Quantitative Evaluation of Focused Ultrasound with a Contrast Agent on Blood-Brain Barrier Disruption

Yang, Feng; Fu, Wen‐Mei; Yang, Rong; Liou, Houng Chi; Kang, Kai-Hsiang; Lin, Wen Chang

doi:10.1016/j.ultrasmedbio.2007.04.006

Cited by 103 publications

(85 citation statements)

References 17 publications

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“…Recently, several papers have described a method to temporarily disrupt the blood-brain barrier (BBB) using ultrasound pulses combined with a circulating ultrasound contrast agent (Hynynen et al 2001;Yang et al 2007;Sheikov et al 2004;Hynynen et al 2005;McDannold et al 2005;McDannold et al 2006;Hynynen et al 2006;Kinoshita et al 2006;Raymond et al 2006;McDannold et al 2007;Treat et al 2007;Choi et al 2007). Since these pulses can be applied at an ultrasound frequency that can readily be applied transcranially by a transducer located outside the body Hynynen et al 2006), the method represents a potentially noninvasive technique to produce targeted BBB disruption.…”

Section: Introductionmentioning

confidence: 99%

Effects of Acoustic Parameters and Ultrasound Contrast Agent Dose on Focused-Ultrasound Induced Blood-Brain Barrier Disruption

McDannold

Vykhodtseva

Hynynen

2008

Ultrasound in Medicine & Biology

237

231

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Previously, it was shown that low-intensity focused ultrasound pulses applied along with an ultrasound contrast agent results in temporary blood-brain barrier (BBB) disruption. This effect could be used for targeted drug delivery in the central nervous system. This study examined the effects of burst length, pulse repetition frequency (PRF), and ultrasound contrast agent dose on the resulting BBB disruption. One hundred non-overlapping brain locations were sonicated through a craniotomy in experiments in rabbits (ultrasound frequency: 0.69 MHz, burst: 0.1, 1, 10 ms, PRF: 0.5, 1, 2, 5 Hz, duration: 20s, peak negative pressure amplitude: 0.1-1.5 MPa, Optison dosage 50, 100, 250 µl/ kg). For each sonication, BBB disruption was evaluated using contrast-enhanced magnetic resonance imaging. The BBB disruption threshold (the pressure amplitude yielding a 50% probability for BBB disruption) was determined using probit regression for the three burst lengths tested. Tissue effects were examined in light microscopy for representative locations with similar amounts of contrast enhancement from each group. While changing the PRF or the Optison dosage did not result in a significant difference in the magnitude of the BBB disruption (P>0.05), reducing the burst length resulted in significantly less contrast enhancement (P<0.01). The BBB disruption thresholds were estimated to be 0.69, 0.47, and 0.36 MPa for 0.1, 1, and 10 ms bursts respectively. No difference was detected in histology between any experimental group. This data suggests that over the range of parameters tested, BBB disruption is not affected by PRF or ultrasound contrast agent dose. However, both the BBB disruption magnitude and its threshold depend on the burst length.

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Section: Introductionmentioning

confidence: 99%

Effects of Acoustic Parameters and Ultrasound Contrast Agent Dose on Focused-Ultrasound Induced Blood-Brain Barrier Disruption

McDannold

Vykhodtseva

Hynynen

2008

Ultrasound in Medicine & Biology

237

231

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“…In the past few years, several studies in animals have demonstrated that low-power ultrasound pulses combined with an ultrasound contrast agent can temporarily disrupt the BBB with negligible associated effects to the brain (Hynynen et al 2001;Choi et al 2007;Yang et al 2007;McDannold et al 2005;Hynynen et al 2005;Hynynen et al 2006;McDannold et al 2006;McDannold et al 2007b;Treat et al 2007). This phenomenon could be exploited for a noninvasive means for targeted drug delivery in the CNS.…”

Section: Introductionmentioning

confidence: 99%

Blood-Brain Barrier Disruption Induced by Focused Ultrasound and Circulating Preformed Microbubbles Appears to Be Characterized by the Mechanical Index

