Spatial Peak Pulse Average Intensity Research Articles

Evaluation of advective solute infiltration into porous media by pulsed focused ultrasound-induced acoustic streaming effects.

Acoustic streaming induced by applying transcranial focused ultrasound (FUS) promotes localized advective solute transport in the brain and has recently garnered research interest for drug delivery and enhancement of brain waste clearance. The acoustic streaming behavior in brain tissue is difficult to model numerically and thus warrants an in vitro examination of the effects of using different sonication parameters, in terms of frequency, intensity, and pulse duration (PD). Melamine and polyvinyl alcohol (PVA) foams were used to mimic the porous brain tissue, which contains leptomeningeal fenestrations and perivascular space, while agar hydrogel was used to emulate denser neuropil. FUS was delivered to these media, which were immersed in a phosphate-buffered saline containing toluidine blue O dye, across various frequencies (400, 500, and 600 kHz; applicable to transcranial delivery) in a pulsed mode at two different spatialpeak pulse-average intensities (3 and 4 W/cm2). Image analysis showed that the use of 400 kHz yielded the greatest dye infiltration in melamine foam, while sonication had no impact on infiltration in the agar hydrogel due to the dominance of diffusional transport. Using a fixed spatial-peak temporal-average intensity of 0.4 W/cm2 at 400 kHz, a PD of 75 ms resulted in the greatest infiltration depth in both melamine and PVA foams among the tested range (50-150 ms). These findings suggest the existence of a specific frequency and PD that induce greater enhancement of solute/fluid movement, which may contribute to eventual in vivo applications in promoting waste clearance from the brain.

Ultrasound neuromodulation of cultured hippocampal neurons.

Ultrasound is becoming an emerging and promising method for neuromodulation due to its advantage of noninvasiveness and its high spatial resolution. However, the underlying principles of ultrasound neuromodulation have not yet been elucidated. We have herein developed a new in vitro setup to study the ultrasonic neuromodulation, and examined various parameters of ultrasound to verify the effective conditions to evoke the neural activity. Neurons were stimulated with 0.5MHz center frequency ultrasound, and the action potentials were recorded from rat hippocampal neural cells cultured on microelectrode arrays. As the intensity of ultrasound increased, the neuronal activity also increased. There was a notable and significant increase in both the spike rate and the number of bursts at 50% duty cycle, 1kHz pulse repetition frequency, and the acoustic intensities of 7.6 W/cm2 and 3.8 W/cm2 in terms of spatial-peak pulse-average intensity and spatial-peak temporal-average intensity, respectively. In addition, the impact of ultrasonic neuromodulation was assessed in the presence of a gamma-aminobutyric acid A (GABAA) receptor antagonist to exclude the effect of activated inhibitory neurons. Interestingly, it is noteworthy that the predominant neuromodulatory effects of ultrasound disappeared when the GABAA blocker was introduced, suggesting the potential of ultrasonic stimulation specifically targeting inhibitory neurons. The experimental setup proposed herein could serve as a useful tool for the clarification of the mechanisms underlying the electrophysiological effects of ultrasound.

Global sonication of the human intracranial space via a jumbo planar transducer

Contrary to conditioning a Focused Ultrasound (FUS) beam to sonicate a localized region of the human brain, the goal of this investigation was to explore the prospect of distributing homogeneous ultrasound energy over the entire brain space with a large cranium-wide ultrasound beam. Recent ultrasound preclincal studies utilizing large or whole brain stimulation regions create a demand for expanding the treatment envelope of transcranial pulsed-low intensity ultrasound towards Global Brain Sonication (GBS) for potential human investigation. Here, we conduct ultrasound field characterizations when transmitting pulsed ultrasound through human skull specimens using a 1–3 piezocomposite planar transducer operating at 464 kHz with an active single-element surface of 30 × 30 cm. Through computational simulation and hydrophone scanning methodology, ultrasound wave behavior and dose homogeneity in the brain space were evaluated under various trajectories of sonication using the planar transducer. Clinically relevant pulse parameters used for transcranial therapeutic ultrasound applications were used in the experiments. Simulations and empirical testing revealed that dose homogeneity and acoustic intensity over the brain space are influenced by sonication trajectory, skull lens effects, and acoustic wave reflections. The transducer can emit a spatial peak pulse average intensity of 4.03 W/cm2 (0.24 MPa) measured in the free-field at 464 kHz with electrical power of 1 kW. The simulation showed that approximately 99 % of the cranial volume was exposed with <30 % of the maximum external acoustic intensity being transmitted into the skull. The transmission loss across all sonication trajectories is similar to previously reported FUS studies. A marker for GBS dose homogeneity is introduced to score the ultrasound pressure field uniformity in the intracranial space. Results of this study identify the initial challenges of exposing the entire human brain space with ultrasound using a large cranium-wide sonication beam intended for global brain therapeutic modulation.

