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Previous studies have investigated a potential method for targeted drug delivery in the central nervous system that uses focused ultrasound bursts combined with an ultrasound contrast agent to temporarily disrupt the blood-brain barrier (BBB). The purpose of this work was to investigate the integrity of the tight junctions (TJs) in rat brain microvessels after this BBB disruption. 1.5-MHz ultrasound bursts in combination with a gas contrast agent (Optison) was applied at two locations in the brain in 25 rats to induce BBB disruption. Using immunoelectron microscopy, the distributions of the TJspecific transmembrane proteins occludin, claudin-1, claudin-5, and of submembranous ZO-1 were examined at 1, 2, 4, 6 and 24 h after sonication. A quantitative evaluation of the protein expression was made by counting the number of immunosignals per micrometer in the junctional clefts. BBB disruption at the sonicated locations was confirmed by the leakage of intravenously administered horseradish peroxidase (HRP, m.w. 40,000 Da) and lanthanum chloride (La 3+ , m.w. ~ 139 Da). Leakage of these agents was observed at 1 and 2 h and in a few vessels at 4 h after ultrasound application. These changes were paralleled by the apparent disintegration of the TJ complexes, as evidenced by the redistribution and loss of the immunosignals for occludin, claudin-5 and ZO-1. Claudin-1 seemed less involved. At 6 and 24 h after sonication, no HRP or lanthanum leakage was observed, and the barrier function of the TJs, as indicated by the localization and density of immunosignals, appeared to be completely restored. This study provides the first direct evidence that ultrasound bursts combined with a gas contrast agent cause disassembling of the TJ molecular structure, leading to loss of the junctional barrier functions in brain microvessels. The BBB disruption appears to last up to 4 h after sonication and permits the paracellular passage of agents with molecular weights up to at least 40 kDa. These promising features can be exploited in the future development of this method that could enable the delivery of drugs, antibodies or genes to targeted locations in the brain.

These results demonstrate that low-frequency ultrasound bursts can induce local, reversible disruption of the BBB without undesired long-term effects. This technique offers a potential noninvasive method for targeted drug delivery in the brain aided by a relatively simple low-frequency device.

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Brain disorders, such as tumors, functional problems, etc., are difficult to treat and the invasive interventions often disturb surrounding brain tissue, resulting in complications. In addition, the delivery of therapeutic agents to the brain via the blood supply is often impossible because the blood brain barrier protects the brain tissue from foreign molecules. Our hypothesis has been that transcranial therapeutic ultrasound exposures can be delivered with an optimized phased-array system. We have demonstrated that highly focused therapeutic ultrasound beams can be accurately delivered through an intact human skull noninvasively. Furthermore, we demonstrated using ex vivo human skulls that we can use CT-derived information to predict the phase shifts required for correcting the wave distortion. We have also developed a method to focally disrupt the blood brain barrier without damaging the neurons in the targeted tissue volume. This may allow delivery of therapeutic or diagnostic agents into image-specified locations. Successful transcranial delivery of ultrasound in a clinical setting may have a major impact on the treatment of brain disorders in the future.

The objective of our research during the past few years has been to develop multichannel ultrasound phased arrays for noninvasive brain interventions. We have been successful in developing methods for correcting the skull induced beam distortions and thus, are able to produce sharp focusing through human skulls. This method is now being tested for thermal ablation of tumors, with results from animal studies demonstrating feasibility. In addition, the ability of ultrasound to open the blood-brain barrier (BBB) locally has been explored in animal models. The results suggest that the transcranial ultrasound exposures can induce BBB opening such that therapeutic agents can be localized in the brain. This tool is especially powerful since the beam can be guided by MR images, thus providing anatomical or functional targeting. This talk will review our current status in this research, which ultimately aims for the clinical use of this methodology.