Ultrasound Modulation Research Articles

MR thermometry imaging for low intensity focused ultrasound modulation of spinal nervous tissue

ObjectivesPreviously in rodent and swine models, we have shown that external low intensity focused ultrasound (liFUS) can be used to modulate pain responses. To ensure no adverse heating events occur with liFUS modulation in a non-invasive manner, we perform initial work in swine to show that magnetic resonance thermometry imaging (MRTI) is capable of measuring <2.0 °C changes at the L5 DRG. Further, we show that our device can be constructed in an MR-compatible fashion to minimize artifact. MethodsThree MRTI techniques (referenceless, corrected proton resonance frequency shift (PRFS), and PRFS) were applied to assess accuracy of detecting thermal changes at the L5 DRG in unheated euthanized swine. A region of interest (ROI) that includes the L5 DRG was delineated, within which MRTI temperature changes were spatially averaged (ground truth 0 °C). In separate experiments with phantoms, B0 field-inhomogeneity, RF transmit (B1+) and fast gradient echo (fSPGR) magnitude images were acquired to downselect liFUS device materials that produce the least MRI artifacts. ResultsReferenceless, corrected PRFS, and PRFS MRTI resulted in temperature measurements of 0.8 ± 1.1 °C, 1.1 ± 1.3 °C and 5.2 ± 5 °C, respectively. Both materials caused B0 perturbation but minimal B1+ and MRTI artifacts. The presence of imaging artifacts did not preclude thermal imaging of the region. SignificanceWe provide preliminary data suggesting that referenceless MRTI can adequately detect small thermal changes at the DRG that may occur with neuromodulation, which is one of the first steps in creating a table of safe parameters for liFUS therapy in humans.

A four-prong approach for engaging biomedical engineering students

My involvement in a large medical imaging company for nearly 20 years shaped my approach to teaching biomedical engineering. These experiences are described in Medical Physics International Journal, 6,602–620, May 2021. At Boston University, I taught undergraduates using a four pronged approach. The first part included a “lessons learned” career overview lecture and discussion to incoming freshman. This talk emphasized shifting paradigms in medical device development and changing trends in research and development and how to best prepare for a biomedical engineering career by prudent course selection, practical experience and life-long networking. Second, I designed two ultrasound lab modules which were part of the mandatory physiology lab all juniors took. These laboratories provided condensed theory with hands-on experiments on imaging and Doppler processing/imaging and data analysis. Third, I taught ultrasound and medical imaging courses which included rigorous theory, applications and examples. My book, Diagnostic Ultrasound Imaging: Inside Out, second edition, is being used in ultrasound courses throughout the world. A new book and curriculum, coauthored with Peter Kaczkowski, and sponsored by Verasonics, is underway. Finally, for 15 years, I taught a usually two semester course in entrepreneurship, innovation and engineering design which culminated in a team-based senior project.

Ultrasound modulation of neurons by sonogenetics

Focused ultrasound (FUS) can noninvasively deliver ultrasound energy to target any area in the whole brain with combined depth penetration and spatial focusing that cannot be achieved with other external stimulations. Sonogenetics, integrating focused ultrasound with genetic engineering, can achieve noninvasive control of neurons genetically modified with ultrasound-sensitive ion channels. Crucial to the development of sonogenetics has been the identification of ultrasound-sensitive probes to control neurons. FUS propagation through the tissue can generate mechanical and thermal effects within its focal region. This talk will present recent progress in the development of mechanosensitive and thermosensitive ion channels as sonogenetic probes. Recent success in using sonogenetics for noninvasive and cell-type-specific behavior control of freely moving mice will also be presented. This noninvasive and cell-type-specific neuromodulation approach has the promise to advance the study of the intact nervous system and uncover new ways to treat neurological disorders.