32 Element Piezoelectric Micromachined Ultrasound Transducer (PMUT) Phased Array for Neuromodulation

Interest in utilizing ultrasound (US) transducers for non-invasive neuromodulation treatment, including for low intensity transcranial focused ultrasound stimulation (tFUS), has grown rapidly. The most widely demonstrated US transducers for tFUS are either bulk piezoelectric transducers or capacitive micromachine transducers (CMUT) which require high voltage excitation to operate. In order to advance the development of the US transducers towards small, portable devices for safe tFUS at large scale, a low voltage array of US transducers with beam focusing and steering capability is of interest. This work presents the design methodology, fabrication, and characterization of 32-element phased array piezoelectric micromachined ultrasound transducers (PMUT) using 1.5 μm thick Pb(Zr0.52 Ti0.48)O3 films doped with 2 mol% Nb. The electrode/piezoelectric/electrode stack was deposited on a silicon on insulator (SOI) wafer with a 2 μm silicon device layer that serves as the passive elastic layer for bending-mode vibration. The fabricated 32-element PMUT has a central frequency at 1.4 MHz. Ultrasound beam focusing and steering (through beamforming) was demonstrated where the array was driven with 14.6 V square unipolar pulses. The PMUT generated a maximum peak-to-peak focused acoustic pressure output of 0.44 MPa at a focal distance of 20 mm with a 9.2 mm and 1 mm axial and lateral resolution, respectively. The maximum pressure is equivalent to a spatial-peak pulse-average intensity of 1.29 W/cm2, which is suitable for tFUS application.

A Wearable Ultrasonic Neurostimulator - Part I: A 1D CMUT Phased Array System for Chronic Implantation in Small Animals.

In this work, we present a wireless ultrasonic neurostimulator, aiming at a truly wearable device for brain stimulation in small behaving animals. A 1D 5-MHz capacitive micromachined ultrasonic transducer (CMUT) array is adopted to implement a head-mounted stimulation device. A companion ASIC with integrated 16-channel high-voltage (60-V) pulsers was designed to drive the 16-element CMUT array. The ASIC can generate excitation signals with element-wise programmable phases and amplitudes: 1) programmable sixteen phase delays enable electrical beam focusing and steering, and 2) four scalable amplitude levels, implemented with a symmetric pulse-width-modulation technique, are sufficient to suppress unwanted sidelobes (apodization). The ASIC was fabricated in the TSMC 0.18- μm HV BCD process within a die size of 2.5 × 2.5 mm2. To realize a completely wearable system, the system is partitioned into two parts for weight distribution: 1) a head unit (17 mg) with the CMUT array, 2) a backpack unit (19.7 g) that includes electronics such as the ASIC, a power management unit, a wireless module, and a battery. Hydrophone-based acoustic measurements were performed to demonstrate the focusing and beam steering capability of the proposed system. Also, we achieved a peak-to-peak pressure of 2.1 MPa, which corresponds to a spatial peak pulse average intensity ( ISPPA) of 33.5 W/cm2, with a lateral full width at half maximum (FWHM) of 0.6 mm at a depth of 3.5 mm.

A Wearable Ultrasonic Neurostimulator-Part II: A 2D CMUT Phased Array System With a Flip-Chip Bonded ASIC.

