Strategies and safety simulations for ultrasonic cervical spinal cord neuromodulation.

Objective. Focused ultrasound spinal cord neuromodulation has been demonstrated in small animals. However, most of the tested neuromodulatory exposures are similar in intensity and exposure duration to the reported small animal threshold for possible spinal cord damage. All efforts must be made to minimize the risk and assure the safety of potential human studies, while maximizing potential treatment efficacy. This requires an understanding of ultrasound propagation and heat deposition within the human spine.Approach. Combined acoustic and thermal modelling was used to assess the pressure and heat distributions produced by a 500 kHz source focused to the C5/C6 level via two approaches (a) the posterior acoustic window between vertebral posterior arches, and (b) the lateral intervertebral foramen from which the C6 spinal nerve exits. Pulse trains of fifty 0.1 s pulses (pulse repetition frequency: 0.33 Hz, free-field spatial peak pulse-averaged intensity: 10 W cm-2) were simulated for four subjects and for ±10 mm translational and ±10∘rotational source positioning errors.Main results.Target pressures ranged between 20%-70% of free-field spatial peak pressures with the posterior approach, and 20%-100% with the lateral approach. When the posterior source was optimally positioned, peak spine heating values were below 1 ∘C, but source mispositioning resulted in bone heating up to 4 ∘C. Heating with the lateral approach did not exceed 2 ∘C within the mispositioning range. There were substantial inter-subject differences in target pressures and peak heating values. Target pressure varied three to four-fold between subjects, depending on approach, while peak heating varied approximately two-fold between subjects. This results in a nearly ten-fold range between subjects in the target pressure achieved per degree of maximum heating.Significance. This study highlights the utility of trans-spine ultrasound simulation software and need for precise source-anatomy positioning to assure the subject-specific safety and efficacy of focused ultrasound spinal cord therapies.

ITRUSST consensus on standardised reporting for transcranial ultrasound stimulation.

As transcranial ultrasound stimulation (TUS) advances as a precise, non-invasive neuromodulatory method, there is a need for consistent reporting standards to enable comparison and reproducibility across studies. To this end, the International Transcranial Ultrasonic Stimulation Safety and Standards Consortium (ITRUSST) formed a subcommittee of experts across several domains to review and suggest standardised reporting parameters for low intensity TUS, resulting in the guide presented here. The scope of the guide is limited to reporting the ultrasound aspects of a study. The guide and supplementary material provide a simple checklist covering the reporting of: (1) the transducer and drive system, (2) the drive system settings, (3) the free field acoustic parameters, (4) the pulse timing parameters, (5) in situ estimates of exposure parameters in the brain, and (6) intensity parameters. Detailed explanations for each of the parameters, including discussions on assumptions, measurements, and calculations, are also provided.

Review of the Low-Temperature Acoustic Properties of Water, Aqueous Solutions, Lipids, and Soft Biological Tissues.

Existing data on the acoustic properties of low-temperature biological materials is limited and widely dispersed across fields. This makes it difficult to employ this information in the development of ultrasound applications in the medical field, such as cryosurgery and rewarming of cryopreserved tissues. In this review, the low-temperature acoustic properties of biological materials, and the measurement methods used to acquire them were collected from a range of scientific fields. The measurements were reviewed from the acoustic setup to thermal methodologies for samples preparation, temperature monitoring, and system insulation. The collected data contain the longitudinal and shear velocity, and attenuation coefficient of biological soft tissues and biologically relevant substances-water, aqueous solutions, and lipids-in the temperature range down to -50 °C and in the frequency range from 108 kHz to 25 MHz. The multiple reflection method (MRM) was found to be the preferred method for low-temperature samples, with a buffer rod inserted between the transducer and sample to avoid direct contact. Longitudinal velocity changes are observed through the phase transition zone, which is sharp in pure water, and occurs more slowly and at lower temperatures with added solutes. Lipids show longer transition zones with smaller sound velocity changes; with the longitudinal velocity changes observed during phase transition in tissues lying between these two extremes. More general conclusions on the shear velocity and attenuation coefficient at low-temperatures are restricted by the limited data. This review enhance knowledge guiding for further development of ultrasound applications in low-temperature biomedical fields, and may help to increase the precision and standardization of low-temperature acoustic property measurements.

