Multiple Low-Pressure Sonications to Improve Safety of Focused-Ultrasound Induced Blood-Brain Barrier Disruption: In a 1.5-MHz Transducer Setup

Abstract

Burst-mode driven high intensity focused ultrasound (HIFU) with the presence of ultrasound micro bubbles has been proven to be capable of locally and reversibly increasing the permeability of blood-brain barrier (BBB). However, the use of excessive acoustic pressure usually accompanied with intracerebral hemorrhage, which is considered a deterred side effect, especially when in applications such as drug delivery. The purpose of the current study is to provide a secure protocol using multiple low-pressure sonications, to disrupt localized BBB and preserve sonicated area without producing intracerebral hemorrhage. The brains of 10 Sprague-Dawley rats were subjected to 16 sonications, either unilaterally or bilaterally. A 1.5-MHz spherically curved 1-3 composite transducer was used to deliver the burst-mode ultrasonic focal energy into the rat brain after both craniotomy and micro bubble injection. Electric powers from 1 to 10 W were tested and sonication mode was adjusted from single high-pressure sonication (2.45 MPa, 30s F1) to multiple shoots (1.1 MPa, 30s×6). The path of sonication could be either a row or a triangle, which depends on the treatment plan. Pathologic examination includes hematoxylin and eosin (H&E) and immuno-histochemistry (IHC) staining. It was used to quantify the damage in accompany with BBB disruption which includes hemorrhage and tissue necrosis. MR imaging was employed to evaluate the BBB disruption and brain tissue hemorrhage in vivo. Pathological examinations showed that the average hemorrhage score decreased from 2.3+/- std (severe) to 0.3+/- std (slight) by using the proposed protocol. The finding was confirmed by In vivo MRI examinations. Compared with single high-pressure sonication, multiple low-pressure sonication effectively reduced the occurrence of hemorrhage noticed in T2*-weighted images. The efficiency of BBB-disruption increased as observed in contrast-enhanced T1 weighted Turbo-spin-echo sequence. The current study provides an improved sonication protocol which could temporally and locally disrupt the Blood-Brain-Barrier. It therefore demonstrated the possibility of safe drug delivery into restricted brain regions in the future applications.