Yunbo Liu

Mechanical Bioeffects of Pulsed High Intensity Focused Ultrasound on a Simple Neural Model

PURPOSE To study how pressure pulses affect nerves through mechanisms that are neither thermal nor cavitational, and investigate how the effects are related to cumulative radiation-force impulse (CRFI). Applications include traumatic brain injury and acoustic neuromodulation. METHODS A simple neural model consisting of the giant axon of a live earthworm was exposed to trains of pressure pulses produced by an 825 kHz focused ultrasound transducer. The peak negative pressure of the pulses and duty cycle of the pulse train were controlled so that neither cavitation nor significant temperature rise occurred. The amplitude and conduction velocity of action-potentials triggered in the worm were measured as the magnitude of the pulses and number of pulses in the pulse trains were varied. RESULTS The functionality of the axons decreased when sufficient pulse energy was applied. The level of CRFI at which the observed effects occur is consistent with the lower levels of injury observed in this study relative to blast tubes. The relevant CRFI values are also comparable to CRFI values in other studies showing measureable changes in action-potential amplitudes and velocities. Plotting the measured action-potential amplitudes and conduction velocities from different experiments with widely varying exposure regimens against the single parameter of CRFI yielded values that agreed within 21% in terms of amplitude and 5% in velocity. A predictive model based on the assumption that the temporal rate of decay of action-potential amplitude and velocity is linearly proportional the radiation force experienced by the axon predicted the experimental amplitudes and conduction velocities to within about 20% agreement. CONCLUSIONS The functionality of axons decreased due to noncavitational mechanical effects. The radiation force, possibly by inducing changes in ion-channel permeability, appears to be a possible mechanism for explaining the observed degradation. The CRFI is also a promising parameter for quantifying neural bioeffects during exposure to pressure waves, and for predicting axon functionality.PURPOSE To study how pressure pulses affect nerves through mechanisms that are neither thermal nor cavitational, and investigate how the effects are related to cumulative radiation-force impulse (CRFI). Applications include traumatic brain injury and acoustic neuromodulation. METHODS A simple neural model consisting of the giant axon of a live earthworm was exposed to trains of pressure pulses produced by an 825 kHz focused ultrasound transducer. The peak negative pressure of the pulses and duty cycle of the pulse train were controlled so that neither cavitation nor significant temperature rise occurred. The amplitude and conduction velocity of action-potentials triggered in the worm were measured as the magnitude of the pulses and number of pulses in the pulse trains were varied. RESULTS The functionality of the axons decreased when sufficient pulse energy was applied. The level of CRFI at which the observed effects occur is consistent with the lower levels of injury observed in this study relative to blast tubes. The relevant CRFI values are also comparable to CRFI values in other studies showing measureable changes in action-potential amplitudes and velocities. Plotting the measured action-potential amplitudes and conduction velocities from different experiments with widely varying exposure regimens against the single parameter of CRFI yielded values that agreed within 21% in terms of amplitude and 5% in velocity. A predictive model based on the assumption that the temporal rate of decay of action-potential amplitude and velocity is linearly proportional the radiation force experienced by the axon predicted the experimental amplitudes and conduction velocities to within about 20% agreement. CONCLUSIONS The functionality of axons decreased due to noncavitational mechanical effects. The radiation force, possibly by inducing changes in ion-channel permeability, appears to be a possible mechanism for explaining the observed degradation. The CRFI is also a promising parameter for quantifying neural bioeffects during exposure to pressure waves, and for predicting axon functionality.

Improved measurement of acoustic output using complex deconvolution of hydrophone sensitivity

The traditional method for calculating acoustic pressure amplitude is to divide a hydrophone output voltage measurement by the hydrophone sensitivity at the acoustic working frequency, but this approach neglects frequency dependence of hydrophone sensitivity. Another method is to perform a complex deconvolution between the hydrophone output waveform and the hydrophone impulse response (the inverse Fourier transform of the sensitivity). In this paper, the effects of deconvolution on measurements of peak compressional pressure (p+), peak rarefactional pressure (p-), and pulse intensity integral (PII) are studied. Time-delay spectrometry (TDS) was used to measure complex sensitivities from 1 to 40 MHz for 8 hydrophones used in medical ultrasound exposimetry. These included polyvinylidene fluoride (PVDF) spot-poled membrane, needle, capsule, and fiber-optic designs. Subsequently, the 8 hydrophones were used to measure a 4-cycle, 3 MHz pressure waveform mimicking a pulsed Doppler waveform. Acoustic parameters were measured for the 8 hydrophones using the traditional approach and deconvolution. Average measurements (across all 8 hydrophones) of acoustic parameters from deconvolved waveforms were 4.8 MPa (p+), 2.4 MPa (p-), and 0.21 mJ/cm2 (PII). Compared with the traditional method, deconvolution reduced the coefficient of variation (ratio of standard deviation to mean across all 8 hydrophones) from 29% to 8% (p+), 39% to 13% (p-), and 58% to 10% (PII).