ITRUSST Consensus on Standardised Reporting for Transcranial Ultrasound Stimulation.

As transcranial ultrasound stimulation (TUS) advances as a precise, non-invasive neuromodulatory method, there is a need for consistent reporting standards to enable comparison and reproducibility across studies. To this end, the International Transcranial Ultrasonic Stimulation Safety and Standards Consortium (ITRUSST) formed a subcommittee of experts across several domains to review and suggest standardised reporting parameters for low intensity TUS, resulting in the guide presented here. The scope of the guide is limited to reporting the ultrasound aspects of a study. The guide and supplementary material provide a simple checklist covering the reporting of: (1) the transducer and drive system, (2) the drive system settings, (3) the free field acoustic parameters, (4) the pulse timing parameters, (5) in situ estimates of exposure parameters in the brain, and (6) intensity parameters. Detailed explanations for each of the parameters, including discussions on assumptions, measurements, and calculations, are also provided.

Safety Review of Therapeutic Ultrasound for Spinal Cord Neuromodulation and Blood-Spinal Cord Barrier Opening.

New focused ultrasound spinal cord applications have emerged, particularly those improving therapeutic agent delivery to the spinal cord via blood-spinal cord barrier opening and the neuromodulation of spinal cord tracts. One hurdle in the development of these applications is safety. It may be possible to use safety trends from seminal and subsequent works in focused ultrasound to guide the development of safety guidelines for spinal cord applications. We collated data from decades of pre-clinical studies and illustrate a clear relationship between damage, time-averaged spatial peak intensity and exposure duration. This relationship suggests a thermal mechanism underlies ultrasound-induced spinal cord damage. We developed minimum and mean thresholds for damage from these pre-clinical studies. When these thresholds were plotted against the parameters used in recent pre-clinical ultrasonic spinal cord neuromodulation studies, the majority of the neuromodulation studies were near or above the minimum threshold. This suggests that a thermal neuromodulatory effect may exist for ultrasonic spinal cord neuromodulation, and that the thermal dose must be carefully controlled to avoid damage to the spinal cord. By contrast, the intensity-exposure duration threshold had no predictive value when applied to blood-spinal cord barrier opening studies that employed injected contrast agents. Most blood-spinal cord barrier opening studies observed slight to severe damage, except for small animal studies that employed an active feedback control method to limit pressures based on measured bubble oscillation behavior. The development of new focused ultrasound spinal cord applications perhaps reflects the recent success in the development of focused ultrasound brain applications, and recent work has begun on the translation of these technologies from brain to spinal cord. However, a great deal of work remains to be done, particularly with respect to developing and accepting safety standards for these applications.

A head template for computational dose modelling for transcranial focused ultrasound stimulation.

Transcranial focused Ultrasound Stimulation (TUS) at low intensities is emerging as a novel non-invasive brain stimulation method with higher spatial resolution than established transcranial stimulation methods and the ability to selectively stimulate also deep brain areas. Accurate control of the focus position and strength of the TUS acoustic waves is important to enable a beneficial use of the high spatial resolution and to ensure safety. As the human skull causes strong attenuation and distortion of the waves, simulations of the transmitted waves are needed to accurately determine the TUS dose distribution inside the cranial cavity. The simulations require information of the skull morphology and its acoustic properties. Ideally, they are informed by computed tomography (CT) images of the individual head. However, suited individual imaging data is often not readily available. For this reason, we here introduce and validate a head template that can be used to estimate the average effects of the skull on the TUS acoustic wave in the population. The template was created from CT images of the heads of 29 individuals of different ages (between 20-50 years), gender and ethnicity using an iterative non-linear co-registration procedure. For validation, we compared acoustic and thermal simulations based on the template to the average of the simulation results of all 29 individual datasets. Acoustic simulations were performed for a model of a focused transducer driven at 500 kHz, placed at 24 standardized positions by means of the EEG 10-10 system. Additional simulations at 250 kHz and 750 kHz at 16 of the positions were used for further confirmation. The amount of ultrasound-induced heating at 500 kHz was estimated for the same 16 transducer positions. Our results show that the template represents the median of the acoustic pressure and temperature maps from the individuals reasonably well in most cases. This underpins the usefulness of the template for the planning and optimization of TUS interventions in studies of healthy young adults. Our results further indicate that the amount of variability between the individual simulation results depends on the position. Specifically, the simulated ultrasound-induced heating inside the skull exhibited strong interindividual variability for three posterior positions close to the midline, caused by a high variability of the local skull shape and composition. This should be taken into account when interpreting simulation results based on the template.

