Blood-Brain Barrier: Real-time Feedback-controlled Focused Ultrasound Disruption by Using an Acoustic Emissions–based Controller

Abstract

Kullervo Hynynen, PhD Purpose:To determine if focused ultrasound disruption of the blood-brain barrier (BBB) can be safely controlled by using real-time modulation of treatment pressures on the basis of acoustic emissions from the exposed microbubbles. Materials and Methods:All experiments were performed with the approval of the institutional animal care committee. Transcranial focused ultrasound (551.5 kHz, 10-msec bursts, 2-Hz pulse repetition frequency, 2 minute sonication) in conjunction with circulating microbubbles was applied in 86 locations in 27 rats to disrupt the BBB. Acoustic emissions captured during each burst by using a wideband polyvinylidene fluoride hydrophone were analyzed for spectral content and used to adjust treatment pressures. Pressures were increased incrementally after each burst until ultraharmonic emissions were detected, at which point the pressure was reduced to a percentage of the pressure required to induce the ultraharmonics and was maintained for the remainder of the sonication. Disruption was evaluated at contrast materialenhanced T1-weighted magnetic resonance (MR) imaging. Mean enhancement was calculated by averaging the signal intensity at the focus over a 3 3 3-pixel region of interest and comparing it with that in nonsonicated tissue. Histologic analysis was performed to determine the extent of damage to the tissue. Statistical analysis was performed by using Student t tests. Results:For sonications resulting in BBB disruption, the mean peak pressure was 0.28 MPa 6 0.05 (standard deviation) (range, 0.18-0.40 MPa). By using the control algorithm, a linear relationship was found between the scaling level and the mean enhancement on T1-weighted MR images after contrast agent injection. At a 50% scaling level, mean enhancement of 19.6% 6 1.7 (standard error of the mean) was achieved without inducing damage. At higher scaling levels, histologic analysis revealed gross tissue damage, while at a 50% scaling level, no damage was observed at high-field-strength MR imaging or histologic examination 8 days after treatment. Conclusion:This study demonstrates that acoustic emissions can be used to actively control focused ultrasound exposures for the safe induction of BBB disruption. (18). We propose that ultraharmonic emissions may be used as the basis for a feedback control algorithm to safely modulate pressures during treatment. The purpose of this study was to determine if focused ultrasound disruption of the BBB can be safely controlled by using real-time modulation of treatment pressures on the basis of acoustic emissions from the exposed microbubbles. Materials and Methods Generation and Monitoring of the UltrasoundThe ultrasound was generated by using a spherically focused transducer constructed in house (focal number = 0.8, external diameter = 75 mm, internal diameter = 20 mm), matched to 551.5 kHz by using an external matching circuit. The transducer had a focal depth of 60 mm and a −6-dB focal zone width of approximately 3 mm and a length of approximately 20 mm. Driving si...

Closed-loop control of targeted ultrasound drug delivery across the blood–brain/tumor barriers in a rat glioma model

“…These main factors can be estimated beforehand, using CT scans and simulation to estimate the acoustic attenuation (39) and MRI or other imaging methods to estimate the vascular density. It may also be possible to use the onset of subharmonic or ultraharmonic emissions observed when the exposure level is increased as a means to estimate (27,30). This onset may represent a distinct threshold that depends predominately on the microbubble properties.…”

“…This potential has been further suggested by several BBBD works with cavitation monitoring (21,(25)(26)(27) and other microbubble-mediated therapies (28,29). O'Reilly and Hynynen (30) designed an active controller that increases the acoustic pressure until ultraharmonic emission is detected and then reduces it by a predetermined amount. The pressure levels were found to be associated with MRI contrast enhancement and damage occurrence.…”

Noninvasive and Targeted Drug Delivery to the Brain Using Focused Ultrasound

“…40 Acoustic emissions are monitored and used to actively control the pressure amplitude of the ultrasound leading to a consistent BBB disruption. 40 …”

“…The acoustic monitoring technique has improved the safety of BBB disruption. 40 Acoustic emissions are monitored and used to actively control the pressure amplitude of the ultrasound, leading to consistent, safe level of BBB disruption.…”

The safest parameters for FUS-induced blood-brain barrier opening without effects on the opening volume

“…The mechanical index (MI), defined as the peak rarefactional pressure (PRP, negative pressure) divided by the square root of the center frequency, was used for the determination of IC likelihood. In order to determine the type of cavitation occurring during BBB opening, passive cavitation detection (PCD) has been used in different animals [8][9][10]. It has been shown that the IC is not required to induce BBB opening and MI = 0.37 was able to induce the IC during BBB opening [11].…”