Comparison Between Ray-Tracing and Full-Wave Simulation for Transcranial Ultrasound Focusing on a Clinical System Using the Transfer Matrix Formalism.

Only one high-intensity focused ultrasound device has been clinically approved for transcranial brain surgery at the time of writing. The device operates within 650 and 720 kHz and corrects the phase distortions induced by the skull of each patient using a multielement phased array. Phase correction is estimated adaptively using a proprietary algorithm based on computed-tomography (CT) images of the patient's skull. In this article, we assess the performance of the phase correction computed by the clinical device and compare it to: 1) the correction obtained with a previously validated full-wave simulation algorithm using an open-source pseudo-spectral toolbox and 2) a hydrophone-based correction performed invasively to measure the aberrations induced by the skull at 650 kHz. For the full-wave simulation, three different mappings between CT Hounsfield units and the longitudinal speed of sound inside the skull were tested. All methods are compared with the exact same setup due to transfer matrices acquired with the clinical system for N = 5 skulls and T = 2 different targets for each skull. We show that the clinical ray-tracing software and the full-wave simulation restore, respectively, 84% ± 5% and 86% ± 5% of the pressure obtained with hydrophone-based correction for targets located in central brain regions. On the second target (off-center), we also report that the performance of both algorithms degrades when the average incident angles of the acoustic beam at the skull surface increase. When incident angles are higher than 20°, the restored pressure drops below 75% of the pressure restored with hydrophone-based correction.

Bedside functional monitoring of the dynamic brain connectivity in human neonates.

Clinicians have long been interested in functional brain monitoring, as reversible functional losses often precedes observable irreversible structural insults. By characterizing neonatal functional cerebral networks, resting-state functional connectivity is envisioned to provide early markers of cognitive impairments. Here we present a pioneering bedside deep brain resting-state functional connectivity imaging at 250-µm resolution on human neonates using functional ultrasound. Signal correlations between cerebral regions unveil interhemispheric connectivity in very preterm newborns. Furthermore, fine-grain correlations between homologous pixels are consistent with white/grey matter organization. Finally, dynamic resting-state connectivity reveals a significant occurrence decrease of thalamo-cortical networks for very preterm neonates as compared to control term newborns. The same method also shows abnormal patterns in a congenital seizure disorder case compared with the control group. These results pave the way to infants' brain continuous monitoring and may enable the identification of abnormal brain development at the bedside.

Steering Capabilities of an Acoustic Lens for Transcranial Therapy: Numerical and Experimental Studies.

For successful brain therapy, transcranial focused ultrasound must compensate for the time shifts induced locally by the skull. The patient-specific phase profile is currently generated by multi-element arrays which, over time, have tended toward increasing element count. We recently introduced a new approach, consisting of a single-element transducer coupled to an acoustic lens of controlled thickness. By adjusting the local thickness of the lens, we were able to induce phase differences which compensated those induced by the skull. Nevertheless, such an approach suffers from an apparent limitation: the lens is a priori designed for one specific target. In this paper, we demonstrate the possibility of taking advantage of the isoplanatic angle of the aberrating skull in order to steer the focus by mechanically moving the transducer/acoustic lens pair around its initial focusing position. This study, conducted on three human skull samples, demonstrates that tilting of the transducer with the lens restores a single -3 dB focal volume at 914 kHz for a steering up to ±11 mm in the transverse direction, and ±10 mm in the longitudinal direction, around the initial focal region.

Computationally Efficient Transcranial Ultrasonic Focusing: Taking Advantage of the High Correlation Length of the Human Skull.

The phase correction necessary for transcranial ultrasound therapy requires numerical simulation to noninvasively assess the phase shift induced by the skull bone. Ideally, the numerical simulations need to be fast enough for clinical implementation in a brain therapy protocol and to provide accurate estimation of the phase shift to optimize the refocusing through the skull. In this article, we experimentally performed transcranial ultrasound focusing at 900 kHz on N = 5 human skulls. To reduce the computation time, we propose here to perform the numerical simulation at 450 kHz and use the corresponding phase shifts experimentally at 900 kHz. We demonstrate that a 450-kHz simulation restores 94.2% of the pressure when compared with a simulation performed at 900 kHz and 85.0% of the gold standard pressure obtained by an invasive time reversal procedure based on the signal recorded by a hydrophone placed at the target. From a 900- to 450-kHz simulation, the grid size is divided by 8, and the computation time is divided by 10.

