Plasticity-Induced Effects of Theta Burst Transcranial Ultrasound Stimulation in Parkinson's Disease.

BACKGROUND: Low-intensity transcranial ultrasound stimulation (TUS) is a noninvasive brain stimulation (NIBS) technique with high spatial specificity. Previous studies showed that TUS delivered in a theta burst pattern (tbTUS) increased motor cortex (MI) excitability up to 30 minutes due to long-term potentiation (LTP)-like plasticity. Studies using other forms of NIBS suggested that cortical plasticity may be impaired in patients with Parkinson's disease (PD). OBJECTIVE: The aim was to investigate the neurophysiological effects of tbTUS in PD patients off and on dopaminergic medications compared to healthy controls. METHODS: We studied 20 moderately affected PD patients in on and off dopaminergic medication states (7 with and 13 without dyskinesia) and 17 age-matched healthy controls in a case-controlled study. tbTUS was applied for 80 seconds to the MI. Motor-evoked potentials (MEP), short-interval intracortical inhibition (SICI), and short-interval intracortical facilitation (SICF) were recorded at baseline, and at 5 minutes (T5), T30, and T60 after tbTUS. Motor Unified Parkinson's Disease Rating Scale (mUPDRS) was measured at baseline and T60. RESULTS: tbTUS significantly increased MEP amplitude at T30 compared to baseline in controls and in PD patients on but not in PD patients off medications. SICI was reduced in PD off medications compared to controls. tbTUS did not change in SICI or SICF. The bradykinesia subscore of mUPDRS was reduced at T60 compared to baseline in PD on but not in the off medication state. The presence of dyskinesia did not affect tbTUS-induced plasticity. CONCLUSIONS: tbTUS-induced LTP plasticity is impaired in PD patients off medications and is restored by dopaminergic medications. © 2024 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Mild hyperthermia with magnetic resonance- guided high intensity focused ultrasound combined with salvage chemoradiation for recurrent rectal cancer.

INTRODUCTION: Pelvic recurrences from rectal cancer present a challenging clinical scenario. Hyperthermia represents an innovative treatment option in combination with concurrent chemoradiation to enhance therapeutic effect. We provide the initial results of a prospective single center feasibility study (NCT02528175) for patients undergoing rectal cancer retreatment using concurrent chemoradiation and mild hyperthermia with MR-guided high intensity focused ultrasound (MR-HIFU). METHODS: All patients were deemed ineligible for salvage surgery and were evaluated in a multidisciplinary fashion with a surgical oncologist, radiation oncologist and medical oncologist. Radiation was delivered to a dose of 30.6 Gy in 1.8 Gy per fraction with concurrent capecitabine. MR-HIFU was delivered on days 1, 8 and 15 of concurrent chemoradiation. Our primary objective was feasibility and toxicity. RESULTS: Six patients (total 11 screened) were treated with concurrent chemoradiation and mild hyperthermia with MR-HIFU. Tumor size varied between 3.1-16.6 cm. Patients spent an average of 228 min in the MRI suite and sonication with the external transducer lasted an average of 35 min. There were no complications on the day of the MR-HIFU procedure and all acute toxicities (no grade >/=3 toxicities) resolved after completion of treatment. There were no late grade >/=3 toxicities. CONCLUSION: Mild hyperthermia with MR-HIFU, in combination with concurrent chemoradiation for appropriately selected patients, is safe for localized pelvic recurrences from rectal cancer. The potential for MR-HIFU to be applied in the recurrent setting in rectal cancer treatment requires further technical development and prospective evaluation.

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.

Motion compensation using principal component analysis and projection onto dipole fields for abdominal magnetic resonance thermometry.