McDannold

Vykhodtseva

Hynynen

2008

Ultrasound in Medicine & Biology

242

199

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This work investigated the effect of ultrasonic frequency on the threshold for blood-brain barrier (BBB) disruption induced by ultrasound pulses combined with an ultrasound contrast agent. Experiments were performed in rabbits using ultrasound pulses at 2.04 MHz using sonications with peak pressure amplitudes ranging from 0.3 to 2.3 MPa. BBB disruption was evaluated using contrastenhanced magnetic resonance imaging. The threshold for BBB disruption was estimated using probit regression. Representative samples with similar amounts of contrast enhancement were examined in light microscopy. Results from these experiments were compared to data from previous studies that used ultrasound frequencies between 0.26 and 1.63 MHz. We found that the BBB disruption threshold (value where the probability for disruption was estimated to be 50%) expressed in terms of the peak negative pressure amplitude increased as a function of the frequency. It appeared to be constant, however, when the exposures were expressed as a function of the mechanical index (peak negative pressure amplitude estimated in situ divided by square root of frequency). Regression of data from all frequencies resulted in an estimated mechanical index threshold of 0.46 (95% confidence intervals: 0.42-0.50). Histological examination of representative samples with similar amounts of blood-brain barrier disruption found that the number of regions containing extravasated red blood cells per unit area was substantially lower on average for lower ultrasound frequencies. This data suggests that the mechanical index is a meaningful metric for ultrasound-induced blood-brain barrier disruption, at least for when other parameters that are not taken into account by the mechanical index are not varied. It also suggests that lower frequency sonication produces less red blood cell extravasation per unit area.

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“…When measuring vascular permeability, it has been shown that BBB disruption can be quantified based on the extravasation of EB, which binds with albumin (9,10,13). Therefore, we used EB to investigate the relationship between MRI signal enhancement and the concentration of EB delivered to the sonicated brain tissue.…”

Section: Eb Detection and Quantificationmentioning

confidence: 99%

“…Furthermore, reducing the burst length also results in significantly less contrast enhancement. Previously, it has shown that injecting an appropriate quantity of UCA effectively increases and localizes the FUS-induced BBB disruption (9,10). In addition, the appropriate dose of UCA not only enhances the BBB opening but also effectively aid in controlling the duration of BBB disruption (11).…”

mentioning

confidence: 99%

Association between contrast‐enhanced MR images and blood–brain barrier disruption following transcranial focused ultrasound

Yang¹,

Horng

Lin³

et al. 2010

Magnetic Resonance Imaging

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Purpose: To investigate the correlation between the contrast-enhanced magnetic resonance imaging (MRI) signal and the duration of blood-brain barrier (BBB) disruption induced by focused ultrasound (FUS).Materials and Methods: FUS was applied to 45 rat brains in the presence of microbubbles, and these rats were scanned on a 3T MRI system at several timepoints. The rat brains were then studied using contrast-enhanced spin echo T1-weighted images. At the same time, BBB disruption was evaluated based on Evans blue (EB) extravasation. The relationship between the normalized signal intensity change of the MRI and EB extravasation was analyzed by least-squares linear regression and the calculation of correlation coefficients.Results: When MRI enhancement was quantitatively evaluated by EB extravasation, a strong correlation between the normalized signal intensity change of the MRI and EB extravasation was identified during BBB disruption after sonication. However, the correlation coefficient decreased as BBB closure occurred after sonication ended. Conclusion:The contrast-enhanced MRI signal can potentially be used to evaluate the amount of chemotherapeutic agents entering the targeted tissue, but the accuracy of the assessment will be affected by the time interval since sonication.

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Quantitative Evaluation of Focused Ultrasound with a Contrast Agent on Blood-Brain Barrier Disruption

Cited by 103 publications

References 17 publications

Effects of Acoustic Parameters and Ultrasound Contrast Agent Dose on Focused-Ultrasound Induced Blood-Brain Barrier Disruption

Effects of Acoustic Parameters and Ultrasound Contrast Agent Dose on Focused-Ultrasound Induced Blood-Brain Barrier Disruption

Blood-Brain Barrier Disruption Induced by Focused Ultrasound and Circulating Preformed Microbubbles Appears to Be Characterized by the Mechanical Index

Association between contrast‐enhanced MR images and blood–brain barrier disruption following transcranial focused ultrasound

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