A 2D ultrasonic array is the ultimate form of a focused ultrasonic system, which enables electronically focusing beams in a 3D space. A 2D array is also a versatile tool for various applications such as 3D imaging, high-intensity focused ultrasound, particle manipulation, and pattern generation. However, building a 2D system involves complicated technologies: fabricating a 2D transducer array, developing a pitch-matched ASIC, and interconnecting the transducer and the ASIC. Previously, we successfully demonstrated 2D capacitive micromachined ultrasonic transducer (CMUT) arrays using various fabrication technologies. In this paper, we present a 2D ultrasonic transmit phased array based on a 32 × 32 CMUT array flip-chip bonded to a pitch-matched pulser ASIC for ultrasonic neuromodulation. The ASIC consists of 32 × 32 unipolar high-voltage (HV) pulsers, each of which occupies an area of 250 μm × 250 μm. The phase of each pulser output is individually programmable with a resolution of 1/fC/16, where fC is less than 10 MHz. This enables the fine granular control of a focus. The ASIC was fabricated in the TSMC 0.18- μm HV BCD process within an area of 9.8 mm × 9.8 mm, followed by a wafer-level solder bumping process. After flip-chip bonding an ASIC and a CMUT array, we identified shorted elements in the CMUT array using the built-in test function in the ASIC, which took approximately 9 minutes to scan the entire 32 × 32 array. A compact-form-factor wireless neural stimulator system-only requiring a connected 15-V DC power supply-was also developed, integrating a power management unit, a clock generator, and a Bluetooth Low-Energy enabled microcontroller. The focusing and steering capability of the system in a 3D space is demonstrated, while achieving a spatial-peak pulse-average intensity ( ISPPA) of 12.4 and 33.1 W/ cm2; and a 3-dB focal volume of 0.2 and 0.05 mm3-at a depth of 5 mm-at 2 and 3.4 MHz, respectively. We also characterized transmission of ultrasound through a mouse skull and compensated the phase distortion due to the skull by using the programmable phase-delay function in the ASIC, achieving 10% improvement in pressure and a tighter focus. Finally, we demonstrated a ultrasonic arbitrary pattern generation on a 5 mm × 5 mm plane at a depth of 5 mm.

Focused ultrasound enhances the anesthetic effects of topical lidocaine in rats

BackgroundHigh-intensity ultrasound has been used to induce acoustic cavitation in the skin and subsequently enhances skin permeability to deliver hydrophobic topical medications including lidocaine. In contrast, instead of changing skin permeability, pulsed application of low-intensity focused ultrasound (FUS) has shown to non-invasively and temporarily disrupt drug-plasma protein binding, thus has potential to enhance the anesthetic effects of hydrophilic lidocaine hydrochloride through unbinding it from serum/interstitial α1-acid glycoprotein (AAG).MethodsFUS, operating at fundamental frequency of 500 kHz, was applied pulse-mode (55-ms pulse duration, 4-Hz pulse repetition frequency) at a spatial-peak pulse-average intensity of 5 W/cm2. In vitro equilibrium dialysis was performed to measure the unbound concentration of lidocaine (lidocaine hydrochloride) from dialysis cassettes, one located at the sonication focus and the other outside the sonication path, all immersed in phosphate-buffered saline solution containing both lidocaine (10 µg/mL) and human AAG (5 mg/mL). In subsequent animal experiments (Sprague-Dawley rats, n = 10), somatosensory evoked potential (SSEP), elicited by electrical stimulations to the unilateral hind leg, was measured under three experimental conditions—applications of FUS to the unilateral thigh area at the site of administered topical lidocaine, FUS only, and lidocaine only. Skin temperature was measured before and after sonication. Passive cavitation detection was also performed during sonication to evaluate the presence of FUS-induced cavitation.ResultsSonication increased the unbound lidocaine concentration (8.7 ± 3.3 %) from the dialysis cassette, compared to that measured outside the sonication path (P < 0.001). Application of FUS alone did not alter the SSEP while administration of lidocaine reduced its P23 component (i.e., a positive peak at 23 ms latency). The FUS combined with lidocaine resulted in a further reduction of the P23 component (in a range of 21.8 − 23.4 ms after the electrical stimulations; F(2,27) = 3.2 − 4.0, P < 0.05), indicative of the enhanced anesthetic effect of the lidocaine. Administration of FUS neither induced cavitation nor altered skin conductance or temperature, suggesting that skin permeability was unaffected.ConclusionsUnbinding lidocaine from the plasma proteins by exposure to non-thermal low-intensity ultrasound is attributed as the main mechanism behind the observation.