PURPOSE: High intensity focused ultrasound (HIFU) has the potential to locally and non-invasively treat cancer with fewer side effects than alternative therapies. However, motion and tissue heterogeneity in the abdomen can compromise the HIFU focus and confound current thermometry methods. METHODS: The proposed thermometry method combines principal component analysis (PCA), as a multi-baseline technique, and projection onto dipole fields (PDF), as a near-referenceless method. PCA forgoes tracking tools by projecting incoming images onto a subspace spanning the motion history. PDF is subsequently used to synthesize the naturally feasible components of the residual phase using a magnetic dipole model. This leaves only the phase shifts that are induced by HIFU. RESULTS: With in vivo measurements, in porcine and human kidneys, the mean pixel-wise temperature SD was 0.86 ± 0.41°C in selected regions of interest (ROIs) across all data sets, without any user-interaction or supplementary tracking tools. This is an improvement over a benchmark hybrid method, which scored 1.36 ± 1.20°C on the same data. Uncorrected subtraction of the data yielded a score of 3.02 ± 2.87°C. CONCLUSION: The PCA-PDF hybrid method achieves superior artifact correction by exploiting the motion history and intrinsic magnetic susceptibility of the underlying tissue.

Magnetic Resonance-guided High-intensity Focused Ultrasound (MRgHIFU) Virtual Treatment Planning for Abdominal Neuroblastoma Utilizing Retrospective Diagnostic 3D CT Images.

Magnetic resonance-guided high-intensity focused ultrasound (MRgHIFU) is a novel treatment for neuroblastoma using ultrasound-induced thermal ablation with real-time MR thermometry. It is unclear which patients would be amenable to MRgHIFU given the retroperitoneal location of many neuroblastomas within the smaller pediatric abdomen. In addition, planning relies on MR scans, which are not routine in the standard pediatric neuroblastoma workup. This study sought to demonstrate that neuroblastomas are targetable with MRgHIFU and available computed tomographic imaging could be utilized for MRgHIFU virtual treatment. Cross-sectional images of 88 pediatric abdominal neuroblastoma patients were retrospectively processed with custom software to be made compatible with the Sonalleve MRgHIFU platform. Targetability measured percent treatment to lesion volume, within adequate safety margins from critical structures. All images were successfully converted into treatment planning files. Median lesion size was 191±195 cm and depth was 29±17 mm. Up to 78 (85%) patients had targetable lesions with a median targetable volume of 15% and ranging up to 79%. Targetability was highest in superficial, right upper quadrant lesions >200 cm, but limited by proximity to bowel and ribs. This study demonstrates the capacity for MRgHIFU to potentially treat the majority of abdominal neuroblastomas and the feasibility of using computed tomographic images for MRgHIFU virtual treatment planning.

Targeting feasibility evaluation of magnetic resonance-guided focused ultrasound in the management of osteomyelitis: a virtual treatment planning study in 75 patients.

Purpose: Osteomyelitis is one of the most serious complications linked to diabetes and increases the possibility of limb amputation considerably. There exists an important clinical need to improve management of osteomyelitis, especially for diabetic patients who are more susceptible to failures, relapses and chronicity of multiple bone infections. Magnetic resonance-guided focused ultrasound (MRgFUS) can offer a clinical management option for patients with osteomyelitis by providing a non-surgical and potentially rapid-recovery treatment option. Material and Methods: A retrospective study with patients with confirmed osteomyelitis (n = 75) was performed at evaluating the feasibility to target bone infection sites with a clinically approved MRgFUS device (Sonalleve, Profound Medical, Mississauga, ON, Canada). The developed methodology allows using preexisting diagnostic magnetic resonance imaging (MRI) or computed tomography (CT) scans to evaluate the treatment feasibility directly using a MRgFUS treatment planning software. Results: 74.7% of the cases included in our study passed the targetability criteria. Cases were deemed non-targetable if the target was less than 1 cm from the skin or close to a neuro-vascular bundle, metallic implants, or in the way of a defect in the overlying skin. For cases that passed the targetability criteria, an average among patients of 92.7 ± 5.2% of the gross treatment volume could be reached using treatment cells available at the Sonalleve system. Conclusion: The retrospective study presented here is the first step to demonstrate the feasibility of utilizing MRgFUS for the thermal treatment of osteomyelitis.

Superposition method for modelling boundaries between media in viscoelastic finite difference time domain simulations.

