Pulse sequence and timing of contrast‐enhanced MRI for assessing blood–brain barrier disruption after transcranial focused ultrasound in the presence of hemorrhage

Weng, Jun; Wu, Sheng Kai; Yang, Feng; Lin, Wen Chang; Tseng, Wen‐Yih Isaac

doi:10.1002/jmri.22174

Cited by 11 publications

(5 citation statements)

References 18 publications

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“…The magnitude has been found to increase with the burst length up to a duration of approximately 10 ms, with further increases in burst length having little or no effect [77,81,86,90,90–92]. Several groups have shown that the disruption magnitude may be increased by using a larger dose of ultrasound contrast agent [83,93–95] (although other works have shown little or no effect [86,90]) or by using larger microbubbles [87–89]. Pulse repetition frequency can also influence the magnitude of disruption up to a point [90,91], but other studies have seen no dependence [86].…”

Section: Ultrasound-induced Bbb Disruptionmentioning

confidence: 99%

Ultrasound-mediated blood–brain barrier disruption for targeted drug delivery in the central nervous system

Aryal

Arvanitis

Alexander

et al. 2014

Advanced Drug Delivery Reviews

362

237

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The physiology of the vasculature in the central nervous system (CNS), which includes the blood-brain barrier (BBB) and other factors, complicates the delivery of most drugs to the brain. Different methods have been used to bypass the BBB, but they have limitations such as being invasive, non-targeted or requiring the formulation of new drugs. Focused ultrasound (FUS), when combined with circulating microbubbles, is a noninvasive method to locally and transiently disrupt the BBB at discrete targets. This review provides insight on the current status of this unique drug delivery technique, experience in preclinical models, and potential for clinical translation. If translated to humans, this method would offer a flexible means to target therapeutics to desired points or volumes in the brain, and enable the whole arsenal of drugs in the CNS that are currently prevented by the BBB.

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Section: Ultrasound-induced Bbb Disruptionmentioning

confidence: 99%

Ultrasound-mediated blood–brain barrier disruption for targeted drug delivery in the central nervous system

Aryal

Arvanitis

Alexander

et al. 2014

Advanced Drug Delivery Reviews

362

237

View full text Add to dashboard Cite

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“…Neuronal nuclei were counted in a microscope field from the center of the sonication and from a field adjacent to the disrupted region (nonsonicated with a 7.0-T small-bore MR imaging unit (BioSpec 70/30 USR; Bruker, Billerica, Mass). T2-weighted and T2*-weighted images were obtained by using the parameters outlined in the Table. High signal intensity on T2-weighted images was considered to be a sign of residual edema and possible lesion formation, while T2*-weighted images were used to determine if bleeding or large extravasations of red blood cells had occurred (22,23).…”

Section: Control Algorithm Performancementioning

confidence: 99%

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

O’Reilly

Hynynen²

2012

Radiology

340

317

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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...

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“…Using a different set of FUS parameters with higher UCA dosage, however, we demonstrated that the contrast enhancement in the spin echo T 1 W sequence was correlated with both the UCA dosage and the degree of BBB disruption quantified by EB extravasation (28). In this study, we further demonstrated that the correlations between MR and UCA dosage as well as the correlations between MR and EB The sonication was applied to the right hemisphere, the left hemisphere was left intact.…”

Section: Correlation Between Mr and Uca Dosagementioning

confidence: 54%

“…It is known that ultrasound pressure, burst length, and FUS duration can influence the degree of BBB disruption. Our previous study showed that using 1.2 MPa (peak negative pressure), a burst length of 50 msec and sonication duration of 60 sec could cause severe hemorrhage (28). To avoid severe hemorrhage and tissue damage, we reduced ultrasound pressure to 0.56 MPa, burst length to 10 msec, and sonication duration to 20 sec in this study.…”

Section: Nonhemorrhagic Vs Biosafety Conditionsmentioning

confidence: 97%

Detecting blood–brain barrier disruption within minimal hemorrhage following transcranial focused ultrasound: A correlation study with contrast‐enhanced MRI

Weng

Lin

et al. 2010

Magnetic Resonance in Med

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Focused ultrasound combined with an intravascular ultrasound contrast agent can induce transient disruption of the blood-brain barrier, and the blood-brain barrier disruption can be detected by contrast-enhanced MRI. There is, however, no study investigating the ability of various MR methods to detect focused ultrasound-induced blood-brain barrier disruption within minimal hemorrhage. Sonication was applied to 15 rat brains with four different doses of ultrasound contrast agent (0, 10, 30, or 50 mL/kg), and contrast-enhanced T1-weighted spin echo, gradient echo images, and longitudinal relaxation rate mapping along with effective transverse relaxation time-weighted and susceptibility-weighted images were acquired. Volume-of-interest-based and threshold-based analyses were performed to quantify the contrast enhancement, which was then correlated with the ultrasound contrast agent dose and with the amount of Evans blue extravasation. Both effective transverse relaxation time-weighted and susceptibility-weighted images did not detect histology-proved intracranial hemorrhage at 10 mL/kg, but MRI failed to detect mild intracranial hemorrhage at 30 mL/kg. All tested sequences showed detectable contrast enhancement increasing with ultrasound contrast agent dose. In correlating with Evans blue extravasation, the gradient echo sequence was slightly better than the spin echo sequence and was comparable to longitudinal relaxation rate mapping. In conclusion, both gradient echo and spin echo sequences were all reliable in indicating the degree of focused ultrasound-induced blood-brain barrier disruption within minimal hemorrhage. Magn Reson Med 65:802-811, 2011. V C 2010 Wiley-Liss, Inc.Key words: magnetic resonance imaging; focused ultrasound; blood-brain barrier; ultrasound contrast agent; microbubbles; R 1 mappingThe blood-brain barrier (BBB) results from the selectivity of the tight junctions between endothelial cells in central nervous system vessels. It limits the passage of most potential diagnostically and therapeutically useful molecules from circulation into the brain parenchyma and precludes their use in diagnosis or treatment in the central nervous system (1-3). Recently, focused ultrasound (FUS) combined with intravascular ultrasound contrast agent (UCA) has been shown to transiently increase the transport of molecules across the BBB (4-7). This increase in BBB permeability can be detected by contrast-enhanced MRI using gadolinium-based (8,9) or iron oxide-based contrast agents (10) or by single-photon emission computed tomography with 99m Tc-based radiotracers (11). Using these imaging methods to guide FUS sonication, BBB at the targeted brain regions can be disrupted accurately, facilitating the delivery of diagnostic or therapeutic agents (12)(13)(14)(15)(16)(17).Although FUS sonication is promising in facilitating drug delivery across BBB, increasing concerns have been raised regarding its potential adverse effects on the brain. Indeed, FUS sonication could damage the brain tissue via FUS-induced edema, hem...

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Pulse sequence and timing of contrast‐enhanced MRI for assessing blood–brain barrier disruption after transcranial focused ultrasound in the presence of hemorrhage

Cited by 11 publications

References 18 publications

Ultrasound-mediated blood–brain barrier disruption for targeted drug delivery in the central nervous system

Ultrasound-mediated blood–brain barrier disruption for targeted drug delivery in the central nervous system

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

Detecting blood–brain barrier disruption within minimal hemorrhage following transcranial focused ultrasound: A correlation study with contrast‐enhanced MRI

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