Original Contribution
Evaluation of the Uncertainty of Passive Cavitation Measurements for Blood–Brain Barrier Disruption Monitoring

https://doi.org/10.1016/j.ultrasmedbio.2020.06.007Get rights and content

Abstract

Exposure to ultrasound combined with intravenous injection of microbubbles is a technique that can be used to temporarily disrupt the blood–brain barrier. Transcranial monitoring of cavitation can be done with one or more passive cavitation detectors (PCDs). However, the positioning of the PCDs relative to the cavitation site and the attenuation of these signals by the skull are two sources of error in the quantification of cavitation activity. The aim of this study was to evaluate in vitro the amplitude variation of cavitation signals that can be expected for an excised porcine skull model. The variation caused by the relative positioning of the PCD with respect to the cavitation site was quantified. A position-based correction of the signal amplitude was evaluated. Pig skull samples were used to assess variation in signal amplitude caused by bone. The overall coefficient of variation of the signals owing to these measurement biases was estimated at 30.8%.

Introduction

The blood–brain barrier (BBB) is an obstacle to most drug therapies for pathologies of the central nervous system (Pardridge 2005). In the 1950s, it was discovered that exposure to high-intensity focused ultrasound in cat brain tissue favored the deposition of trypan blue in damaged tissue, suggesting an opening of the BBB (Bakay et al. 1956). These openings were initially not repeatable and likely to cause significant lesions in brain tissue. Since then, much progress has been made in understanding the BBB disruption (BBBD) caused by exposure to ultrasound and in improving this technique. Notably, these BBBDs were found to be temporary and were unlikely to produce lesions (Ballantine et al. 1960), and the physical phenomenon mainly responsible for these permeabilizations was cavitation (Vykhodtseva et al. 1995).

Cavitation corresponds to the dynamics of gas bubbles subjected to an ultrasonic field at a frequencyf0. It is typically differentiated into two regimes. Stable cavitation corresponds to non-linear oscillations of the bubble radius. It is characterized by the emission of harmonic (2f0, 3f0, etc.), subharmonic (f0/2) and associated ultraharmonic (3f0/2, 5f0/2, etc.) frequencies. Inertial cavitation corresponds to a violent implosion of the bubbles and is characterized by broadband noise.

In the early 2000s, Hynynen et al. (2001) reported that the ultrasonic power necessary for BBBD could be greatly reduced by the simultaneous injection of microbubbles (MBs) into the bloodstream These MBs, originally marketed as contrast agents for ultrasound imaging, allow better control of cavitation activity, while reducing the harmful mechanical and thermal effects of high-power ultrasound.

The first BBBDs in humans were performed in a phase I/IIa clinical study using an unfocused ultrasound implant (Carpentier et al. 2016; Idbaih et al. 2019). A method for automatic quantification of BBBD volumes using magnetic resonance images of these treatments has also been published (Asquier et al. 2019). Clinical trials using focused and transcranial systems were carried out concurrently (Lipsman et al. 2018; Mainprize et al. 2019).

To monitor cavitation activity during an ultrasound treatment, passive cavitation monitoring can be performed using one or several passive cavitation detectors (PCDs) placed on the head. The signal emitted by the bubbles is recovered by the PCD, and its spectrum is then calculated. Indices of stable cavitation activity (harmonics, subharmonics and ultraharmonics of the excitation frequency of the bubbles) and inertial cavitation activity (broadband noise) can be defined to compare with the disruption and the undesirable effects obtained. Numerous pre-clinical studies have reported the link between cavitation activity, BBBD efficacy and related side effects (O'Reilly and Hynynen 2010; Tung et al. 2010; Tsai et al. 2016). PCD feedback has been used to set ultrasound excitation amplitudes (McDannold et al. 2006; O'Reilly and Hynynen 2012).

Treatment feedback with passive monitoring of cavitation is typically used in a transcranial configuration as the ultrasonic waves are attenuated and aberrated by the bone. The treatment amplitudes are adjusted based on detection of the different cavitation indices. In treatments using an implantable unfocused ultrasonic device, uncertainty over the acoustic pressure in situ is much lower. In this case, which infers no skull aberration, a free-field propagation assumption can reasonably be made. The calculation of free field wave propagation in homogeneous tissue is possible by taking viscosity into account in the Rayleigh integral (Strutt 1877).

The correlation between the efficacy of BBBD and the intensity of cavitation activity, however, has not yet been proven in humans. Passive monitoring of cavitation for exploratory purposes may be useful in gaining an understanding of the BBBD phenomenon and improving the efficacy of future clinical treatments safely. This article addresses the quantification of the cavitation activity induced during treatment performed with an unfocused ultrasonic transducer. The aim was to evaluate the uncertainty that exists concerning the amplitudes of the subharmonic perceived when monitoring with a single-element sensor, simply placed against the temple of patients. The measurement biases evaluated are the position and orientation of the PCD with respect to the cavitation source and the influence of the skull on the amplitudes. The uncertainties related to these two parameters were initially evaluated in vitro, and a correction of the amplitudes based on a prior knowledge of the positioning of the PCD with respect to the cavitation source was proposed and validated.

Section snippets

Experimental setup

The experimental setup is illustrated in Figure 1. The experiments were performed in a tank filled with de-gassed water at ambient temperature. A homemade 10-mm-diameter planar piezoceramic transducer was held vertically by a 3-D support designed and printed for the experiment. The transducer fired on a polyimide tube (external diameter: 1.9 mm, internal diameter: 1.8 mm; IM307190, Goodfellow, Huntingdon, UK) held perpendicular to the acoustic axis 2.5 cm from the surface of the transducer.

A

Influence of the position and validation of the correction

The results are illustrated in Figure 2. The coefficients of variation Cv obtained with the reference PCD were 5.8%, 4.8% and 4.5% for 0.34, 0.39 and 0.46 MPa, respectively. They represent the minimum uncertainty of cavitation measurements under ideal conditions (single cavitation source; a priori knowledge of relative distance and orientation of the PCD with respect to the focal point; and no skull to traverse).

For the moving PCD, the coefficients of variation were 29.2%, 29.1% and 34.1%

Discussion

The main objective of this study was to quantify the uncertainties caused by the position of the PCD with respect to a unique cavitation source and to the variability of patient's skull properties. The secondary objective was to propose measurement or treatment methods to be implemented to have the signals recorded by the PCD quantitatively comparable.

Signal correction as a function of sensor position was proposed. It allows for a better quantitative comparison of the amplitudes received. It

Conclusions

In our setup, the overall coefficient of variation of the amplitude of the subharmonic emitted by a single cavitation source, taking into account the positioning variability of the PCD in clinical conditions, as well as the measurement bias induced by the temporal bone, was evaluated at 30.8%.

A method for reducing measurement uncertainty, based on prior knowledge of the position of the PCD with respect to the cavitation source, was evaluated and validated in the absence of bone.

The variability

conflict of interest to disclose

N.A. is an employee of CarThera, a private medical device company developing an implantable unfocused transducer to disrupt the blood–brain barrier. In addition, J.Y.C. and C.L. have an ownership interest in CarThera. N.A. was funded in part by a French public grant that funds doctoral students that perform research on joint public/private research projects (ANRT, No. 2016/0979).

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