Finite-difference time domain (FDTD) techniques are widely used to model the propagation of viscoelastic waves through complex and heterogeneous structures. However, in the specific case of media mixing liquid and solid, attempts to model continuous media onto a Cartesian grid produces errors when the liquid-solid interface between different media do not align precisely with the Cartesian grid. The increase in spatial resolution required to eliminate this grid staircasing effect can be computationally prohibitive. Here, a modification to the Virieux staggered-grid FDTD scheme called the superposition method is presented. This method is intended to reduce this staircasing effect while keeping a manageable computational time. The method was validated by comparing low-spatial-resolution simulations against simulations with sufficiently high resolution to provide reasonably accurate results at any incident angle. The comparison of the root-mean-square of the stress amplitude maps showed that the amplitude of artifactual waves could be reduced by several orders of magnitude when compared to the Virieux staggered-grid FDTD method and that the superposition method helped to significantly reduce the staircasing effect in FDTD simulations.

Development of custom RF coils for use in a small animal platform for magnetic resonance-guided focused ultrasound hyperthermia compatible with a clinical MRI scanner.

Three different magnetic resonance imaging (MRI) coils were developed and assessed for use with an experimental platform designed to generate hyperthermia in mice using magnetic resonance-guided focused ultrasound (MRgFUS). An ergonomic animal treatment bed was integrated with MRI coils. Three different coil designs optimized for small targets were tested, and performance in targeting and conducting accurate temperature imaging was evaluated. Two transmit/receive surface coils of different diameters (4 and 7 cm) and a transmit-only/receive-only (TORO) coil were used. A software platform was developed to provide real-time targeting and temperature maps and to deliver controlled ultrasound exposure. MR thermometry was conducted on different targets, including fresh chicken breasts and mouse cadavers. Multiple experiments were performed in which tissues were targeted with high reproducibility. The TORO coil was the most resilient to temperature drift, resulting in an increase in the calculated temperature of 0.29 ± 0.12 °C, compared to 1.27 ± 0.13 °C and 0.47 ± 0.04 °C for the medium and small coils, respectively. Controlled closed-loop hyperthermia exposure was successfully performed with all three coils. Considering all assessments, the TORO coil exhibited the best overall performance for thermometry acquisition when accounting for stability, precision, temperature spread and resilience to temperature drift. B1 maps of the three coils confirmed that the TORO coil exhibited the most homogeneous B1 field, which explained the improved thermometry performance. The use of coils specifically designed for small targets within the proposed experimental platform allowed accurate thermometry during hyperthermia.

In vivo optimisation study for multi-baseline MR-based thermometry in the context of hyperthermia using MR-guided high intensity focused ultrasound for head and neck applications.

PURPOSE: In this in vivo study, the feasibility to perform hyperthermia treatments in the head and neck using magnetic resonance image-guided high intensity focused ultrasound (MRgHIFU) was established using a porcine acute model. MATERIALS AND METHODS: Porcine specimens with a weight between 17 and 18 kg were treated in the omohyoid muscle in the neck. Hyperthermia was applied with a target temperature of 41 °C for 30 min using a Sonalleve MRgHIFU system. MR-based thermometry was calculated using water-proton resonance frequency shift and multi-baseline look-up tables indexed by peak-to-peak displacement (Dpp) measurements using a pencil-beam navigator. Three hyperthermia experiments were conducted at different Dpp values of 0.2, 1.0 and 3.0 mm. An optimisation study was carried out to establish the optimal parameters controlling the multi-baseline method that ensured a minimisation of spatial-average peak-to-peak temperature (TSA-pp) and temperature direct current bias (TSA-DC). RESULTS: The multi-baseline technique reduced considerably the noise on both TSA-pp and TSA-DC. The reduction of noise was more important when Dpp was higher. For Dpp = 3 mm the average (±standard deviation (SD)) of TSA-pp and TSA-DC was reduced from 4.5 (± 2.5) and 2.5 (±0.6) °C, respectively, to 0.8 (± 0.7) and 0.09 (± 0.2) °C. CONCLUSIONS: This in vivo study showed the level of noise in PRFS-based thermometry introduced by respiratory motion in the context of MRgHIFU hyperthermia treatment for head and neck and the feasibility of reducing this noise using a multi-baseline technique.

High intensity focused ultrasound technology, its scope and applications in therapy and drug delivery.

