ELISA were used to evaluate the effect of LIFU on the structure and function of the heart. Finally, ELISA, flow cytometry, qRT-PCR, and Western blot analysis were performed to determine the effect of LIFU on the inflammation and the expression of the cholinergic anti-inflammatory pathway (CAP)-related mediators. RESULTS: LIFU reduced heart rate in rats (control vs LIFU, P < .01), and vagotomy (VT) eliminated this effect of LIFU on heart rate (VT vs LIFU + VT, P > .01). LIFU-ameliorated IHF in terms of cardiac structure and function (MI vs MI + LIFU, P < .01), but VT abrogated the beneficial effect of LIFU (MI + VT vs MI + LIFU + VT, P > .01). After the treatment of LIFU, decreased levels of inflammatory cytokines, increased proportion of anti-inflammatory macrophages, and increased expression of CAP-related mediators (MI vs MI + LIFU, P < .01). CONCLUSIONS: LIFU ameliorates IHF whereas the CAP plays a promising role. LIFU has the potential to be a novel nonpharmacological and noninvasive therapy for the treatment of coronary artery disease and other cardiovascular diseases.

[FPGA Implementation of Digital Coordinate Conversion of Intravascular Ultrasound Imaging System Based on CORDIC Algorithm].

In order to facilitate doctors to better obtain cardiovascular images by using intravascular ultrasound imaging system and make a more accurate diagnosis, a digital coordinate conversion method of intravascular ultrasound imaging system based on CORDIC algorithm is proposed, it converts polar coordinates into rectangular coordinates through angular rotation and orientation calculation. The experimental simulation test is carried out on the platform of intravascular ultrasound imaging system by FPGA. Experimental simulation shows that, CORDIC algorithm can effectively output sine and cosine values, compared with the traditional table finding method, this algorithm has faster speed, stronger real-time performance and needs less hardware resources. It is more suitable for intravascular ultrasound imaging system.

On-Chip Multicolor Photoacoustic Imaging Flow Cytometry.

On-chip imaging flow cytometry has been widely used in cancer biology, immunology, microbiology, and drug discovery. Pure optical imaging combined with flow cytometry to derive chemical, structural, and morphological features of cells provides systematic insights into biological processes. However, due to the high concentration and strong optical attenuation of red blood cells, preprocessing is necessary for optical flow cytometry while dealing with whole blood. In this study, we develop an on-chip photoacoustic imaging flow cytometry (PAIFC), which combines multicolor high-speed photoacoustic microscopy and microfluidics for cell imaging. The device employs a micro-optical scanner to achieve a miniaturized outer size of 30 × 17 × 24 mm3 and ultrafast cross-sectional imaging at a frame rate of 1758 Hz and provides lateral and axial resolutions of 2.2 and 33 µm, respectively. Using a multicolor strategy, PAIFC is able to differentiate cells labeled by external contrast agents, detect melanoma cells with an endogenous contrast in whole blood, and image melanoma cells in blood samples from tumor-bearing mice. The results suggest that PAIFC has sufficient sensitivity and specificity for future cell-on-chip applications.

A Novel Racing Array Transducer for Noninvasive Ultrasonic Retinal Stimulation: A Simulation Study.

Neurostimulation has proved to be an effective method for the restoration of visual perception lost due to retinal diseases. However, the clinically available retinal neurostimulation method is based on invasive electrodes, making it a high-cost and high-risk procedure. Recently, ultrasound has been demonstrated to be an effective way to achieve noninvasive neurostimulation. In this work, a novel racing array transducer with a contact lens shape is proposed for ultrasonic retinal stimulation. The transducer is flexible and placed outside the eyeball, similar to the application of a contact lens. Ultrasound emitted from the transducer can reach the retina without passing through the lens, thus greatly minimizing the acoustic absorption in the lens. The discretized Rayleigh-Sommerfeld method was employed for the acoustic field simulation, and patterned stimulation was achieved. A 5 MHz racing array transducer with different element numbers was simulated to optimize the array configuration. The results show that a 512-element racing array is the most appropriate configuration considering the necessary tradeoff between the element number and the stimulation resolution. The stimulation resolution at a focus of 24 mm is about 0.6 mm. The obtained results indicate that the proposed racing array design of the ultrasound transducer can improve the feasibility of an ultrasound retinal prosthesis.