Radiogenomic analysis of prediction HER2 status in breast cancer by linking ultrasound radiomic feature module with biological functions

BackgroundHuman epidermal growth factor receptor 2 (HER2) overexpressed associated with poor prognosis in breast cancer and HER2 has been defined as a therapeutic target for breast cancer treatment. We aimed to explore the molecular biological information in ultrasound radiomic features (URFs) of HER2-positive breast cancer using radiogenomic analysis. Moreover, a radiomics model was developed to predict the status of HER2 in breast cancer.MethodsThis retrospective study included 489 patients who were diagnosed with breast cancer. URFs were extracted from a radiomics analysis set using PyRadiomics. The correlations between differential URFs and HER2-related genes were calculated using Pearson correlation analysis. Functional enrichment of the identified URFs-correlated HER2 positive-specific genes was performed. Lastly, the radiomics model was developed based on the URF-module mined from auxiliary differential URFs to assess the HER2 status of breast cancer.ResultsEight differential URFs (p < 0.05) were identified among the 86 URFs extracted by Pyradiomics. 25 genes that were found to be the most closely associated with URFs. Then, the relevant biological functions of each differential URF were obtained through functional enrichment analysis. Among them, Zone Entropy is related to immune cell activity, which regulate the generation of calcification in breast cancer. The radiomics model based on the Logistic classifier and URF-module showed good discriminative ability (AUC = 0.80, 95% CI).ConclusionWe searched for the URFs of HER2-positive breast cancer, and explored the underlying genes and biological functions of these URFs. Furthermore, the radiomics model based on the Logistic classifier and URF-module relatively accurately predicted the HER2 status in breast cancer.

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 New Fast Logarithm Algorithm Using Advanced Exponent Bit Extraction for Software-Based Ultrasound Imaging Systems

Ultrasound B-mode imaging provides anatomical images of the body with a high resolution and frame rate. Recently, to improve its flexibility, most ultrasound signal and image processing modules in modern ultrasound B-mode imaging systems have been implemented in software. In a software-based B-mode imaging system, an efficient processing technique for calculating a logarithm instruction is required to support its high computational burden. In this paper, we present a new method to efficiently implement a logarithm operation based on exponent bit extraction. In the proposed method, the exponent bit field is first extracted and then some algebraic operations are applied to improve its precision. To evaluate the performance of the proposed method, the peak signal-to-noise ratio (PSNR) and the execution time were measured. The proposed efficient logarithm operation method substantially reduced the execution time, i.e., eight times, compared to direct computation while providing a PSNR of over 50 dB. These results indicate that the proposed efficient logarithm computation method can be used for lowering the computational burden in software-based ultrasound B-mode ultrasound imaging systems while improving or maintaining the image quality.

Homodyne time-of-flight acousto-optic imaging for low-gain photodetector.

Acousto-optics imaging (AOI) is a hybrid imaging modality that is capable of mapping the light fluence rate in deep tissue by local ultrasound modulation of the diffused photons. Since the intensity of the modulated photons is relatively low, AOI systems often rely on high-gain photodetectors, e.g. photomultiplier tubes (PMTs), which limit scalability due to size and cost and may significantly increase the relative shot-noise in the detected signal due to low quantum yields or gain noise. In this work, we have developed a homodyne AOI scheme in which the modulated photons are amplified by interference with a reference beam, enabling their detection with a single low-gain photodetector in reflection-mode configuration. We experimentally demonstrate our approach with a silicon photodiode, achieving over a 4-fold improvement in SNR in comparison to a PMT-based setup. The increased SNR manifested in lower background noise level thus enabling deeper imaging depths. The use of a fiber-based configuration enables the integration of our scheme in a hand-held AOI probe.

Contrast-Enhanced Ultrasound Tumor Therapy With Abdominal Imaging Transducer.