Selection of Excitation Signals and Acoustic Pressure Measurement for In-Vivo Studies with Ultrasound Array Research Platform II

In recent years, the Ultrasound Group at the University of Leeds has developed an open platform (OP) known as Ultrasound Array Research Platform II (UARPII). The OP serves as a main component for researchers to test and implement new algorithms which is not feasible with the commercially available clinical scanners. In this paper, three types of excitation signals, the square pulse, 2-cycle sinusoid and linear frequency modulated chirps which are commonly employed in ultrasound imaging, were investigated for in-vivo experiments with the UARP II OP. The USA food and drug administration (FDA) provides strict guidelines that need to be followed when working with in-vivo medium. This is to ensure that the acoustic beam intensities do not cause any types of thermal damage and cavitation. The acoustic pressures produced by those excitation signals were measured with a needle hydrophone. The main three parameters of the excitation signals measured and calculated are the mechanical index (MI), spatial peak pulse average intensity (SPPA) and spatial peak temporal average intensity (SPTA). By considering advantages and disadvantages of all investigated excitation signals, the 2-cycle sinusoidal signal has been selected for all simulations and experiments with the in-vivo medium.

In Vivo Non-Thermal, Selective Cancer Treatment With High-Frequency Medium-Intensity Focused Ultrasound.

Focused ultrasound (FUS) has proven its efficacy in non-invasive, radiation-free cancer treatment. However, the commonly used low-frequency high-intensity focused ultrasound (HIFU) destroys both cancerous and healthy tissues non-specifically through extreme heat and inertial cavitation with low spatial resolution. To address this issue, we evaluate the therapeutic effects of pulsed (60 Hz pulse repetition frequency, 1.45 ms pulse width) high-frequency (20.7 MHz) medium-intensity (spatial-peak pulse-average intensity ISPPA < 279.1 W/cm2, spatial-peak temporal-average intensity ISPTA < 24.3 W/cm2) focused ultrasound (pHFMIFU) for selective cancer treatment without thermal damage and with low risk of inertial cavitation (mechanical index < 0.66), in an in vivo subcutaneous B16F10 melanoma tumor growth model in mice. The pHFMIFU with 104 μm focal diameter is generated by a microfabricated self-focusing acoustic transducer (SFAT) with a Fresnel acoustic lens. A three-axis positioning system has been developed for automatic scanning of the transducer to cover a larger treatment volume, while a water-cooling system is custom-built for dissipating non-acoustic heat from the transducer surface. Initial testing revealed that pHFMIFU treatment can be applied to a living animal while maintaining skin temperature under 35.6 °C without damaging normal skin and tissue. After eleven days of treatment with pHFMIFU, the treated tumors were significantly smaller with large areas of necrosis and apoptosis in the treatment field compared to untreated controls. Potential mechanisms of this selective, non-thermal killing effect, as well as possible causes of and solutions to the variation in treatment results, have been analyzed and proposed. The pHFMIFU could potentially be used as a new therapeutic modality for safer cancer treatment especially in critical body regions, due to its cancer-specific effects and high spatial resolution.

Non-invasive ultrasonic neuromodulation of neuronal excitability for treatment of epilepsy.