open-UST: An Open-Source Ultrasound Tomography Transducer Array System.

Fast imaging methods are needed to promote clinical adoption of ultrasound tomography (UST), and more widely available UST hardware could support the experimental validation of new measurement configurations. In this work, an open-source 256-element transducer ring array was developed (morganjroberts.github. io/open-UST) and manufactured using rapid prototyping, for only £2k. Novel manufacturing techniques were used, resulting in a 1.17° mean beam axis skew angle, a [Formula: see text] mean element position error, and a [Formula: see text] deviation in matching layer thickness. The nominal acoustic performance was measured using hydrophone scans and watershot data, and the 61.2 dB signal-to-noise ratio (SNR), 55.4° opening angle, 10.2 mm beamwidth, and 54% transmit-receive bandwidth (-12 dB) were found to be similar to existing systems and compatible with state-of-the-art full-waveform-inversion image reconstruction methods. The interelement variation in acoustic performance was typically < 10% without using normalization, meaning that the elements can be modeled identically during image reconstruction, removing the need for individual source definitions based on hydrophone measurements. Finally, data from a phantom experiment were successfully reconstructed. These results demonstrate that the open-UST system is accessible for users and is suitable for UST imaging research.

Transcranial ultrasound simulation with uncertainty estimation.

Transcranial ultrasound simulations are increasingly used to predict in situ exposure parameters for ultrasound therapies in the brain. However, there can be considerable uncertainty in estimating the acoustic medium properties of the skull and brain from computed tomography (CT) images. This paper shows how the resulting uncertainty in the simulated acoustic field can be predicted in a computationally efficient way using linear uncertainty propagation. Results for a representative transcranial simulation using a focused bowl transducer at 500 kHz show good agreement with unbiased uncertainty estimates obtained using Monte Carlo.

A learned Born series for highly-scattering media.

A new method for solving the wave equation is presented, called the learned Born series (LBS), which is derived from a convergent Born series but its components are found through training. The LBS is shown to be significantly more accurate than the convergent Born series for the same number of iterations, in the presence of high contrast scatterers, while maintaining a comparable computational complexity. The LBS is able to generate a reasonable prediction of the global pressure field with a small number of iterations, and the errors decrease with the number of learned iterations.

Experiments and simulations demonstrating the rapid ultrasonic rewarming of frozen tissue cryovials.

The development of methods to safely rewarm large cryopreserved biological samples remains a barrier to the widespread adoption of cryopreservation. Here, experiments and simulations were performed to demonstrate that ultrasound can increase rewarming rates relative to thermal conduction alone. An ultrasonic rewarming setup based on a custom 444 kHz tubular piezoelectric transducer was designed, characterized, and tested with 2 ml cryovials filled with frozen ground beef. Rewarming rates were characterized in the -20 °C to 5 °C range. Thermal conduction-based rewarming was compared to thermal conduction plus ultrasonic rewarming, demonstrating a tenfold increase in rewarming rate when ultrasound was applied. The maximum recorded rewarming rate with ultrasound was 57° C/min, approximately 2.5 times faster than with thermal conduction alone. Coupled acoustic and thermal simulations were developed and showed good agreement with the heating rates demonstrated experimentally and were also used to demonstrate spatial heating distributions with small (<3° C) temperature differentials throughout the sample when the sample was below 0° C. The experiments and simulations demonstrate the potential for ultrasonic cryovial rewarming with a possible application to large volume rewarming, as faster rewarming rates may improve the viability of cryopreserved tissues and reduce the time needed for cells to regain normal function.