A diagnostic ultrasound machine add-on module (AOM) was created to enable an off-the-shelf abdominal imaging transducer to perform contrast-enhanced therapeutic ultrasound. The AOM creates plane-wave ultrasound through an abdominal imaging transducer targeting intravascular microbubbles within tumors. This therapeutic antivascular ultrasound (AVUS) causes heating and cavitation effects that destroy tumor vasculature and starves it of nutrients. The AOM can switch between therapeutic and imaging modes for monitoring AVUS treatment. The therapeutic capability of the AOM was validated in murine hepatocellular carcinomas (HCC) grown in adult mice. Contrast-enhanced ultrasound imaging performed before and after the therapeutic treatment evaluated the AVUS response to the treatment. The peak enhancement (PE), perfusion index (PI), and area under the curve (AUC) were measured for the control and AOM treatment groups. The AOM group showed a substantial decrease in these parameters compared to the control group. The difference between the pre- and post-therapy was significant, (p < 0.001) for the AOM group and not significant (p > 0.5) for the control group. Tumor temperatures increased markedly for the AOM group with a thermal dose (CEM43) of 124.8 (±2.5). Histochemical analysis of the excised HCC samples revealed several hemorrhagic pools in tumors from the AOM group, absent in the tumors of the control group. These results demonstrate the theranostic potential of the AOM to induce and monitor vascular disruption within murine tumors.

Low-frequency, low-intensity ultrasound modulates light responsiveness of mouse retinal ganglion cells

Objective. Ultrasound modulates the firing activity of retinal ganglion cells (RGCs), but the effects of lower-frequency, lower-intensity ultrasound on RGCs and underlying mechanism(s) remain poorly understood. This study aims to address these questions. Approach. Multi-electrode recordings were used in this study to record the firing sequences of RGCs in isolated mouse retinas. RGCs’ background firing activities as well as their light responses were recorded with or without ultrasound stimulation. Cross-correlation analyses were performed to investigate the possible cellular/circuitry mechanism(s) underlying ultrasound modulation. Main results. It was found that ultrasound stimulation of isolated mouse retina enhanced the background activity of ON-RGCs and OFF-RGCs. In addition, background ultrasound stimulation shortened the light response latency of both ON-RGCs and OFF-RGCs, while enhancing part of the RGCs’ (both ON- and OFF-subtypes) light response and decreasing that of the others. In some ON-OFF RGCs, the ON- and OFF-responses of an individual cell were oppositely modulated by the ultrasound stimulation, which suggests that ultrasound stimulation does not necessarily exert its effect directly on RGCs, but rather via its influence on other type(s) of cells. By analyzing the cross-correlation between the firing sequences of RGC pairs, it was found that concerted activity occurred during ultrasound stimulation differed from that occurred during light stimulation, in both spatial and temporal aspects. These results suggest that the cellular circuits involved in ultrasound- and light-induced concerted activities are different and glial cells may be involved in the circuit in response to ultrasound. Significance. These findings demonstrate that ultrasound affects neuronal background activity and light responsiveness, which are critical for visual information processing. These results may also imply a hitherto unrecognized role of glial cell activation in the bidirectional modulation effects of RGCs and may be critical for the nervous system.

Ultrasound-Triggered on Demand Lidocaine Release Relieves Postoperative Pain.

Safe and non-invasive on-demand relief is a crucial and effective treatment for postoperative pain because it considers variable timing and intensity of anesthetics. Ultrasound modulation is a promising technique for this treatment because it allows convenient timed and non-invasive controlled drug release. Here, we created an ultrasound-triggered lidocaine (Lido) release platform using an amino acid hydrogel functioning as three-dimensional (3D) scaffold material (Lido-PPIX@ER hydrogel). It allows control of the timing, intensity and duration of lidocaine (Lido) to relieve postoperative pain. The hydrogel releases Lido due to the elevated reactive oxygen species (ROS) levels generated by PPIX under ultrasound triggering. The Lido-PPIX@ER hydrogel under individualized ultrasound triggering released lidocaine and provided effective analgesia for more than 72 h. The withdrawal threshold was higher than that in the control group at all time points measured. The hydrogel showed repeatable and adjustable ultrasound-triggered nerve blocks in vivo, the duration of which depended on the extent and intensity of insonation. On histopathology, no systemic effect or tissue reaction was observed in the ultrasound-triggered Lido-PPIX@ER hydrogel-treated group. The Lido-PPIX@ER hydrogel with individualized (highly variable) ultrasound triggering is a convenient and effective method that offers timed and spatiotemporally controlled Lido release to manage postoperative pain. This article presents the delivery system for a new effective strategy to reduce pain, remotely control pain, and offer timed and spatiotemporally controlled release of Lido to manage postoperative pain.