Non-invasive low-intensity pulsed ultrasound has been employed for direct neuro-modulation. However, its range and effectiveness for different neurological disorders have not been fully elucidated.Methods: We used multiple approaches of electrophysiology, immunohistochemistry, and behavioral tests as potential epilepsy treatments in non-human primate model of epilepsy and human epileptic tissues. Low-intensity pulsed ultrasound with a frequency of 750 kHz and acoustic pressure of 0.35 MPa (the spatial peak pulse average intensity, ISPPA = 2.02 W/cm2) were delivered to the epileptogenic foci in five penicillin-induced epileptic monkey models. An ultrasound neuro-modulation system with a frequency of 28 MHz and acoustic pressure of 0.13 MPa (ISPPA = 465 mW/cm2) compatible with patch-clamp systems was used to stimulate the brain slices prepared from fifteen patients with epilepsy.Results: After 30 min of low-intensity pulsed ultrasound treatment, total seizure count for 16 hours (sham group: 107.7 ± 1.2, ultrasound group: 66.0 ± 7.9, P < 0.01) and seizure frequency per hour (sham group: 15.6 ± 1.2, ultrasound group: 9.6 ± 1.5, P < 0.05) were significantly reduced. The therapeutic efficacy and underlying potential mechanism of low-intensity pulsed ultrasound treatment were studied in biopsy specimens from epileptic patients in vitro. Ultrasound stimulation could inhibit epileptiform activities with an efficiency exceeding 65%, potentially due to adjusting the balance of excitatory-inhibitory (E/I) synaptic inputs by the increased activity of local inhibitory neurons.Conclusion: Herein, we demonstrated for the first time that low-intensity pulsed ultrasound improves electrophysiological activities and behavioral outcomes in a non-human primate model of epilepsy and suppresses epileptiform activities of neurons from human epileptic slices. The study provides evidence for the potential clinical use of non-invasive low-intensity pulsed ultrasound stimulation for epilepsy treatment.

Towards an Untethered Ultrasound Beamforming System for Brain Stimulation in Behaving Animals.

In this paper, we present a wireless ultrasound transmit (TX) beamforming system, potentially enabling wearable brain stimulation for small awake/behaving animals. The system is comprised of a 16-element capacitive micromachined transducer (CMUT) array, driven by a custom phased-array integrated circuit (IC), which is capable of generating high-voltage (13.5 V) excitation signals with sixteen phase delays and four amplitude levels. In addition, a Bluetooth low-energy module and a power management unit were integrated into the system, which realizes a battery-operated self-contained unit. We validated the functionality of the system by demonstrating beamforming and steering with a hydrophone measurement setup. We achieved an acoustic pressure output of 554 kPapp at the depth of 5 mm, which corresponds to a spatial-peak pulse-average intensity (ISPPA) of 2.9 W/cm2. The measured 6-dB beamwidth (0.4 mm) is promising in that it can stimulate a specific region of the brain, especially for small animals such as mice. Further smart partitioning of the system will enable a truly wearable device for small animals.

Acoustic field characterization of a clinical magnetic resonance-guided high-intensity focused ultrasound system inside the magnet bore.

With the expanding clinical application of magnetic resonance-guided high-intensity focused ultrasound (MR-HIFU), acoustic field characterization of MR-HIFU systems is needed for facilitating regulatory approval and ensuring consistent and safe power output of HIFU transducers. However, the established acoustic field measurement techniques typically use equipment that cannot be used in a magnetic resonance imaging (MRI) suite, thus posing a challenge to the development and execution of HIFU acoustic field characterization techniques. In this study, we developed and characterized a technique for HIFU acoustic field calibration within the MRI magnet bore, and validated the technique with standard hydrophone measurements outside of the MRI suite. A clinical Philips MR-HIFU system (Sonalleve V2, Philips, Vantaa, Finland) was used to assess the proposed technique. A fiber-optic hydrophone with a long fiber was inserted through a 24-gauge angiocatheter and fixed inside a water tank that was placed on the HIFU patient table above the acoustic window. The long fiber allowed the hydrophone control unit to be placed outside of the magnet room. The location of the fiber tip was traced on MR images, and the HIFU focal point was positioned at the fiber tip using the MR-HIFU therapy planning software. To perform acoustic field mapping inside the magnet, the HIFU focus was positioned relative to the fiber tip using an MRI-compatible 5-axis robotic transducer positioning system embedded in the HIFU patient table. To perform validation measurements of the acoustic fields, the HIFU table was moved out of the MRI suite, and a standard laboratory hydrophone measurement setup was used to perform acoustic field measurements outside the magnetic field. The pressure field scans along and across the acoustic beam path obtained inside the MRI bore were in good agreement with those obtained outside of the MRI suite. At the HIFU focus with varying nominal acoustic powers of 10-500W, the peak positive pressure and peak negative pressure measured inside the magnet bore were 3.87-68.67MPa and 3.56-12.06MPa, respectively, while outside the MRI suite the corresponding pressures were 3.27-67.32MPa and 3.06-12.39MPa, respectively. There was no statistically significant difference (P>0.05) between measurements inside the magnet bore and outside the MRI suite for the p+ and p- at any acoustic power level. The spatial-peak pulse-average intensities (ISPPA ) for these powers were 312-17816W/cm2 and 220-15698W/cm2 for measurements inside and outside the magnet room, respectively. In addition, when the scanning step size of the HIFU focus was increased from 100μmto 500μm, the execution time for scanning a 4×4mm2 area decreased from 210min to 10min, the peak positive pressure decreased by 14%, the peak negative pressure decreased by 5%, and the lateral full width at half maximum dimension of pressure profiles increased from 1.15mm to 1.55mm. The proposed hydrophone measurement technique offers a convenient and reliable method for characterizing the acoustic fields of clinical MR-HIFU systems inside the magnet bore. The technique was validated for use by measurements outside the MRI suite using a standard hydrophone calibration technique. This technique can be a useful tool in MR-HIFU quality assurance and acoustic field assessment.