Monitoring the Opening and Recovery of the Blood-Brain Barrier with Noninvasive Molecular Imaging by Biodegradable Ultrasmall Cu2- xSe Nanoparticles.

The reversible and controllable opening and recovery of the blood-brain barrier (BBB) is crucial for the treatment of brain diseases, and it is a big challenge to noninvasively monitor these processes. In this article, dual-modal photoacoustic imaging and single-photon-emission computed tomography imaging based on ultrasmall Cu2- xSe nanoparticles (3.0 nm) were used to noninvasively monitor the opening and recovery of the BBB induced by focused ultrasound in living mice. The ultrasmall Cu2- xSe nanoparticles were modified with poly(ethylene glycol) to exhibit a long blood circulation time. Both small size and long blood circulation time enable them to efficiently penetrate into the brain with the assistance of ultrasound, which resulted in a strong signal at the sonicated site and allowed for photoacoustic and single-photon emission computed tomography imaging monitoring the recovery of the opened BBB. The results of biodistribution, blood routine examination, and histological staining indicate that the accumulated Cu2- xSe nanoparticles could be excreted from the brain and other major organs after 15 days without causing side effects. By the combination of the advantages of noninvasive molecular imaging and focused ultrasound, the ultrasmall biocompatible Cu2- xSe nanoparticles holds great potential for the diagnosis and therapeutic treatment of brain diseases.

Ultrasonic Control of Neural Activity through Activation of the Mechanosensitive Channel MscL.

Externally controlling the excitation of a neuronal subset through ion channels activation can modulate the firing pattern of an entire neural circuit in vivo. As nanovalves in the cell membrane, ion channels can be opened by light (optogenetics) or ultrasonic (sonogenetics) means. A thoroughly analyzed force sensor is the Escherichia coli mechano sensitive channel of large conductance (MscL). Here we expressed MscL in rat hippocampal neurons in a primary culture and showed that it could be activated by low-pressure ultrasound pulses. The gain-of-function mutation, I92L, sensitized MscL's sonic response, triggering action potentials at a peak negative pressure as low as 0.25 MPa. Further, the I92L MscL reliably elicited individual spikes by timed brief pulses, making excitation programmable. Because MscL opens to tension in the lipid bilayer, requiring no other proteins or ligands, it could be developed into a general noninvasive sonogenetic tool to manipulate the activities of neurons or other cells and potential nanodevices.

Effects of Non-Elevation-Focalized Linear Array Transducer on Ultrasound Plane-Wave Imaging.

Plane-wave ultrasound imaging (PWUS) has become an important method of ultrasound imaging in recent years as its frame rate has exceeded 10,000 frames per second, allowing ultrasound to be used for two-dimensional shear wave detection and functional brain imaging. However, compared to the traditional focusing and scanning method, PWUS images always suffer from a degradation of lateral resolution and contrast. To improve the image quality of PWUS, many different beamforming algorithms have been proposed and verified. Yet the influence of transducer structure is rarely studied. For this paper, the influence of using an acoustic lens for PWUS was evaluated. Two linear array transducers were fabricated. One was not self-focalized in the elevation direction (non-elevation-focalized transducer, NEFT); the other one was a traditional elevation-focalized transducer (EFT). An initial simulation was conducted to show the influence of elevation focusing. Then the images obtained with NEFT on a standard ultrasound imaging phantom were compared with those obtained with EFT. It was demonstrated that, in a relatively deep region, the contrast of an NEFT image is better than that of an EFT image. These results indicate that a more sophisticated design of ultrasound transducer would further improve the image quality of PWUS.