Snapshot time-reversed ultrasonically encoded optical focusing guided by time-reversed photoacoustic wave

Deep-tissue optical imaging is a longstanding challenge limited by scattering. Both optical imaging and treatment can benefit from focusing light in deep tissue beyond one transport mean free path. Wavefront shaping based on time-reversed ultrasonically encoded (TRUE) optical focusing utilizes ultrasound focus, which is much less scattered than light in biological tissues as the 'guide star'. However, the traditional TRUE is limited by the ultrasound focusing area and pressure tagging efficiency, especially in acoustically heterogeneous medium. Even the improved version of iterative TRUE comes at a large time consumption, which limits the application of TRUE. To address this problem, we proposed a method called time-reversed photoacoustic wave guided time-reversed ultrasonically encoded (TRPA-TRUE) optical focusing by integrating accurate ultrasonic focusing through acoustically heterogeneous medium guided by time-reversing PA signals, and the ultrasound modulation of diffused coherent light with optical phase conjugation (OPC), achieving dynamic focusing of light into scattering medium. Simulation results show that the focusing accuracy of the proposed method has been significantly improved compared with conventional TRUE, which is more suitable for practical applications that suffers severe acoustic distortion, e.g. transcranial optical focusing.

Ultrasound deep brain stimulation decelerates telomere shortening in Alzheimer's disease and aging mice

Telomere length is a reliable biomarker for health and longevity prediction in both humans and animals. The common neuromodulation techniques, including deep brain stimulation (DBS) and optogenetics, have excellent spatial resolution and depth penetration but require implementation of electrodes or optical fibers. Therefore, it is important to develop methods for noninvasive modulation of telomere length. Herein, we reported on a new method for decelerating telomere shortening using noninvasive ultrasound deep brain stimulation (UDBS). Firstly, we found that UDBS could activate the telomerase-associated proteins in normal mice. Then, in the Alzheimer's disease mice, UDBS was observed to decelerate telomere shortening of the cortex and myocardial tissue and to effectively improve spatial learning and memory abilities. Similarly, UDBS was found to significantly slow down telomere shortening of the cortex and peripheral blood, and improve motor and cognitive functions in aging mice. Finally, transcriptome analysis revealed that UDBS upregulated the neuroactive ligand–receptor interaction pathway. Overall, the present findings established the critical role of UDBS in delaying telomere shortening and indicated that ultrasound modulation of telomere length may constitute an effective therapeutic strategy for aging and aging-related diseases.

Very Low Frequency Radial Modulation for Deep Penetration Contrast-Enhanced Ultrasound Imaging.

Contrast-enhanced ultrasound imaging allows vascular imaging in a variety of diseases. Radial modulation imaging is a contrast agent-specific imaging approach for improving microbubble detection at high imaging frequencies (≥7.5 MHz), with imaging depth limited to a few centimeters. To provide high-sensitivity contrast-enhanced ultrasound imaging at high penetration depths, a new radial modulation imaging strategy using a very low frequency (100 kHz) ultrasound modulation wave in combination with imaging pulses ≤5 MHz is proposed. Microbubbles driven at 100 kHz were imaged in 10 successive oscillation states by manipulating the pulse repetition frequency to unlock the frame rate from the number of oscillation states. Tissue background was suppressed using frequency domain radial modulation imaging (F-RMI) and singular value decomposition-based radial modulation imaging (S-RMI). One hundred-kilohertz modulation resulted in significantly higher microbubble signal magnitude (63-88 dB) at the modulation frequency relative to that without 100-kHz modulation (51-59 dB). F-RMI produced images with high contrast-to-tissue ratios (CTRs) of 15 to 22 dB in a stationary tissue phantom, while S-RMI further improved the CTR (19-26 dB). These CTR values were significantly higher than that of amplitude modulation pulse inversion images (11.9 dB). In the presence of tissue motion (1 and 10 mm/s), S-RMI produced high-contrast images with CTR up to 18 dB; however, F-RMI resulted in minimal contrast enhancement in the presence of tissue motion. Finally, in transcranial ultrasound imaging studies through a highly attenuating ex vivo cranial bone, CTR values with S-RMI were as high as 23 dB. The proposed technique demonstrates successful modulation of microbubble response at 100 kHz for the first time. The presented S-RMI low-frequency radial modulation imaging strategy represents the first demonstration of real-time (20 frames/s), high-penetration-depth radial modulation imaging for contrast-enhanced ultrasound imaging.