A quick and reliable acoustic calibration method for a clinical magnetic resonance guided high-intensity focused ultrasound system

With the expanding use and applications of MR-HIFU in both thermal-based and pressure-based therapies, there is an urgent need to develop acoustic field characterization and quality assurance (QA) tools for MR-HIFU systems. We developed a method for quick and reliable acoustic field assessment inside the magnet bore of a clinical MRI system. A fiber-optic hydrophone with a 2-m long fiber was fixed inside a water tank that was placed on the HIFU table above the acoustic window. The long fiber allowed the MRI-incompatible hydrophone control unit to be located outside the MRI suite. MR images of the fiber were used to position the HIFU focus approximately at the tip of the fiber. The HIFU focus was electronically steered within a 5×5×5mm3 volume in synchronization with hydrophone measurements. The HIFU focus location was then identified based on the 3D field scans. Peak positive and negative pressures were measured at the focus at various nominal acoustic powers. Furthermore, focus dimensions and spatial peak pulse average intensities were assessed. The results were compared to and were consistent with standard hydrophone measurements outside the MRI suite. This method provides a useful tool for field characterization and QA of MR-HIFU systems.

Prolonged stimulation with low-intensity ultrasound induces delayed increases in spontaneous hippocampal culture spiking activity.

Ultrasound is a promising neural stimulation modality, but an incomplete understanding of its range and mechanism of effect limits its therapeutic application. We investigated the modulation of spontaneous hippocampal spike activity by ultrasound at a lower acoustic intensity and longer time scale than has been previously attempted, hypothesizing that spiking would change conditionally upon the availability of glutamate receptors. Using a 60-channel multielectrode array (MEA), we measured spontaneous spiking across organotypic rat hippocampal slice cultures (N = 28) for 3 min each before, during, and after stimulation with low-intensity unfocused pulsed or sham ultrasound (spatial-peak pulse average intensity 780 μW/cm2 ) preperfused with artificial cerebrospinal fluid, 300 μM kynurenic acid (KA), or 0.5 μM tetrodotoxin (TTX) at 3 ml/min. Spike rates were normalized and compared across stimulation type and period, subregion, threshold level, and/or perfusion condition using repeated-measures ANOVA and generalized linear mixed models. Normalized 3-min spike counts for large but not midsized, small, or total spikes increased after but not during ultrasound relative to sham stimulation. This result was recapitulated in subregions CA1 and dentate gyrus and replicated in a separate experiment for all spike size groups in slices pretreated with aCSF but not KA or TTX. Increases in normalized 18-sec total, midsized, and large spike counts peaked predominantly 1.5 min following ultrasound stimulation. Our low-intensity ultrasound setup exerted delayed glutamate receptor-dependent, amplitude- and possibly region-specific influences on spontaneous spike rates across the hippocampus, expanding the range of known parameters at which ultrasound may be used for neural activity modulation. © 2016 Wiley Periodicals, Inc.