Benchmark problems for transcranial ultrasound simulation: Intercomparison of compressional wave models.

Computational models of acoustic wave propagation are frequently used in transcranial ultrasound therapy, for example, to calculate the intracranial pressure field or to calculate phase delays to correct for skull distortions. To allow intercomparison between the different modeling tools and techniques used by the community, an international working group was convened to formulate a set of numerical benchmarks. Here, these benchmarks are presented, along with intercomparison results. Nine different benchmarks of increasing geometric complexity are defined. These include a single-layer planar bone immersed in water, a multi-layer bone, and a whole skull. Two transducer configurations are considered (a focused bowl and a plane piston operating at 500 kHz), giving a total of 18 permutations of the benchmarks. Eleven different modeling tools are used to compute the benchmark results. The models span a wide range of numerical techniques, including the finite-difference time-domain method, angular spectrum method, pseudospectral method, boundary-element method, and spectral-element method. Good agreement is found between the models, particularly for the position, size, and magnitude of the acoustic focus within the skull. When comparing results for each model with every other model in a cross-comparison, the median values for each benchmark for the difference in focal pressure and position are less than 10% and 1 mm, respectively. The benchmark definitions, model results, and intercomparison codes are freely available to facilitate further comparisons.

On-the-Fly Calculation of Time-Averaged Acoustic Intensity in Time-Domain Ultrasound Simulations Using a k-Space Pseudospectral Method.

This article presents a method to calculate the average acoustic intensity during ultrasound simulation using a new approach that exploits compression of intermediate results. One of the applications of high-intensity focused ultrasound (HIFU) simulations is the calculation of the thermal dose, which indicates the amount of tissue destroyed using a state-of-the-art k-space pseudospectral method. The thermal simulation is preceded by the calculation of the average intensity within the acoustic simulation. Due to the time staggering between the particle velocity and the acoustic pressure used in such simulations, the average intensity calculation is typically executed offline after the acoustic simulation consuming both disk space and time (the data can spread over terabytes). Our new approach calculates the average intensity during the acoustic simulation using the output coefficients of a new compression method which enables resolving the time staggering on-the-fly with huge disk space savings. To reduce RAM requirements, the article also presents a new 40-bit method for encoding compression complex coefficients. Experimental numerical simulations with the proposed method have shown that disk space requirements are up to 99% lower. The simulation speed was not significantly affected by the approach and the compression error did not affect the prediction accuracy of the thermal dose. From the standpoint of supercomputers, the new approach is significantly more economical. Saving computing resources increases the chances of real use of acoustic simulations in practice. The method can be applied to signals of a similar character, e.g., for electromagnetic radio waves.

Classical and Learned MR to Pseudo-CT Mappings for Accurate Transcranial Ultrasound Simulation.

Model-based treatment planning for transcranial ultrasound therapy typically involves mapping the acoustic properties of the skull from an X-ray computed tomography (CT) image of the head. Here, three methods for generating pseudo-CT (pCT) images from magnetic resonance (MR) images were compared as an alternative to CT. A convolutional neural network (U-Net) was trained on paired MR-CT images to generate pCT T images from either T1-weighted or zero-echo time (ZTE) MR images (denoted tCT and zCT, respectively). A direct mapping from ZTE to pCT was also implemented (denoted cCT). When comparing the pCT and ground-truth CT images for the test set, the mean absolute error was 133, 83, and 145 Hounsfield units (HU) across the whole head, and 398, 222, and 336 HU within the skull for the tCT, zCT, and cCT images, respectively. Ultrasound simulations were also performed using the generated pCT images and compared to simulations based on CT. An annular array transducer was used targeting the visual or motor cortex. The mean differences in the simulated focal pressure, focal position, and focal volume were 9.9%, 1.5 mm, and 15.1% for simulations based on the tCT images; 5.7%, 0.6 mm, and 5.7% for the zCT; and 6.7%, 0.9 mm, and 12.1% for the cCT. The improved results for images mapped from ZTE highlight the advantage of using imaging sequences, which improves the contrast of the skull bone. Overall, these results demonstrate that acoustic simulations based on MR images can give comparable accuracy to those based on CT.

