PURPOSE: To determine if focused ultrasound beams can be used to locally open the blood-brain barrier without damage to surrounding brain tissue and if magnetic resonance (MR) imaging can be used to monitor this procedure. MATERIALS AND METHODS: The brains of 18 rabbits were sonicated (pulsed sonication) in four to six locations, with temporal peak acoustic power ranging from 0.2 to 11.5 W. Prior to each sonication, a bolus of ultrasonographic (US) contrast agent was injected into the ear vein of the rabbit. A series of fast or spoiled gradient-echo MR images were obtained during the sonications to monitor the temperature elevation and potential tissue changes. Contrast material–enhanced MR images obtained minutes after sonications and repeated 1–48 hours later were used to depict blood-brain barrier opening. Whole brain histologic evaluation was performed. RESULTS: Opening of the blood-brain barrier was confirmed with detection of MR imaging contrast agent at the targeted locations. The lowest power leve...

Noninvasive MR Imaging-Guided Focal Opening of the Blood-Brain Barrier in Rabbits

The blood-brain barrier in brain homeostasis and neurological diseases.

Developing minimally invasive brain surgery by high-intensity focused ultrasound beams is of great interest in cancer therapy. However, the skull induces strong aberrations both in phase and amplitude, resulting in a severe degradation of the beam shape. Thus, an efficient brain tumor therapy would require an adaptive focusing, taking into account the effects of the skull. In this paper, we will show that the acoustic properties of the skull can be deduced from high resolution CT scans and used to achieve a noninvasive adaptive focusing. Simulations have been performed with a full 3-D finite differences code, taking into account all the heterogeneities inside the skull. The set of signals to be emitted in order to focus through the skull can thus be computed. The complete adaptive focusing procedure based on prior CT scans has been experimentally validated. This could have promising applications in brain tumor hyperthermia but also in transcranial ultrasonic imaging.

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Experimental demonstration of noninvasive transskull adaptive focusing based on prior computed tomography scans

A technique for focusing ultrasound through the human skull is described and verified. The approach is based on a layered wavevector-frequency domain model, which propagates ultrasound from a hemisphere-shaped transducer through the skull using input from CT scans of the head. The algorithm calculates the driving phase of each transducer element in order to maximize the signal at the intended focus. This approach is tested on ten ex vivo human skulls using a 0.74 MHz, 320-element array. A stereotaxic reference frame is affixed to the skulls in order to provide accurate registration between the CT images and the transducer. The focal quality is assessed with a hydrophone placed inside the skull. In each trial the phase correction algorithm successfully restored the focus inside the skull at a location within 1 mm from the intended focal point. The results demonstrate the feasibility of using the method for completely non-invasive ultrasound brain surgery and therapy.

https://iopscience.iop.org/article/10.1088/0031-9155/47/8/301/pdf

A non-invasive method for focusing ultrasound through the human skull

Object. The goal of this study was to explore the feasibility of using low-frequency magnetic resonance (MR) image‐guided focused ultrasound as a noninvasive method for the temporary disruption of the blood‐brain barrier (BBB) at targeted locations. Methods. Rabbits were placed inside a clinical 1.5-tesla MR imaging unit, and sites in their brains were targeted for 20-second burst sonications (frequency 260 kHz). The peak pressure amplitude during the burst varied between 0.1 and 0.9 MPa. Each sonication was performed after an intravenous injection of an ultrasound contrast agent (Optison). The disruption of the BBB was evaluated with the aid of an injection of an MR imaging contrast agent (MAGNEVIST). Additional tests involving the use of MION-47, a 20-nm magnetic nanoparticle contrast agent, were also performed. The animals were killed at different time points between 3 minutes and 5 weeks postsonication, after which light or electron microscopic evaluation was performed. The threshold for BBB disruption was approximately 0.2 MPa. More than 80% of the brain sites sonicated showed BBB disruption when the pressure amplitude was 0.3 MPa; at 0.4 MPa, this percentage was greater than 90%. Tissue necrosis, ischemia, and apoptosis were not found in tissue in which the pressure amplitude was less than 0.4 MPa; however, in a few areas of brain tissue erythrocytes were identified outside blood vessels following exposures of 0.4 MPa or higher. Survival experiments did not show any long-term adverse events. Conclusions. These results demonstrate that low-frequency ultrasound bursts can induce local, reversible disruption of the BBB without undesired long-term effects. This technique offers a potential noninvasive method for targeted drug delivery in the brain aided by a relatively simple low-frequency device.

Focal disruption of the blood–brain barrier due to 260-kHz ultrasound bursts: a method for molecular imaging and targeted drug delivery

Recent papers have shown that focused ultrasound therapy may be feasible in the brain through an intact human skull by using phased arrays to correct the phase distortion induced by the skull bone. The hypothesis of this study is that the required phase shifts for the phased array can be calculated from the skull shape and thickness provided by modern imaging techniques. The shape and thickness of a piece of human skull was traced from the serial images and used in a theoretical model to calculate the phase distribution for a phased array. A 76-element phased array was manufactured and used in the tests. The piece of skull and the transducer array were positioned in a waterbath, and the ultrasound field distributions were mapped with and without the phase correction. The image-derived phase correction produced a sharp focus through the skull. These results showed that ultrasound brain therapy may be executed completely noninvasively through an intact skull by using a phased array and the skull thickness information derived from MRI scans.

J. Sun

Papers

Trans-skull ultrasound therapy: the feasibility of using image-derived skull thickness information to correct the phase distortion