Ultrasonography is a safe, inexpensive and wide-spread diagnostic tool capable of producing real-time non-invasive images without significant biological effects. However, the propagation of higher energy, intensity and frequency ultrasound waves through living tissues can induce thermal, mechanical and chemical effects useful for a variety of therapeutic applications. With the recent development of clinically approved High Intensity Focused Ultrasound (HIFU) systems, therapeutic ultrasound is now a medical reality. Indeed, HIFU has been used for the thermal ablation of pathological lesions; localized, minimally invasive ultrasound-mediated drug delivery through the transient formation of pores on cell membranes; the temporary disruption of skin and the blood brain barrier; the ultrasound induced break-down of blood clots; and the targeted release of drugs using ultrasound and temperature sensitive drug carriers. This review seeks to engage the pharmaceutical research community by providing an overview on the biological effects of ultrasound as well as highlighting important therapeutic applications, current deficiencies and future directions.

Biaxial Excitation and Reception Method Applied to Ultrasound Imaging.

The biaxial method consists of the utilization of orthogonal electric fields in single-element piezoceramics both in transmission and reception. This study demonstrates the application of the biaxial method to broadband transducers. We developed a three-element biaxial transducer array to demonstrate the feasibility of biaxial method in imaging applications. Finite element analysis was used to model the response of a single transducer element. An electric characterization was performed at each transducer element to determine their driving frequency. Each transducer was driven at 6.25 MHz and tested in different phases to determine the phase that produced the maximum pressure amplitude and shortest pulsewidth. Both simulations and experimental results showed that the acoustic pressure and half-pulsewidth followed a sinusoidal response as a function of the difference in phase applied to the lateral electrodes, as it has been described in our previous work. An imaging test was performed by placing a 0.36-mm diameter nylon wire 20 mm away from the transducer while driving and receiving each element with different combinations of conventional and biaxial driving. By applying a biaxial rephasing at the receiving electrodes during the data analysis, we obtained a maximum reduction in the axial resolution from 4.6 to 1.3 mm and signal-to-noise ratio (SNR) improvements from 15.2 to 24.4 dB, when compared to conventional driving.

A systematic review of preclinical and clinical transcranial ultrasound neuromodulation and opportunities for functional connectomics.

BACKGROUND: Low-intensity transcranial ultrasound has surged forward as a non-invasive and disruptive tool for neuromodulation with applications in basic neuroscience research and the treatment of neurological and psychiatric conditions. OBJECTIVE: To provide a comprehensive overview and update of preclinical and clinical transcranial low intensity ultrasound for neuromodulation and emphasize the emerging role of functional brain mapping to guide, better understand, and predict responses. METHODS: A systematic review was conducted by searching the Web of Science and Scopus databases for studies on transcranial ultrasound neuromodulation, both in humans and animals. RESULTS: 187 relevant studies were identified and reviewed, including 116 preclinical and 71 clinical reports with subjects belonging to diverse cohorts. Milestones of ultrasound neuromodulation are described within an overview of the broader landscape. General neural readouts and outcome measures are discussed, potential confounds are noted, and the emerging use of functional magnetic resonance imaging is highlighted. CONCLUSION: Ultrasound neuromodulation has emerged as a powerful tool to study and treat a range of conditions and its combination with various neural readouts has significantly advanced this platform. In particular, the use of functional magnetic resonance imaging has yielded exciting inferences into ultrasound neuromodulation and has the potential to advance our understanding of brain function, neuromodulatory mechanisms, and ultimately clinical outcomes. It is anticipated that these preclinical and clinical trials are the first of many; that transcranial low intensity focused ultrasound, particularly in combination with functional magnetic resonance imaging, has the potential to enhance treatment for a spectrum of neurological conditions.

Microbubble-enhanced transcranial MR-guided focused ultrasound brain hyperthermia: heating mechanism investigation using finite element method.

