The Effects of Oxygen on Ultrasound-Induced Blood–Brain Barrier Disruption in Mice

Abstract

Numerous researchers are investigating the use of microbubble-enhanced ultrasound to disrupt the blood-brain barrier (BBB) disruption and deliver drugs to the brain. This study investigated the impact of using oxygen as a carrier gas for anesthesia on microbubble activity and BBB disruption. Targets in mice were sonicated in combination with administration of Optison microbubbles (100 μl/kg) under isoflurane anesthesia with either oxygen or medical air. A 690 kHz focused ultrasound transducer applied 10 ms bursts at peak pressure amplitudes of 0.46-0.54 MPa (N=2) or 0.34-0.36 MPa (N=5). After sonication of two locations in one hemisphere, the carrier gas for the anesthesia was changed, and the sonications were repeated in the contralateral hemisphere. The BBB disruption, measured via contrast-enhanced MRI, was significantly greater (P<0.001) with medical air than with oxygen. Harmonic emissions were also greater with air (P<0.001), while the decay rate of the harmonic emissions was 1.5 times faster with oxygen. A good correlation (R2: 0.46) was observed between the harmonic emissions strength and MRI signal enhancement. At 0.46-0.54 MPa, both the occurrence and strength of wideband emissions was greater with medical air. However, at lower peak pressure amplitudes of 0.34-0.36 MPa, the strength and probability for wideband emissions were higher with oxygen. Little or no effects were observed in histology at 0.34-0.36 MPa. These findings show that use of oxygen as a carrier gas can result in a substantial diminution of BBB disruption. These results should be taken into account when comparing studies from different researchers and in translating this method to humans.

Reply to Silburt et al.: Concerning sterile inflammation following focused ultrasound and microbubbles in the brain

“…Definity's dispersity is more uniform than Optison's, translating to a greater fraction of Definity's population cavitating under similar sonication parameters. McDannold et al (8) reported that BBBD is further hampered by inspiring 100% O 2 , like our study, resulting from decreased MB lifetimes in circulation (9). Our experimental parameters essentially reduced acoustic cavitation effects relative to several other studies in the literature, but resulted in BBBD accompanied by sterile inflammation nonetheless.…”

State-of-the-art of microbubble-assisted blood-brain barrier disruption

“…Additionally, it is known that decreasing pO 2 can trigger the formation of adenosine and other potent vasodilators, increasing cerebral blood flow and likely the concentration of microbubbles at the target site 73 . Results by McDannold et al may corroborate this effect, as BBBD in mice injected with Optison and targeted with 690 kHz 0.54 MPa PNP showed a significantly greater volume of BBBD (as quantified by MRI) after inhaling 21% (air) vs. 100% O 2 74 . The partial pressure of oxygen in the blood can affect heart rate as well 73 , a physiological parameter that can differ greatly between species and individuals, and the effects of which are unexplored regarding MB+FUS BBBD.…”

“…Some studies have observed the presence of petechiae, or visually detectable extravasated red blood cells 90 , 88 , 13 , 74 . Contradictory interpretations regarding the impact of petechiae on safety have been presented.…”

MRI and histological evaluation of pulsed focused ultrasound and microbubbles treatment effects in the brain

“…Pharmacokinetic modeling would indicate that the infusion rate, initial concentration of injected MB, plasma concentration of MB, T 1/2 , volume of distribution, and oxygenation status all contribute to the numbers of MB exposed to pFUS PNP over the sonication period used to cause BBBD 20 . It has been reported that pFUS+MB BBBD experiments performed while animals inhale 100% O 2 resulted in less enhancement on GdT1w MRI compared to when animals inhaled 21% O 2 72 . In addition, animals on 100% oxygen had a greater amount of wideband emissions that could have led to an increase in the number of petechia compared to animals breathing air 72 , which may appear as hypointense voxels on T2*w MRI.…”