Image-Guided Focused Ultrasound-Mediated Regional Brain Stimulation in Sheep

Non-invasive brain stimulation using focused ultrasound has largely been carried out in small animals. In the present study, we applied stimulatory focused ultrasound transcranially to the primary sensorimotor (SM1) and visual (V1) brain areas in sheep (Dorset, all female, n = 8), under the guidance of magnetic resonance imaging, and examined the electrophysiologic responses. By use of a 250-kHz focused ultrasound transducer, the area was sonicated in pulsed mode (tone-burst duration of 1 ms, duty cycle of 50%) for 300 ms. The acoustic intensity at the focal target was varied up to a spatial peak pulse-average intensity (Isppa) of 14.3 W/cm2. Sonication of SM1 elicited electromyographic responses from the contralateral hind leg, whereas stimulation of V1 generated electroencephalographic potentials. These responses were detected only above a certain acoustic intensity, and the threshold intensity, as well as the degree of responses, varied among sheep. Post-sonication animal behavior was normal, but minor microhemorrhages were observed from the V1 areas exposed to highly repetitive sonication (every second for ≥500 times for electroencephalographic measurements, Isppa = 6.6–10.5 W/cm2, mechanical index = 0.9–1.2). Our results suggest the potential translational utility of focused ultrasound as a new brain stimulation modality, yet also call for caution in the use of an excessive number of sonications.

Acoustic output of multi-line transmit beamforming for fast cardiac imaging: a simulation study.

Achieving higher frame rates in cardiac ultrasound could unveil short-lived myocardial events and lead to new insights on cardiac function. Multi-line transmit (MLT) beamforming (i.e., simultaneously transmitting multiple focused beams) is a potential approach to achieve this. However, two challenges come with it: first, it leads to cross-talk between the MLT beams, appearing as imaging artifacts, and second, it presents acoustic summation in the near field, where multiple MLT beams overlap. Although several studies have focused on the former, no studies have looked into the implications of the latter on acoustic safety. In this paper, the acoustic field of 4-MLT was simulated and compared with single-line transmit (SLT). The findings suggest that standard MLT does present potential concerns. Compared with SLT, it shows a 2-fold increase in mechanical index (MI) (from 1.0 to 2.3), a 6-fold increase in spatial-peak pulse-average intensity (I(sppa)) (from 99 to 576 W∙cm(-2)) and a 12-fold increase in spatial-peak temporalaverage intensity (I(spta)) (from 119 to 1407 mW∙cm(-2)). Subsequently, modifications of the transmit pulse and delay line of MLT were studied. These modifications allowed for a change in the spatio-temporal distribution of the acoustic output, thereby significantly decreasing the safety indices (MI = 1.2, I(sppa) = 92 W∙cm(-2) and I(spta) = 366 mW∙cm(-2)). Accordingly, they help mitigate the concerns around MLT, reducing potential tradeoffs between acoustic safety and image quality.

Focused ultrasound-mediated non-invasive brain stimulation: examination of sonication parameters.

Transcranial focused ultrasound (FUS) has emerged as a new brain stimulation modality. The range of sonication parameters for successful brain stimulation warrants further investigation. The objective of this study was to examine the range of FUS sonication parameters that minimize the acoustic intensity/energy deposition while successfully stimulating the motor brain area in Sprague-Dawley rats. We transcranially administered FUS to the somatomotor area of the rat brain and measured the acoustic intensity that caused excitatory effects with respect to different pulsing parameters (tone-burst duration, pulse-repetition frequency, duty cycle, and sonication duration) at 350 and 650kHz of fundamental frequency. We observed that motor responses were elicited at minimum threshold acoustic intensities (4.9-5.6W/cm(2) in spatial-peak pulse-average intensity; 2.5-2.8W/cm(2) in spatial-peak temporal-average intensity) in a limited range of sonication parameters, i.e. 1-5ms of tone-burst duration, 50% of duty cycle, and 300ms of sonication duration, at 350kHz fundamental frequency. We also found that the pulsed sonication elicited motor responses at lower acoustic intensities than its equivalent continuous sonication. Our results suggest that the pulsed application of FUS selectively stimulates specific brain areas-of-interest at an acoustic intensity that is compatible with regulatory safety limits on biological tissue, thus allowing for potential applications in neurotherapeutics.