Recently, our group developed a synergistic brain drug delivery method to achieve simultaneous transcranial hyperthermia and localized blood-brain barrier opening via MR-guided focused ultrasound (MRgFUS). In a rodent model, we demonstrated that the ultrasound power required for transcranial MRgFUS hyperthermia was significantly reduced by injecting microbubbles (MBs). However, the specific mechanisms underlying the power reduction caused by MBs remain unclear. The present study aims to elucidate the mechanisms of MB-enhanced transcranial MRgFUS hyperthermia through numerical studies using the finite element method. The microbubble acoustic emission (MAE) and the viscous dissipation (VD) were hypothesized to be the specific mechanisms. Acoustic wave propagation was used to model the FUS propagation in the brain tissue, and a bubble dynamics equation for describing the dynamics of MBs with small shell thickness was used to model the MB oscillation under FUS exposures. A modified bioheat transfer equation was used to model the temperature in the rodent brain with different heat sources. A theoretical model was used to estimate the bubble shell's surface tension, elasticity, and viscosity losses. The simulation reveals that MAE and VD caused a 40.5% and 52.3% additional temperature rise, respectively. Compared with FUS only, MBs caused a 64.0% temperature increase, which is consistent with our previous animal experiments. Our investigation showed that MAE and VD are the main mechanisms of MB-enhanced transcranial MRgFUS hyperthermia.

An intraoperative accelerometry and real-time analysis tool for magnetic resonance-guided focused ultrasound thalamotomy.

Magnetic resonance-guided focused ultrasound (MRgFUS) is one of the newest surgical treatments for essential tremor (ET). During this procedure, a lesion is created within the thalamus to mitigate tremor. Targeting is done using a combination of stereotaxy, MR tractography, and sublesional heating, with tremor assessed during the procedure to gauge therapeutic effectiveness. Currently, tremor assessments are done qualitatively, but this approach requires the tremor change to be above a subjective threshold and provides no objective record of surgical tremor progression. Here, the authors present and demonstrate an MR-compatible accelerometer with custom MATLAB analysis code and graphical user interface to record, visualize, and quantify tremor in near real-time. Results can be exported and saved for future review. This method was used in 20 surgeries, with patients experiencing a 50.7% (95% CI -64.1% to -37.3%) improvement in the treated limb per the Clinical Rating Scale for Tremor. This method does not interrupt the surgery and is quantitative. As research on optimizing MRgFUS treatment for ET continues-for example, the refinement of targeting during sublesional sonications-such quantifying and recording of tremor changes will provide rapid and objective feedback.

The effect of transcranial ultrasound pulse repetition frequency on sustained inhibition in the human primary motor cortex: A double-blind, sham-controlled study.

BACKGROUND: Non-invasive brain stimulation techniques such as transcranial magnetic stimulation and transcranial direct current stimulation hold promise for inducing brain plasticity. However, their limited precision may hamper certain applications. In contrast, Transcranial Ultrasound Stimulation (TUS), known for its precision and deep brain targeting capabilities, requires further investigation to establish its efficacy in producing enduring effects for treating neurological and psychiatric disorders. OBJECTIVE: To investigate the enduring effects of different pulse repetition frequencies (PRF) of TUS on motor corticospinal excitability. METHODS: T1-, T2-weighted, and zero echo time magnetic resonance imaging scans were acquired from 21 neurologically healthy participants for neuronavigation, skull reconstruction, and the performance of transcranial ultrasound and thermal modelling. The effects of three different TUS PRFs (10, 100, and 1000 Hz) with a constant duty cycle of 10 % on corticospinal excitability in the primary motor cortex were assessed using TMS-induced motor evoked potentials (MEPs). Each PRF and sham condition was evaluated on separate days, with measurements taken 5-, 30-, and 60-min post-TUS. RESULTS: A significant decrease in MEP amplitude was observed with a PRF of 10 Hz (p = 0.007), which persisted for at least 30 min, and with a PRF of 100 Hz (p = 0.001), lasting over 60 min. However, no significant changes were found for the PRF of 1000 Hz and the sham conditions. CONCLUSION: This study highlights the significance of PRF selection in TUS and underscores its potential as a non-invasive approach to reduce corticospinal excitability, offering valuable insights for future clinical applications.

BabelBrain: An Open-Source Application for Prospective Modeling of Transcranial Focused Ultrasound for Neuromodulation Applications.