[Preliminary Comparison of Two Compression Methods for Ultrasonic Plane Wave Data].

Ultrasonic plane wave imaging is one of the hot topics in the study of ultrasound imaging, but the plane wave ultra-high frequency ultrasound has brought a large amount of data. If these data are transmitted directly through the hardware, it will not only bring a great burden on the hardware, but also put a requirement for the ability of the hardware processing data. In order to reduce the problem caused by the high frame frequency and large amount of data, the data compression methods are used to reduce the amount of data acquisition and transmission. In this paper both lossy compression and lossless compression are studied, where LZW compression algorithm is chosen to test lossless compression effect, and based on the plane wave characteristics, the frequency domain cutting compression algorithm is developed as a lossy compression method. In this paper, the LZW algorithm is implemented in FGPA, and it can achieve a certain compression ratio after testing the ultra sonic simulation data. Under the condition of known fractional bandwidth, it is found that the main bandwidth can be preserved in the spectrum, while the rest of the frequency signal has little effect on the image. By testing the ultrasonic simulation data, the frequency domain cutting algorithm can achieve high compression ratio, and the difference between the original image and the reconstructed image is relatively smal . So from the point of the compression ratio, the frequency domain cutting algorithm is the primary choice of the ultrasonic data compression algorithm.

Feasibility of multiple micro-particle trapping--a simulation study.

Both optical tweezers and acoustic tweezers have been demonstrated for trapping small particles in diverse biomedical applications. Compared to the optical tweezers, acoustic tweezers have deeper penetration, lower intensity, and are more useful in light opaque media. These advantages enable the potential utility of acoustic tweezers in biological science. Since the first demonstration of acoustic tweezers, various applications have required the trapping of not only one, but more particles simultaneously in both the axial and lateral direction. In this research, a method is proposed to create multiple trapping patterns, to prove the feasibility of trapping micro-particles. It has potential ability to electronically control the location and movement of the particles in real-time. A multiple-focus acoustic field can be generated by controlling the excitation of the transducer elements. The pressure and intensity of the field are obtained by modeling phased array transducer. Moreover, scattering force and gradient force at various positions are also evaluated to analyze their relative components to the effect of the acoustic tweezers. Besides, the axial and lateral radiation force and the trapping trajectory are computed based on ray acoustic approach. The results obtained demonstrate that the acoustic tweezers are capable of multiple trapping in both the axial and lateral directions.

Piezoelectric single crystals for ultrasonic transducers in biomedical applications.

Piezoelectric single crystals, which have excellent piezoelectric properties, have extensively been employed for various sensors and actuators applications. In this paper, the state-of-art in piezoelectric single crystals for ultrasonic transducer applications is reviewed. Firstly, the basic principles and design considerations of piezoelectric ultrasonic transducers will be addressed. Then, the popular piezoelectric single crystals used for ultrasonic transducer applications, including LiNbO3 (LN), PMN-PT and PIN-PMN-PT, will be introduced. After describing the preparation and performance of the single crystals, the recent development of both the single-element and array transducers fabricated using the single crystals will be presented. Finally, various biomedical applications including eye imaging, intravascular imaging, blood flow measurement, photoacoustic imaging, and microbeam applications of the single crystal transducers will be discussed.

A digital multigate Doppler method for high frequency ultrasound.

Noninvasive visualization of blood flow with high frequency Doppler ultrasound has been extensively used to assess the morphology and hemodynamics of the microcirculation. A completely digital implementation of multigate pulsed-wave (PW) Doppler method was proposed in this paper for high frequency ultrasound applications. Analog mixer was eliminated by a digital demodulator and the same data acquisition path was shared with traditional B-mode imaging which made the design compact and flexible. Hilbert transform based quadrature demodulation scheme was employed to achieve the multigate Doppler acquisition. A programmable high frequency ultrasound platform was also proposed to facilitate the multigate flow visualization. Experimental results showed good performance of the proposed method. Parabolic velocity gradient inside the vessel and velocity profile with different time slots were acquired to demonstrate the functionality of the multigate Doppler. Slow wall motion was also recorded by the proposed method.