Effect of ethanol injection on cavitation and heating of tissues exposed to high-intensity focused ultrasound

Cavitation activity and temperature rise have been investigated in a tissue-mimicking material and excised bovine liver treated with ethanol and insonated with a 0.825 MHz focused acoustic transducer. The acoustic power was varied from 1.3 to 26.8 W to find the threshold leading to the onset of inertial cavitation. Cavitation events were quantified by three independent techniques: B-mode ultrasound imaging, needle hydrophone measurements and passive cavitation detection. Temperature in or near the focal zone was measured by thermocouples embedded in the samples. The results of this study indicate that the treatment of tissue phantoms and bovine liver samples with ethanol reduces their threshold power for inertial cavitation. This in turn leads to a sudden rise in temperature in ethanol-treated samples at a lower acoustic power than that in untreated ones. The analysis of passive cavitation detection data shows that once the threshold acoustic power is reached, inertial cavitation becomes a major contributor to acoustic scattering in ethanol-treated phantoms and bovine liver samples as compared to control. This study opens up the possibility of improved tumor ablation therapy via a combination of percutaneous ethanol injection and high-intensity focused ultrasound.

Correction for frequency-dependent hydrophone response to nonlinear pressure waves using complex deconvolution and rarefactional filtering: application with fiber optic hydrophones

Nonlinear acoustic signals contain significant energy at many harmonic frequencies. For many applications, the sensitivity (frequency response) of a hydrophone will not be uniform over such a broad spectrum. In a continuation of a previous investigation involving deconvolution methodology, deconvolution (implemented in the frequency domain as an inverse filter computed from frequency-dependent hydrophone sensitivity) was investigated for improvement of accuracy and precision of nonlinear acoustic output measurements. Timedelay spectrometry was used to measure complex sensitivities for 6 fiber-optic hydrophones. The hydrophones were then used to measure a pressure wave with rich harmonic content. Spectral asymmetry between compressional and rarefactional segments was exploited to design filters used in conjunction with deconvolution. Complex deconvolution reduced mean bias (for 6 fiber-optic hydrophones) from 163% to 24% for peak compressional pressure (p+), from 113% to 15% for peak rarefactional pressure (p-), and from 126% to 29% for pulse intensity integral (PII). Complex deconvolution reduced mean coefficient of variation (COV) (for 6 fiber optic hydrophones) from 18% to 11% (p+), 53% to 11% (p-), and 20% to 16% (PII). Deconvolution based on sensitivity magnitude or the minimum phase model also resulted in significant reductions in mean bias and COV of acoustic output parameters but was less effective than direct complex deconvolution for p+ and p-. Therefore, deconvolution with appropriate filtering facilitates reliable nonlinear acoustic output measurements using hydrophones with frequency-dependent sensitivity.

Application of high-intensity focused ultrasound to the study of mild traumatic brain injury.

Though intrinsically of much higher frequency than open-field blast overpressures, high-intensity focused ultrasound (HIFU) pulse trains can be frequency modulated to produce a radiation pressure having a similar form. In this study, 1.5-MHz HIFU pulse trains of 1-ms duration were applied to intact skulls of mice in vivo and resulted in blood-brain barrier disruption and immune responses (astrocyte reactivity and microglial activation). Analyses of variance indicated that 24 h after HIFU exposure, staining density for glial fibrillary acidic protein was elevated in the parietal and temporal regions of the cerebral cortex, corpus callosum and hippocampus, and staining density for the microglial marker, ionized calcium binding adaptor molecule, was elevated 2 and 24 h after exposure in the corpus callosum and hippocampus (all statistical test results, p < 0.05). HIFU shows promise for the study of some bio-effect aspects of blast-related, non-impact mild traumatic brain injuries in animals.

Quantitative estimation of ultrasound beam intensities using infrared thermography—Experimental validation

Infrared (IR) thermography is a technique that has the potential to rapidly and noninvasively determine the intensity fields of ultrasound transducers. In the work described here, IR temperature measurements were made in a tissue phantom sonicated with a high-intensity focused ultrasound (HIFU) transducer, and the intensity fields were determined using a previously published mathematical formulation relating intensity to temperature rise at a tissue/air interface. Intensity fields determined from the IR technique were compared with those derived from hydrophone measurements. Focal intensities and beam widths determined via the IR approach agreed with values derived from hydrophone measurements to within a relative difference of less than 10%, for a transducer with a gain of 30, and about 13% for a transducer with a gain of 60. At axial locations roughly 1 cm in front (pre-focal) and behind (post-focal) the focus, the agreement with hydrophones for the lower-gain transducer remained comparable to that in the focal plane. For the higher-gain transducer, the agreement with hydrophones at the pre-focal and post-focal locations was around 40%.

