Assessment of temporary cerebral effects induced by focused ultrasound with optical coherence tomography angiography.

Focused ultrasound (FUS) in combination with microbubbles temporally and locally increases the permeability of the blood-brain barrier (BBB) for facilitating drug delivery. However, the temporary effects of FUS on the brain microstructure and microcirculation need to be addressed. We used label-free optical coherence tomography (OCT) and OCT angiography (OCTA) to investigate the morphological and microcirculation changes in mouse brains due to FUS exposure at different power levels. Additionally, the recovery progress of the induced effects was studied. The results show that FUS exposure causes cerebral vessel dilation and can be identified and quantitatively analyzed via OCT/OCTA. Micro-hemorrhages can be detected when an excessive FUS exposure power is applied, causing the degradation of OCTA signal owing to strong scattering by leaked red blood cells (RBCs) and weaker backscattered intensity from RBCs in vessels. The vessel dilation effect due to FUS exposure was found to abate in several hours. This study demonstrates that the FUS-induced cerebral transiently dilated effects can be in-vivo differentiated and monitored with OCTA, and shows the feasibility of using OCT/OCTA as a novel tool for long-time monitoring of cerebral vascular dynamics during FUS-BBB opening process.

Dynamic perfusion assessment by contrast-enhanced ultrasound in blood-brain barrier disruption.

Recently, blood-brain barrier disruption (BBBD) has been performed by focused ultrasound (FUS) combining with microbubbles (MBs). The outcome of BBBD enhances local drug or gene delivery for improving the treatment efficiency of brain diseases. However, over-excitation of FUS may cause brain damage such as shutdown blood flow, intracerebral hemorrhage and brain edema. Therefore, it is essential to develop a an imaging system to assess dynamic perfusion changes during FUS-induced BBBD process. Here, we used the high-frequency destruction/reperfusion contrast-enhanced imaging technique to observe the cerebral perfusion under the cases of with/without hemorrhage in BBBD procedure. The BBB was disrupted by a 2.25 MHz FUS combining with MBs at 0.5-0.7 MPa (pulse repetition frequency: 1 Hz, pulse length: 1 ms, sonication time: 60 s). The results showed that the velocity of blood flow decreased after BBBD induced by FUS sonication. Particularly, the plateau of time-intensity curve was higher than prior to MBs destruction at 20 s after sonication and the blood flow would be obstructed due to the blood coagulates at 60s after sonication. The pattern of hemorrhagic damage caused by FUS can be monitored by the TIC. In addition, the location of blood flow velocity decrease was consistent with the areas of BBBD and the variation of blood flow depends on the applied acoustic pressure. In conclusion, the blood flow velocity changes have potential as an in vivo tool for quantifying the extent of the FUS-induced BBBD and detecting intracerebral hemorrhage occurrence.

Manipulation of magnetic nanoparticle retention and hemodynamic consequences in microcirculation: assessment by laser speckle imaging.

Magnetic nanoparticles (MNPs) have been proposed for targeted or embolization therapeutics. How MNP retention occurs in circulation may critically determine local hemodynamics, tissue distribution of MNPs, and the therapeutic effects. We attempted to establish a microcirculation model to study the magnetic capture of MNPs in small vessels and to determine the factors affecting MNP retention. Two-dimensional hemodynamic changes in response to magnet-induced MNP retention in the microvessels of the cremaster muscle in vivo were observed in a real-time manner using a laser speckle imaging technique. Changes in tissue perfusion of the cremaster muscle appeared to be closely correlated with the location of the magnet placement underneath the muscle in response to intra-arterial administration of dextran-coated MNPs. Magnet-related retention was observed along the edge of the magnet, as corroborated by the results of histology analysis and microcomputed tomography. In these preparations, tissue iron content almost doubled, as revealed by inductively coupled plasma optical emission spectroscopy. In addition, MNP retention was associated with reduced downstream flow in a dose-dependent manner. Dissipation of MNPs (5 mg/kg) occurred shortly after removal of the magnet, which was associated with significant recovery of tissue flow. However, MNP dissipation did not easily occur after administration of a higher MNP dose (10 mg/kg) or prolonged exposure to the magnetic field. An ultrasound after removal of the magnet may induce the partial dispersion of MNPs and thus partially improve hemodynamics. In conclusion, our results revealed the important correlation of local MNP retention and hemodynamic changes in microcirculation, which can be crucial in the application of MNPs for effective targeted therapeutics.

In vivo assessment of macrophage CNS infiltration during disruption of the blood-brain barrier with focused ultrasound: a magnetic resonance imaging study.

Focused ultrasound has been discovered to locally and reversibly increase permeability of the blood-brain barrier (BBB). However, inappropriate sonication of the BBB may cause complications, such as hemorrhage and brain tissue damage. Tissue damage may be controlled by selecting optimal sonication parameters. In this study, we sought to investigate the feasibility of labeling cells with superparamagnetic iron oxide particles to assess the inflammatory response during focused-ultrasound-induced BBB opening. We show that infiltration of phagocytes does not occur using optimal parameters of sonication. Taken together, the results of our study support the usefulness and safety of focused-ultrasound-induced BBB opening for enhancing drug delivery to the brain. These findings may have implications for the optimization of sonication parameters.