High performance relaxor-based ferroelectric single crystals for ultrasonic transducer applications.

Relaxor-based ferroelectric single crystals Pb(Mg1/3Nb2/3)O3-PbTiO3 (PMN-PT) have drawn much attention in the ferroelectric field because of their excellent piezoelectric properties and high electromechanical coupling coefficients (d33~2000 pC/N, kt~60%) near the morphotropic phase boundary (MPB). Ternary Pb(In1/2Nb1/2)O3-Pb(Mg1/3Nb2/3)O3-PbTiO3 (PIN-PMN-PT) single crystals also possess outstanding performance comparable with PMN-PT single crystals, but have higher phase transition temperatures (rhombohedral to tetragonal Trt, and tetragonal to cubic Tc) and larger coercive field Ec. Therefore, these relaxor-based single crystals have been extensively employed for ultrasonic transducer applications. In this paper, an overview of our work and perspectives on using PMN-PT and PIN-PMN-PT single crystals for ultrasonic transducer applications is presented. Various types of single-element ultrasonic transducers, including endoscopic transducers, intravascular transducers, high-frequency and high-temperature transducers fabricated using the PMN-PT and PIN-PMN-PT crystals and their 2-2 and 1-3 composites are reported. Besides, the fabrication and characterization of the array transducers, such as phased array, cylindrical shaped linear array, high-temperature linear array, radial endoscopic array, and annular array, are also addressed.

A Multiplexed 32 × 32 2D Matrix Array Transducer for Flexible Sub-Aperture Volumetric Ultrasound Imaging.

A fully-sampled two-dimensional (2D) matrix array ultrasonic transducer is essential for fast and accurate three-dimensional (3D) volumetric ultrasound imaging. However, these arrays, usually consisting of thousands of elements, not only face challenges of poor performance and complex wiring due to high-density elements and small element sizes but also put high requirements for electronic systems. Current commercially available fully-sampled matrix arrays, dividing the aperture into four fixed sub-apertures to reduce system channels through multiplexing are widely used. However, the fixed sub-aperture configuration limits imaging flexibility and the gaps between sub-apertures lead to reduced imaging quality. In this study, we propose a high-performance multiplexed matrix array by the design of 1-3 piezocomposite and gapless sub-aperture configuration, as well as optimized matching layer materials. Furthermore, we introduce a sub-aperture volumetric imaging method based on the designed matrix array, enabling high-quality and flexible 3D ultrasound imaging with a low-cost 256-channel system. The influence of imaging parameters, including the number of sub-apertures and steering angle on imaging quality was investigated by simulation, in vitro and in vivo imaging experiments. The fabricated matrix array has a center frequency of 3.4 MHz and a -6 dB bandwidth of above 70%. The proposed sub-aperture volumetric imaging method demonstrated a 10% improvement in spatial resolution, a 19% increase in signal-to-noise ratio, and a 57.7% increase in contrast-to-noise ratio compared with the fixed sub-aperture array imaging method. This study provides a new strategy for high-quality volumetric ultrasound imaging with a low-cost system.

A New Method of Plane-Wave Ultrasound Imaging Based on Reverse Time Migration.