BabelBrain is an open-source standalone graphic-user-interface application designed for studies of neuromodulation using transcranial-focused ultrasound (FUS). It calculates the transmitted acoustic field in the brain tissue, taking into account the distortion effects caused by the skull barrier. The simulation is prepared using scans from magnetic resonance imaging (MRI) and, if available, computed tomography (CT) and zero-echo time MRI scans. It also calculates the thermal effects based on a given ultrasound regime, such as the total duration of exposure, the duty cycle, and acoustic intensity. The tool is designed to work in tandem with neuronavigation and visualization software, such as 3-DSlicer. It uses image processing to prepare domains for ultrasound simulation and uses the BabelViscoFDTD library for transcranial modeling calculations. BabelBrain supports multiple GPU backends, including Metal, OpenCL, and CUDA, and works on all major operating systems including Linux, macOS, and Windows. This tool is particularly optimized for Apple ARM64 systems, which are common in brain imaging research. The article presents the modeling pipeline used in BabelBrain and a numerical study where different methods of acoustic properties mapping were tested to select the best method that can reproduce the transcranial pressure transmission efficiency reported in the literature.

Higher harmonics dynamic focalization in single-element ring transducers using biaxial driving.

Biaxial driving is a new driving technique that allows the steering of the ultrasound field generated by a single-element piezoceramic transducer. Because of their natural axisymmetric geometry, ultrasound generation with ring transducers can take advantage of the biaxial driving to change the focus of the beam generated by this type of transducer using only two driving signals. In this study, we applied the biaxial driving technique into a single-element PZT ring transducer operating at 500 kHz to produce a change in size and position of the focal spot while using the 1st (482 kHz), 3rd (1.362 MHz) and 5th (2.62 MHz) harmonic excitation. The transducer had a thickness of 2.85 mm, an inner diameter of 9.75 mm and a ring width of 2.0 mm, and two pairs of electrodes as required for biaxial driving. Simulation and experimental results showed that both the focal area and the distance at which the focal area centre was located changed as a function of the phase and power difference between the two driving signals. Experimental results showed that the focal area could be reduced from 31.6 mm2 (conventional driving) to 3.4 mm2 (89 % reduction) when using the first harmonic excitation. For the third harmonic, the focal area could be reduced from 4.0 mm2 (conventional driving) to 3.3 mm2 (17.5 % reduction). For the fifth harmonic, the focal area could be reduced from 1.7 mm2 (conventional driving) to 1 mm2 (41.7 % reduction). Results also demonstrated the centre of the focus could be displaced between 3.0 mm and 9.3 mm from the surface of the transducer when using the first harmonic, between 7.3 mm and 8.4 mm at the third harmonic, and between 4.9 mm and 8.2 mm at the fifth harmonic. The reduction in the focus area, as well as the possibility to displace the focus dynamically will be advantageous for preclinical applications of focused ultrasound, especially on drug delivery and neuromodulation studies in small rodents.

Passive Directivity Detection Using Individual Biaxial Ultrasound Transducers.

Biaxial transducers are an emerging technology that can steer generated ultrasound waves using a single piezoceramic component. Simulations have also shown that biaxial transducers can passively estimate the direction of arrival (DOA) of sound waves when operating in the receive mode. This research seeks to experimentally verify biaxial directivity estimates and establish directivity as an independent parameter detected by biaxial transducers. Three cuboid ( 3.84×3.84×5.92 mm) biaxial piezoceramics with two pairs of orthogonal electrodes (one pair applied laterally and one pair applied in the polling direction) were manufactured and characterized. Each transducer was placed in a water tank where an independent hemispherical source was attached to a moveable arm and operated at 250 kHz. Terminal voltages were recorded for 81 source positions in a plane parallel to the transducer's front face and at a depth of approximately 9 cm. Collection was repeated three times per transducer to ensure reproducibility. In silico results were compared with the experimental results. Two derived metrics were then calculated using both the forward and lateral terminal voltages: the phase difference and amplitude ratio. Biaxial transducers demonstrate an ability to estimate the DOA of incident sound waves, independently of any time-of-flight (TOF) information. The phase difference and amplitude ratio complement each other to provide statistically significant and repeatable estimates over a range of 48° (from -24° to +24°). These results can be used to augment a variety of medical, geophysical, and industrial passive ultrasound imaging techniques.