Binary amplitude switch for photoacoustic transducer toward dynamic spatial acoustic field modulation.

Photoacoustic (PA) transducers are an attractive method of producing high-amplitude, high-frequency, broad-bandwidth ultrasound signals with excellent immunity to electromagnetic interference, when compared with their traditional electroacoustic counterparts. However, the lack of effective control over the spatial sound field prohibits PA transducer technology from further widespread application. This paper presents the first, to the best of our knowledge, experimental study on the dynamic spatial ultrasound modulation strategy for the use of PA transducers, in which a novel PA transducer element is designed. This consists of a suspended compound PA conversion film, whose backing condition can be switched between air and glass through pneumatic actuation to create destructive and constructive acoustic wave interference, respectively. As a result, nearly an order of magnitude contrast in the output acoustic amplitude can be obtained by switching the device's backing condition given the same laser excitation, thus achieving a binary amplitude tuning. Furthermore, a linear PA transducer array consisting of three independently controllable elements is used for a proof-of-concept demonstration of the dynamic spatial sound field manipulation. To the best of the authors' knowledge, this is the first time that such a unique capability has been successfully applied to PA transducer technology.

Constructing a Deep Image Analysis System Based on Self-Driving and AIoT

This research is based on the system architecture of Edge Computing in the AIoT (Artificial Intelligence & Internet of Things) field. In terms of receiving data, the authors proposed approach employed the camera module as the video source, the ultrasound module as the distance measurement source, and then compile C++ with Raspberry Pi 4B for image lane analysis, while Jetson Nano uses the YOLOv3 algorithm for image object detection. The analysis results of the two single-board computers are transmitted to Motoduino U1 in binary form via GPIO, which is used for data integration and load driving. The load drive has two parts: DC motor (rear wheel drive) and servo motor (front wheel steering). Then the final data of NodeMCU is wirelessly transmitted to the router, and then transmitted to the terminal smart device through the 4G network, thus completing the task of monitoring automatic driving. At present, artificial intelligence, the Internet of Things, and autonomous driving technologies are developing rapidly. The highlights of this research are three parts. The first part is the use of two image analysis methods to complete the automatic driving work, and the second part is the hardware architecture and circuit combination. The third part is that the system of this research is designed based on the Internet of Things architecture. The proposed system is to realize the data integration of various analysis platforms such as Raspberry Pi 4B, Jetson Nano, Motoduino U1, and mobile phone APP. The proposed method can not only realize the driving of an autonomous driving model car through image analysis but also monitor the autonomous driving process.

High resolution ultrasonic neural modulation observed via in vivo two-photon calcium imaging

Neural modulation plays a major role in delineating the circuit mechanisms and serves as the cornerstone of neural interface technologies. Among the various modulation mechanisms, ultrasound enables noninvasive label-free deep access to mammalian brain tissue. To date, most if not all ultrasonic neural modulation implementations are based on ∼1 MHz carrier frequency. The long acoustic wavelength results in a spatially coarse modulation zone, often spanning over multiple function regions. The modulation of one function region is inevitably linked with the modulation of its neighboring regions. Moreover, the lack of in vivo cellular resolution cell-type-specific recording capabilities in most studies prevents the revealing of the genuine cellular response to ultrasound. To significantly increase the spatial resolution, we explored the application of high-frequency ultrasound. To investigate the neuronal response at cellular resolutions, we developed a dual-modality system combining in vivo two-photon calcium imaging and focused ultrasound modulation. The studies show that the ∼30 MHz ultrasound can suppress the neuronal activity in awake mice at 100-μm scale spatial resolutions, paving the way for high-resolution ultrasonic neural modulation. The dual-modality in vivo system validated through this study will serve as a general platform for studying the dynamics of various cell types in response to ultrasound.

