Influence of exposure time and pressure amplitude on blood-brain-barrier opening using transcranial ultrasound exposures

Pulsed ultrasound exposures of brain tissue in the presence of microbubble contrast agents have been shown to achieve transient focal disruption of the blood-brain barrier without significant damage to surrounding brain tissue. The effects of overall exposure duration on the extent of blood-brain barrier disruption was studied in these experiments to determine operating conditions for increasing the amount of therapeutic agents delivered to the brain. Exposures at 1.08 MHz ranging from 0.2 to 0.8 MPa in amplitude were delivered transcranially to the brains of rabbits and rats for durations ranging from 30 to 1200 s. The amount of signal enhancement on contrast-enhanced T1-weighted MR images were used to quantify the extent of blood-brain barrier disruption, and histological evaluation of the exposed regions was performed to evaluate the impact on brain tissue. A subset of four rats underwent weekly exposures for 3 weeks to evaluate the feasibility of repeat sonications to the brain. The results suggest that exposures less than 180 s in duration are associated with a low probability of irreversible damage to brain tissue at pressure amplitudes of 0.38 MPa. Although exposures greater than 300 s were associated with an increase in the proportion of irreversible damage, this may be acceptable for chemotherapy delivery, where the therapeutic goal is tissue destruction. Repeat exposures to the brain were feasible but resulted in evidence of focal brain damage in 50% of animals.