Biaxial ultrasound driving technique for small animal blood-brain barrier opening.

Biaxial driving can more efficiently convert electrical power to forward acoustic power in piezoelectric materials, and the interaction between the orthogonal electric fields can produce a combination of extensional and shear deformations as a function of the phase difference between them to allow dynamic steering of the beam with a single-element. In this study, we demonstrate for the first time the application of a single-element biaxially driven ring transducerin vivofor blood-brain barrier opening in mice, and compare it to that achieved with a conventional single-element highly focused (F# = 0.7) spherical transducer operating at a similar frequency. Transcranial focused ultrasound (0.45 MPa, 10 ms pulse length, 1 Hz repetition frequency, 30 s duration) was applied bilaterally to mice with a 40µl/kg bolus of DefinityTMmicrobubbles, employing either a single-element biaxial ring (1.482 MHz, 10 mm inner diameter, 13.75 mm outer diameter) or spherical (1.5 MHz, 35 mm diameter, F# = 0.7; RK50, FUS Instruments) transducer on each side. Follow-up MRI scans (T1 pre- and post- 0.2 mmol/kg Gd injection, T2) were acquired to assess blood-brain barrier opening volume and potential damage. Compared to blood-brain barrier opening achieved with a conventional single-element spherical focused transducer, the opening volume achieved with a single-element biaxial ring transducer was 35% smaller (p= 0.002) with a device of a ring diameter of 40% the aperture size. Axial refocusing was further demonstrated with the single-element biaxial ring transducer, yielding a 1.63 mm deeper, five-fold larger opening volume (p= 0.048) relative to its small-focus mode. The biaxial ring transducer achieved a more localized opening compared to the spherical focused transducer under the same parameters, and further enabled dynamic axial refocusing with a single-element transducer with a smaller fabrication footprint.

An adaptive targeting algorithm for magnetic resonance-guided high-intensity focused ultrasound controlled hyperthermia.

BACKGROUND: Mild hyperthermia has been demonstrated to improve the efficacy of chemotherapy, radiation, and immunotherapy in various cancer types. One localized, non-invasive method of administering mild hyperthermia is magnetic resonance-guided high-intensity focused ultrasound (MRgHIFU). However, challenges for ultrasound such as beam deflection, refraction and coupling issues may result in a misalignment of the HIFU focus and the tumor during hyperthermia. Currently, the best option is to stop the treatment, wait for the tissue to cool, and redo the treatment planning before restarting the hyperthermia. This current workflow is both time-consuming and unreliable. PURPOSE: An adaptive targeting algorithm was developed for MRgHIFU controlled hyperthermia treatments for cancer therapeutics. This algorithm executes in real time while hyperthermia is being administered to ensure that the focus is within our target region. If a mistarget is detected, the HIFU system will electronically steer the focus of the HIFU beam to the correct target. The goal of this study was to quantify the accuracy and precision of the adaptive targeting algorithm's ability to correct a purposely misplanned hyperthermia treatment in real-time using a clinical MRgHIFU system. METHODS: A gelatin phantom with acoustic properties matched to the average speed of sound in human tissue was used to test the adaptive targeting algorithm's accuracy and precision. The target was purposely offset 10 mm away from the focus at the origin, in four orthogonal directions, allowing the algorithm to correct for this mistarget. In each direction, 10 data sets were collected for a total sample size of 40. Hyperthermia was administered with a target temperature set at 42°C. The adaptive targeting algorithm was run during the hyperthermia treatment and 20 thermometry images were collected after the beam steering occurred. The location of the focus was quantified by calculating the center of heating on the MR thermometry data. RESULTS: The average calculated trajectory passed to the HIFU system was 9.7 mm ± 0.4 mm where the target trajectory was 10 mm. The accuracy of the adaptive targeting algorithm after the beam steering correction was 0.9 mm and the precision was 1.6 mm. CONCLUSION: The adaptive targeting algorithm was implemented successfully and was able to correct the 10 mm mistargets with high accuracy and precision in gelatin phantoms. The results demonstrate the capability to correct the MRgHIFU focus location during controlled hyperthermia.