Measurement of the ultrasound attenuation and dispersion in 3D-printed photopolymer materials from 1 to 3.5 MHz.

Over the past decade, the range of applications in biomedical ultrasound exploiting 3D printing has rapidly expanded. For wavefront shaping specifically, 3D printing has enabled a diverse range of new, low-cost approaches for controlling acoustic fields. These methods rely on accurate knowledge of the bulk acoustic properties of the materials; however, to date, robust knowledge of these parameters is lacking for many materials that are commonly used. In this work, the acoustic properties of eight 3D-printed photopolymer materials were characterised over a frequency range from 1 to 3.5 MHz. The properties measured were the frequency-dependent phase velocity and attenuation, group velocity, signal velocity, and mass density. The materials were fabricated using two separate techniques [PolyJet and stereolithograph (SLA)], and included Agilus30, FLXA9960, FLXA9995, Formlabs Clear, RGDA8625, RGDA8630, VeroClear, and VeroWhite. The range of measured density values across all eight materials was 1120-1180 kg · m-3, while the sound speed values were between 2020 to 2630 m · s-1, and attenuation values typically in the range 3-9 dB · MHz-1· cm-1.

Modelling and measurement of laser-generated focused ultrasound: Can interventional transducers achieve therapeutic effects?

Laser-generated focused ultrasound (LGFU) transducers used for ultrasound therapy commonly have large diameters (6-15 mm), but smaller lateral dimensions (<4 mm) are required for interventional applications. To address the question of whether miniaturized LGFU transducers could generate sufficient pressure at the focus to enable therapeutic effects, a modelling and measurement study is performed. Measurements are carried out for both linear and nonlinear propagation for various illumination schemes and compared with the model. The model comprises several innovations. First, the model allows for radially varying acoustic input distributions on the surface of the LGFU transducer, which arise from the excitation light impinging on the curved transducer surfaces. This realistic representation of the source prevents the overestimation of the achievable pressures (shown here to be as high as 1.8 times). Second, an alternative inverse Gaussian illumination paradigm is proposed to achieve higher pressures; a 35% increase is observed in the measurements. Simulations show that LGFU transducers as small as 3.5 mm could generate sufficient peak negative pressures at the focus to exceed the cavitation threshold in water and blood. Transducers of this scale could be integrated with interventional devices, thereby opening new opportunities for therapeutic applications from inside the body.

Measurement and simulation of steered acoustic fields generated by a multielement array for therapeutic ultrasound.

Modelling of fields generated by therapeutic ultrasound arrays can be prone to errors arising from differences from nominal transducer parameters, and variations in relative outputs of array elements when driven under different conditions, especially when simulating steered fields. Here, the effect of element size, element positions, relative source pressure variations, and electrical crosstalk on the accuracy of modelling pressure fields generated by a 555 kHz 32-element ultrasonic array were investigated. For this transducer, errors in pressure amplitude and focal position were respectively reduced from 20% to 4% and 3.3 mm to 1.5 mm using crosstalk prediction, and experimentally determined positions.

Measurement of the temperature-dependent output of lead zirconate titanate transducers.

The effect of temperature and electrical drive conditions on the output of lead zirconate titanate (PZT) transducers is of particular interest in ultrasound metrology and medical ultrasound applications. In this work, the temperature-dependent output of two single-element PZT transducers was measured between 22 °C and 46 °C. Two independent measurement methods were used, namely radiation force balance measurements and laser vibrometry. When driven at constant voltage using a 50 Ω matched signal generator and amplifier using continuous wave (CW) or quasi-CW excitation, the output of the two transducers increased on average by 0.6 % per degree, largely due to an increase in transducer efficiency with temperature. The two measurement methods showed close agreement. Similar trends were observed when using single cycle excitation with the same signal chain. However, when driven using a pulser (which is not electrically matched), the two transducers exhibited different behaviour depending on their electrical impedance. Accounting for the temperature-dependent output of PZT transducers could have implications for many areas of ultrasound metrology, for example, in therapeutic ultrasound where a coupling fluid at an increased or decreased temperature is often used.