Non-invasive recanalization of deep venous thrombosis by high frequency ultrasound in a swine model with follow-up.

AIMS: Pulsed cavitational ultrasound therapy (thombotripsy) allows the accurate fractionation of a distant thrombus. We aimed to evaluate the efficacy and safety of non-invasive thrombotripsy using a robotic assisted and high frequency ultrasound approach to recanalize proximal deep venous thrombosis (DVT) in a swine model. METHODS: Occlusive thrombosis was obtained with a dual jugular and femoral endoveinous approach. The therapeutic device was composed of a 2.25 MHz focused transducer centered by a linear ultrasound probe, and a robotic arm. The feasibility, security, and efficacy (venous channel patency) assessment after thrombotripsy was performed on 13 pigs with acute occluded DVT. To assess the mid-term efficacy of this technique, 8 pigs were followed up for 14 days after thrombotripsy and compared with 8 control pigs. The primary efficacy endpoint was the venous patency. Safety was assessed by the search for local vessel wall injury and pulmonary embolism. RESULTS: We succeeded in treating all pigs except two with no accessible femoral vein. After median treatment duration of 23 minutes of cavitation, all treated DVT were fully recanalized acutely. At 14 days, in the treated group, six of the eight pigs had a persistent patent vein and two pigs had a venous reocclusion. In the control group all pigs had a persistent venous occlusion. At sacrifice, no local vein nor arterial wall damage were observed as well as no evidence of pulmonary embolism in all pigs. CONCLUSION: High frequency thrombotripsy seems to be effective and safe for non-invasive venous recanalization of DVT.

3D-printed adaptive acoustic lens as a disruptive technology for transcranial ultrasound therapy using single-element transducers.

The development of multi-element arrays for better control of the shape of ultrasonic beams has opened the way for focusing through highly aberrating media, such as the human skull. As a result, the use of brain therapy with transcranial-focused ultrasound has rapidly grown. Although effective, such technology is expensive. We propose a disruptive, low-cost approach that consists of focusing a 1 MHz ultrasound beam through a human skull with a single-element transducer coupled with a tailored silicone acoustic lens cast in a 3D-printed mold and designed using computed tomography-based numerical acoustic simulation. We demonstrate on N = 3 human skulls that adding lens-based aberration correction to a single-element transducer increases the deposited energy on the target 10 fold.

Inside/outside the brain binary cavitation localization based on the lowpass filter effect of the skull on the harmonic content: a proof of concept study.

Cavitation activity induced by ultrasound may occur during high intensity focused ultrasound (HIFU) treatment, due to bubble nucleation under high peak negative pressure, and during blood-brain-barrier (BBB) disruption, due to injected ultrasound contrast agents (UCAs). Such microbubble activity has to be monitored to assess the safety and efficiency of ultrasonic brain treatments. In this study, we aim at assessing whether cavitation occurs within cerebral tissue by binary discriminating cavitation activity originating from the inside or the outside of the skull. The results were obtained from both in vitro experiments mimicking BBB opening, by using UCA flow, and in vitro thermal necrosis in calf brain samples. The sonication was applied using a 1 MHz focused transducer and the acoustic response of the microbubbles was recorded with a wideband passive cavitation detector. The spectral content of the recorded signal was used to localize microbubble activity. Since the skull acts as a low pass filter, the ratio of high harmonics to low harmonics is lower for cavitation events located inside the skull compared to events outside the skull. Experiments showed that the ratio of the 5/2 ultraharmonic to the 1/2 subharmonic for binary localization cavitation activity achieves 100% sensitivity and specificity for both monkey and human skulls. The harmonic ratio of the fourth to the second harmonic provided 100% sensitivity and 96% and 46% specificity on a non-human primate for thermal necrosis and BBB opening, respectively. Nonetheless, the harmonic ratio remains promising for human applications, as the experiments showed 100% sensitivity and 100% specificity for both thermal necrosis and BBB opening through the human skull. The study requires further validation on a larger number of skull samples.