In vivotranscranial cavitation threshold detection during ultrasound-induced blood–brain barrier opening in mice

Abstract

The in vivo cavitation response associated with blood–brain barrier (BBB) opening as induced by transcranial focused ultrasound (FUS) in conjunction with microbubbles was studied in order to better identify the underlying mechanism in its noninvasive application. A cylindrically focused hydrophone, confocal with the FUS transducer, was used as a passive cavitation detector (PCD) to identify the threshold of inertial cavitation (IC) in the presence of Definity® microbubbles (mean diameter range: 1.1–3.3 μm, Lantheus Medical Imaging, MA, USA). A vessel phantom was first used to determine the reliability of the PCD prior to in vivo use. A cerebral blood vessel was simulated by generating a cylindrical channel of 610 μm in diameter inside a polyacrylamide gel and by saturating its volume with microbubbles. The microbubbles were sonicated through an excised mouse skull. Second, the same PCD setup was employed for in vivo noninvasive (i.e. transdermal and transcranial) cavitation detection during BBB opening. After the intravenous administration of Definity® microbubbles, pulsed FUS was applied (frequency: 1.525 or 1.5 MHz, peak-rarefactional pressure: 0.15–0.60 MPa, duty cycle: 20%, PRF: 10 Hz, duration: 1 min with a 30 s interval) to the right hippocampus of twenty-six (n = 26) mice in vivo through intact scalp and skull. T1 and T2-weighted MR images were used to verify the BBB opening. A spectrogram was generated at each pressure in order to detect the IC onset and duration. The threshold of BBB opening was found to be at a 0.30 MPa peak-rarefactional pressure in vivo. Both the phantom and in vivo studies indicated that the IC pressure threshold had a peak-rarefactional amplitude of 0.45 MPa. This indicated that BBB opening may not require IC at or near the threshold. Histological analysis showed that BBB opening could be induced without any cellular damage at 0.30 and 0.45 MPa. In conclusion, the cavitation response could be detected without craniotomy in mice and IC may not be required for BBB opening at relatively low pressures.

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

“…In this study, MRI and fluorescence microscopic examination of dextran delivery was used to confirm the BBB opening. The quantification methods of the BBB opening volume and cavitation response were used as previously described [11]. A Student's ttest was used to determine whether the ICD was statistically different across different pressure amplitudes.…”

“…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]. Our objective of this study is to transcranially and noninvasively determines the difference in mechanism between stable-cavitation (SC) and inertial-cavitation (IC) induced BBB opening in mice at the safest pressures in vivo.…”

Ultrasound enhanced drug delivery to the brain and central nervous system

“…McDannold et al demonstrated an increase in harmonic emissions from the MBs when BBBD occurred, and thus that harmonic emissions may be usable to indicate treatment progress [74]. Another group has suggested that higher harmonics, such as the fourth and fifth harmonics, may be an indicator of disruption [75]. Recently, it has been shown that treatment pressures can be modulated real-time to induce consistent, safe BBBD by utilizing ultraharmonic emissions information to actively control exposures [76].…”

Ultrasound-Based Therapies for the Treatment of Cancer

“…Passive cavitation detection (PCD) allows real-time assessment of MB cavitation 74 . While stable cavitation is most likely responsible for reversible BBBD 65,75 , inertial cavitation has been linked with tissue damage 76 . Importantly, acquired PCD intensity is well correlated with BBBD 65,75 .…”

“…While stable cavitation is most likely responsible for reversible BBBD 65,75 , inertial cavitation has been linked with tissue damage 76 . Importantly, acquired PCD intensity is well correlated with BBBD 65,75 . PCD non-invasively detects the acoustic signatures resulting from MB oscillations, and can distinguish between stable oscillations and MB collapse.…”