Ultrasound modulation of macaque prefrontal cortex selectively alters credit assignment-related activity and behavior.

Credit assignment is the association of specific instances of reward to the specific events, such as a particular choice, that caused them. Without credit assignment, choice values reflect an approximate estimate of how good the environment was when the choice was made—the global reward state—rather than exactly which outcome the choice caused. Combined transcranial ultrasound stimulation (TUS) and functional magnetic resonance imaging in macaques demonstrate credit assignment–related activity in prefrontal area 47/12o, and when this signal was disrupted with TUS, choice value representations across the brain were impaired. As a consequence, behavior was no longer guided by choice value, and decision-making was poorer. By contrast, global reward state–related activity in the adjacent anterior insula remained intact and determined decision-making after prefrontal disruption.

Linear and nonlinear ultrasound time reversal using a condensing raster operation

One of the weaknesses of nonlinear methods is the excitation power required to generate nonlinear effects such as higher order harmonics (single frequency) and sidebands (dual excitation). In conjunction with the high-power prerequisite, is the required sensitivity of sensors to capture nonlinear effects which can be multiple orders of magnitude lower than the fundamental/linear response of the system. In this work a semi-air coupled nonlinear ultrasound modulation method combining phase symmetry analysis and time reversal is developed, in the aim of alleviating some of these issues. Phase symmetry analysis is used to characterise the second order and modulated nonlinear responses of a dual frequency excitation signal containing a single frequency (f1) and a sweep burst (f2). Time reversal allows for optimal focusing, in this case at locations on composites panels with barely visible impact damage. Time reversed signals typically focus at single locations at a time, in this work, a raster time reversal methodology is proposed which focuses on multiple locations simultaneously. The raster methodology reduces distortions which may affect air-coupled techniques, reduces inspection time, and shows clear enhancement of damage imaging when compared against the raw fundamental response and standard time reversal.

Wild Mixed Culture Microalgae Biomass from UI Agathis Small Lake Harvested Directly using an Ultrasound Harvesting Module as Biofuel Raw Material

A follow-up study on the use of ultrasonic sound for harvesting a mixed culture of microalgae from a small lake for biofuel feedstock has been carried out. Observations were made at the Agathis small lake of Universitas Indonesia during the rainy

Ultrasound assisted modulation of yeast growth and inactivation kinetics

The yeast Saccharomyces cerevisiae is well known for its application in the food industry for the purpose of developing fermented food. The ultrasound (US) technology offer a wide range of applications for the food industry, including the enhancement of fermentation rates and inactivation of microbial cells. However, a better understanding and standardization of this technology is still required to ensure the scaling-up process. This study investigated the effect of the US technology on the growth of S. cerevisiae using frequencies of 20, 25, 45 and 130 kHz, treatment periods from 2 to 30 min. Furthermore, yeast kinetics subjected to US treatments were evaluated using modelling tools and scanning electron microscopy (SEM) analysis to explore the impact of sonication on yeast cells. Yeast growth was monitored after different US treatments plotting optical density (OD) at 660 nm for 24 h at 30 ⁰C. Growth curves were fitted using models of modified Gompertz and Scale-Free which showed good parameters of the fit. In particular, US frequencies of 45 and 130 kHz did not have a disruptive effect in lag phase and growth rate of the yeast populations, unlike the frequency of 20 kHz. Moreover, inactivation curves of yeast cells obtained after exposure to 20 and 25 kHz also observed the best fit using the Weibull model. US frequency of 20 kHz achieved significant reductions of 1.3 log cfu/mL in yeast concentration and also induced important cell damage on the external structures of S. cerevisiae. In conclusion, the present study demonstrated the significant effect of applying different US frequencies on the yeast growth for potential application in the food industry.