Coherent plane-wave compounding technique enables rapid ultrasound imaging with comparable image quality to traditional B-mode imaging that relies on focused beam transmission. However, existing methods assume homogeneity in the imaged medium, neglecting the heterogeneity in sound velocities and densities present in real tissues, resulting in noise reverberation. This study introduces the Reverse Time Migration (RTM) method for ultrasound plane-wave imaging to overcome this limitation, which is combined with a method for estimating the speed of sound in layered media. Simulation results in a homogeneous background demonstrate that RTM reduces side lobes and grating lobes by approximately 30 dB, enhancing the contrast-to-noise ratio by 20% compared to conventional delay and sum (DAS) beamforming. Moreover, RTM achieves superior imaging outcomes with fewer compounding angles. The lateral resolution of the RTM with 5-9 angle compounding is able to achieve the effectiveness of the DAS method with 15-19 angle compounding, and the CNR of the RTM with 11-angle compounding is almost the same as that of the DAS with 21-angle compounding. In a heterogeneous background, experimental simulations and in vitro wire phantom experiments confirm RTM's capability to correct depth imaging, focusing reflected waves on point targets. In vitro porcine tissue experiments enable accurate imaging of layer interfaces by estimating the velocities of multiple layers containing muscle and fat. The proposed imaging procedure optimizes velocity estimation in complex media, compensates for the impact of velocity differences, provides more reliable imaging results.

Portal Vein Pressure Estimation and Portal Hypertension Discrimination Based on Subharmonic Scattering of Ultrasound Contrast Agent Microbubbles.

OBJECTIVE: The acquisition of real-time portal vein pressure (PVP) is important for portal hypertension (PH) discrimination to monitor disease progress and select treatment options. To date, the PVP evaluation approaches are either invasive or noninvasive but with less stability and sensitivity. METHODS: We customized an open ultrasound scanner to explore in vitro and in vivo the ultrasound contrast agent SonoVue microbubbles' subharmonic characteristics with acoustic pressure and local ambient pressure, and obtained promising results of PVP measurements in canine models with induced PH by ligation or embolization of portal vein. RESULTS: In in vitro experiments, the highest correlations between the subharmonic amplitude of SonoVue microbubbles and ambient pressure were observed at acoustic pressures of 523 kPa and 563 kPa (r = -0.993, -0.993, P<0.05, respectively). The correlation coefficients between absolute subharmonic amplitudes and PVP (10.7-35.4 mmHg) were the highest among existing studies using microbubbles as pressure sensors (r values ranged from -0.819 to -0.918). The PH (>16 mmHg) diagnostic capacity also achieved a high level (563 kPa, sensitivity = 93.3%, specificity = 91.7%, accuracy = 92.6%). CONCLUSION: This study proposes a promising measurement for PVP with the highest accuracy, sensitivity, and specificity in an in vivo model compared to existing studies. Future investigations are planned to assess the feasibility of this technique in clinical practice. SIGNIFICANCE: This is the first study that comprehensively investigates the role of the subharmonic scattering signals from SonoVue microbubbles in evaluating PVP in vivo. It represents a promising alternative to invasive measurements for portal pressure.

Low-intensity focused ultrasound stimulation promotes stroke recovery via astrocytic HMGB1 and CAMK2N1 in mice.

BACKGROUND: Low-intensity focused ultrasound stimulation (LIFUS) has been developed to enhance neurological repair and remodelling during the late acute stage of ischaemic stroke in rodents. However, the cellular and molecular mechanisms of neurological repair and remodelling after LIFUS in ischaemic stroke are unclear. METHODS: Ultrasound stimulation was treated in adult male mice 7 days after transient middle cerebral artery occlusion. Angiogenesis was measured by laser speckle imaging and histological analyses. Electromyography and fibre photometry records were used for synaptogenesis. Brain atrophy volume and neurobehaviour were assessed 0-14 days after ischaemia. iTRAQ proteomic analysis was performed to explore the differentially expressed protein. scRNA-seq was used for subcluster analysis of astrocytes. Fluorescence in situ hybridisation and Western blot detected the expression of HMGB1 and CAMK2N1. RESULTS: Optimal ultrasound stimulation increased cerebral blood flow, and improved neurobehavioural outcomes in ischaemic mice (p<0.05). iTRAQ proteomic analysis revealed that the expression of HMGB1 increased and CAMK2N1 decreased in the ipsilateral hemisphere of the brain at 14 days after focal cerebral ischaemia with ultrasound treatment (p<0.05). scRNA-seq revealed that this expression pattern belonged to a subcluster of astrocytes after LIFUS in the ischaemic brain. LIFUS upregulated HMGB1 expression, accompanied by VEGFA elevation compared with the control group (p<0.05). Inhibition of HMGB1 expression in astrocytes decreased microvessels counts and cerebral blood flow (p<0.05). LIFUS reduced CAMK2N1 expression level, accompanied by increased extracellular calcium ions and glutamatergic synapses (p<0.05). CAMK2N1 overexpression in astrocytes decreased dendritic spines, and aggravated neurobehavioural outcomes (p<0.05). CONCLUSION: Our results demonstrated that LIFUS promoted angiogenesis and synaptogenesis after focal cerebral ischaemia by upregulating HMGB1 and downregulating CAMK2N1 in a subcluster of astrocytes, suggesting that LIFUS activated specific astrocyte subcluster could be a key target for ischaemic brain therapy.