Development and characterization of a blood mimicking fluid for high intensity focused ultrasound.

A blood mimicking fluid (BMF) has been developed for the acoustic and thermal characterizations of high intensity focused ultrasound (HIFU) ablation devices. The BMF is based on a degassed and de-ionized water solution dispersed with low density polyethylene microspheres, nylon particles, gellan gum, and glycerol. A broad range of physical parameters, including attenuation coefficient, speed of sound, viscosity, thermal conductivity, and diffusivity, were characterized as a function of temperature (20-70 degrees C). The nonlinear parameter B/A and backscatter coefficient were also measured at room temperature. Importantly, the attenuation coefficient is linearly proportional to the frequency (2-8 MHz) with a slope of about 0.2 dB cm(-1) MHz(-1) in the 20-70 degrees C range as in the case of human blood. Furthermore, sound speed and bloodlike backscattering indicate the usefulness of the BMF for ultrasound flow imaging and ultrasound-guided HIFU applications. Most of the other temperature-dependent physical parameters are also close to the reported values in human blood. These properties make it a unique HIFU research tool for developing standardized exposimetry techniques, validating numerical models, and determining the safety and efficacy of HIFU ablation devices.

Comparison between experimental and computational methods for the acoustic and thermal characterization of therapeutic ultrasound fields

For high intensity therapeutic ultrasound (HITU) devices, pre-clinical testing can include measurement of power, pressure/intensity and temperature distribution, acoustic and thermal simulations, and assessment of targeting accuracy and treatment monitoring. Relevant International Electrotechnical Commission documents recently have been published. However, technical challenges remain because of the often focused, large amplitude pressure fields encountered. Measurement and modeling issues include using hydrophones and radiation force balances at HITU power levels, validation of simulation models, and tissue-mimicking material (TMM) development for temperature measurements. To better understand these issues, a comparison study was undertaken between simulations and measurements of the HITU acoustic field distribution in water and TMM and temperature rise in TMM. For the specific conditions of this study, the following results were obtained. In water, the simulated values for p+ and p- were 3% lower and 10% higher, respectively, than those measured by hydrophone. In TMM, the simulated values for p+ and p- were 2% and 10% higher than those measured by hydrophone, respectively. The simulated spatial-peak temporal-average intensity values in water and TMM were greater than those obtained by hydrophone by 3%. Simulated and measured end-of-sonication temperatures agreed to within their respective uncertainties (coefficients of variation of approximately 20% and 10%, respectively).

Temperature Measurements in Tissue‐Mimicking Material during HIFU Exposure

Cavitation in high intensity focused ultrasound (HIFU) procedures can yield unpredictable results, particularly when the same location is targeted for more than several seconds. To study this effect, temperature rise was measured in tissue mimicking material (TMM) during HIFU exposures. A 50 um thin wire thermocouple (TC) was embedded in the center of a hydrogel‐based TMM that was previously developed for HIFU applications. HIFU at 825 kHz was focused at the TC junction. Thirty second HIFU exposures of increasing pressure from 1–7 MPa were applied and the temperature rise and decay during and after sonication were recorded. B‐mode imaging was used to monitor any cavitation activity during sonication. If cavitation was noted during the sonication, the sonication was repeated at the same pressure level two more times at 20 minute intervals in order to characterize the repeatability given that cavitation had occurred. The cavitation threshold of the TMM was determined to be approximately 3 MPa at 825 kHz. Te...

Evaluation of temperature rise in a tissue mimicking material during HIFU exposure

In pre-clinical testing it is essential to characterize clinical high intensity focused ultrasound (HIFU) devices using tissue-mimicking materials (TMMs) with well known characteristics, including temperature rise and cavitation properties. The purpose of this study was to monitor cavitation behavior and correlate its effect with temperature rise in a HIFU TMM containing an embedded thermocouple. A 75-μm fine wire thermocouple was embedded in a hydrogel-based TMM previously developed for HIFU. HIFU at 1.1 and 3.3 MHz was focused at the thermocouple junction. Focal pressures from 1-11 MPa were applied and the temperature profiles were recorded. Three hydrophones were used to monitor cavitation activity during sonication. A hydrophone confocal with the HIFU transducer and a cylindrical hydrophone lateral to the HIFU beam were used as passive cavitation detectors for spectral analysis of signals, and a needle hydrophone placed beyond the HIFU focus was used to record changes in the pressure amplitude due to blockage by bubbles at or near the focus. B-mode imaging scans were employed to visualize bubble presence during sonication. In a separate measurement, schlieren imaging was used to monitor the change in field distribution behind the TMM. All hydrophone methods correlated well with cavitation in the TMM.