Focused ultrasound to displace renal calculi: threshold for tissue injury.

BackgroundThe global prevalence and incidence of renal calculi is reported to be increasing. Of the patients that undergo surgical intervention, nearly half experience symptomatic complications associated with stone fragments that are not passed and require follow-up surgical intervention. In a clinical simulation using a clinical prototype, ultrasonic propulsion was proven effective at repositioning kidney stones in pigs. The use of ultrasound to reposition smaller stones or stone fragments to a location that facilitates spontaneous clearance could therefore improve stone-free rates. The goal of this study was to determine an injury threshold under which stones could be safely repositioned.MethodsKidneys of 28 domestic swine were treated with exposures that ranged in duty cycle from 0%–100% and spatial peak pulse average intensities up to 30 kW/cm2 for a total duration of 10 min. The kidneys were processed for morphological analysis and evaluated for injury by experts blinded to the exposure conditions.ResultsAt a duty cycle of 3.3%, a spatial peak intensity threshold of 16,620 W/cm2 was needed before a statistically significant portion of the samples showed injury. This is nearly seven times the 2,400-W/cm2 maximum output of the clinical prototype used to move the stones effectively in pigs.ConclusionsThe data obtained from this study show that exposure of kidneys to ultrasonic propulsion for displacing renal calculi is well below the threshold for tissue injury.

Precision control of lesions by high-intensity focused ultrasound cavitation-based histotripsy through varying pulse duration

The goal of this experimental study was to explore the feasibility of acquiring controllable precision through varying pulse duration for lesions generated by cavitation-based histotripsy. Histotripsy uses high-intensity focused ultrasound (HIFU) at low duty factor to create energetic bubble clouds inside tissue to liquefy a region. It uses cavitation-mediated mechanical effects while minimizing heating, and has the advantages of real-time monitoring and lesion fidelity to treatment planning. In our study, histotripsy was applied to three groups of tissue-mimicking agar samples of different stiffnesses (29.4 ± 5.3, 44.8 ± 5.9, and 66.4 ± 7.1 kPa). B-mode imaging was used first to quantify bubble cluster dimensions in both water and agar. Then, a 4.5-mm-wide square (lateral to the focal plane) was scanned in a raster pattern with a step size of 0.75 mm in agar histotripsy experiments to estimate equivalent bubble cluster dimensions based on the histotripsyinduced damage. The 15-s exposure at each treatment location comprised 5000 sine-wave tone bursts at a spatial-peak pulseaverage intensity of 41.1 kW/cm2, with peak compressional and rarefactional pressures of 102 and 17 MPa, respectively. The results showed that bubble cluster width and length increased with pulse duration and decreased with agar stiffness. Therefore, a significant improvement in histotripsy precision could be achieved by reducing the pulse duration.

Determination of tissue injury thresholds from ultrasound in a porcine kidney model

Therapeutic ultrasound has an increasing number of applications in urology, including shockwave lithotripsy, stone propulsion, tissue ablation, and hemostasis. However, the threshold of renal injury using ultrasound is unknown. The goal of this study was to determine kidney injury thresholds for a range of intensities between diagnostic and ablative therapeutic ultrasound. A 2 MHz annular array generating spatial peak pulse average intensities (ISPPA) up to 30,000 W/cm2 in water was placed on the surface of in vivo porcine kidneys and focused on the adjacent parenchyma. Treatments consisted of pulses of 100 μs duration triggered every 3 ms for 10 min at various intensities. The perfusion-fixed tissue was scored by three blinded independent experts. Above a threshold of 20,000 W/cm2, the majority of injury observed included emulsification, necrosis, and hemorrhage. Below this threshold, almost all injury presented as focal cell and tubular swelling and/or degeneration. These findings provide evidence for a wide range of potentially therapeutic ultrasound intensities that has a low probability of causing injury. While this study did not examine all combinations of treatment parameters of therapeutic ultrasound, tissue injury appears dose-dependent. [Work supported by NIH DK43881, DK092197, and NSBRI through NASA NCC 9-58.]