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Intranasal delivery provides non-invasive delivery of drugs from the nose to the brain bypassing the blood-brain barrier (BBB). We previously reported the focused ultrasound (FUS)-mediated intranasal delivery (FUSIN) of various agents in mice using FUS. However, no study has investigated the feasibility of FUSIN in large animals. The objective of this study was to investigate the feasibility of MR-guided FUS-mediated intranasal delivery in a large animal model. Pigs were used as the large animal model due to their clinical relevance to humans. Fluorescence-labeled albumin was mixed with an MRI contrast agent and administrated intranasally to the pig using a catheter. Followed by intravenous injection of microbubbles, FUS sonication was performed at two brain regions, the cortex and brainstem. T1-weighted MR images showed enhancement of MRI contrast agent at the olfactory region of the pig nose. Fluorescence imaging displayed enhanced fluorescence intensity at the FUS-targeted brain regions. These findings suggest that MR-guided FUS can achieve noninvasive and localized delivery of intranasally administered agents to the brain in large animals.

To demonstrate that focused ultrasound-induced blood-brain barrier opening (FUS-BBBO) in mice can be achieved without shaving hairs. We performed FUS-BBBO in mice by using oil as the coupling medium without shaving hairs. The hydrophobic nature of oil leads to a higher affinity to hair than water-based ultrasound gel. FUS-BBBO outcome was compared under three conditions: “oil + hairs,” “gel + hairs,” and “gel + no hairs.” T2-weighted, T1-weighted MRI, and fluorescence imaging of the ex vivo brain slices were performed to measure the quality of coupling and outcome of FUS-BBBO. Results showed that “oil + hairs” consistently achieved high-quality acoustic coupling without trapping air bubbles (Figures A & B). FUS-BBBO outcome was not significantly different between the “oil + hairs” group and the “gel + no hairs” group based on T1-weighted MRI (Figures C & D) and ex vivo fluorescence imaging (Figure E). The FUS-BBBO efficiencies for both the “oil + hairs” and “gel + no hairs” groups were significantly higher than the “gel + hairs” group. This study demonstrated that FUS-BBBO in mice could be achieved without shaving hairs. Oil provides a simple solution for achieving effective acoustic coupling for transcranial FUS procedures.

The static magnetic field of an MRI scanner was found to dampen the microbubble cavitation activity and decrease the focused ultrasound-combined with microbubble-mediated blood-brain barrier opening.

Cavitation is widely existing in focused ultrasound (FUS)-mediated therapies in the brain, such as FUS in combination with microbubble-induced blood-brain barrier disruption, nonthermal ablation, as well as transcranial histotripsy therapy. Accurately knowing the 3-D location of cavitation in real time can improve the treatment targeting accuracy and avoid off-target tissue damage. However, the skull induces strong phase and amplitude aberration to the cavitation signals and presents a significant challenge to the transcranial cavitation localization. Existing techniques for 3-D cavitation localization use hemispherical multi-element arrays combined with passive beamforming and adaptive skull-specific correction algorithm. However, these techniques require expensive equipment and treatment planning. Their time-consuming computations limit applications in real-time cavitation monitoring, which is critically needed to ensure the safety and efficacy of the FUS treatment. The object of this study was to investigate the feasibility of using a four-sensor network to transcranially locate the cavitation source in 3-D by time difference of arrival algorithm. The positional error of transcranial cavitation localization with the human skull along x, y, and z axes were 1.7 ± 1.2 mm, 1.6 ± 1.7 mm, and 4.1 ± 1.5 mm, respectively. For comparison, the positional error of without the human skull were 1.2 ± 1.8 mm, 0.9 ± 1.6 mm, and 3.1 ± 2.3 mm, respectively.