The Emergence of Functional Ultrasound for Noninvasive Brain-Computer Interface.

A noninvasive brain-computer interface is a central task in the comprehensive analysis and understanding of the brain and is an important challenge in international brain-science research. Current implanted brain-computer interfaces are cranial and invasive, which considerably limits their applications. The development of new noninvasive reading and writing technologies will advance substantial innovations and breakthroughs in the field of brain-computer interfaces. Here, we review the theory and development of the ultrasound brain functional imaging and its applications. Furthermore, we introduce latest advancements in ultrasound brain modulation and its applications in rodents, primates, and human; its mechanism and closed-loop ultrasound neuromodulation based on electroencephalograph are also presented. Finally, high-frequency acoustic noninvasive brain-computer interface is prospected based on ultrasound super-resolution imaging and acoustic tweezers.

A Novel Dual-Element Catheter for Improving Non-Uniform Rotational Distortion in Intravascular Ultrasound.

For the early diagnosis of atherosclerosis and interventions, intravascular ultrasound (IVUS) is a valuable tool for intravascular luminal imaging. Compared with the array-based method, mechanically rotating IVUS catheters dominate the clinical applications because of their less complexity and better suitability for high-frequency ultrasound imaging. However, mechanically rotating catheters are suffering from non-uniform rotational distortion (NURD) which hinders accurate image acquisition. In this study, a dual-element imaging catheter is proposed, in which two elements with the same frequency and similar performance are assembled in a back-to-back arrangement. When the catheter encounters a NURD due to acute bending, the abnormal image of one element can be replaced by the normal image of the opposite element, thus eliminating the NURD in the reconstructed image. Moreover, two images can be obtained in one rotation and the imaging frame rate is doubled in the absence of NURD. The performance of the two elements was quantitatively assessed by a wire phantom. And the complementary imaging protocols were evaluated by a tissue phantom and ex vivo porcine vessel. The results show that the proposed strategy can be promising in clinical studies.

Recent Advances in LDH/g-C3N4 Heterojunction Photocatalysts for Organic Pollutant Removal.

Environmental pollution has been decreased by using photocatalytic technology in conjunction with solar energy. An efficient method to obtain highly efficient photocatalysts is to build heterojunction photocatalysts by combining graphitic carbon nitride (g-C3N4) with layered double hydroxides (LDHs). In this review, recent developments in LDH/g-C3N4 heterojunctions and their applications for organic pollutant removal are systematically exhibited. The advantages of LDH/g-C3N4 heterojunction are first summarized to provide some overall understanding of them. Then, a variety of approaches to successfully assembling LDH and g-C3N4 are simply illustrated. Last but not least, certain unmet research needs for the LDH/g-C3N4 heterojunction are suggested. This review can provide some new insights for the development of high-performance LDH/g-C3N4 heterojunction photocatalysts. It is indisputable that the LDH/g-C3N4 heterojunctions can serve as high-performance photocatalysts to make new progress in organic pollutant removal.