6A-4 Focused Ultrasound Potential to Initiate Spreading Depression for Disruption of Blood Brain Barrier

Blood-brain barrier (BBB) has long been known to impede the delivery of therapeutic and diagnostic agents into the central nervous system. Although ultrasound with microbubbles has been shown to disrupt the BBB, we presently examine another ultrasound-induced mechanism for opening of the BBB: ultrasound induction of spreading depression. In this process, local physical changes induced by the ultrasound pressure field, increase regional [K
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concentration to the point of depolarization, thus initiating an oscillation process known as auto-waves or Leao spreading depression that propagates through the nerve tissue causing reversible depression of spontaneous neuronal activity. Cortical spreading depression (CSD) was induced in the brain of 18 rats by focused ultrasound (FUS) exposure (frequency: 4.89 MHz) through both the skull window (n=13) and the intact skull (n=5). CSD was also induced by application of 4 muL of 2%KCl to the cortex (n=10). Electrical activity of the cerebral cortex (ECoG) was recorded by using implanted electrodes. Occurrence of the CSD was verified through the depression of the ECoG high-frequency activity in a gamma band (>20 Hz). Five to seven CSD's were initiated in each animal at the first day (electrode implantation) and induced repeatedly 1-7 days later. The CSD induced by both FUS and KCl was associated with BBB disruption detected by a leakage of trypan blue IV injected 18-20 hours after the last induced CSD. This result suggests that the FUS-induced spreading depression can be used for non-invasive BBB disruption in targeted locations. This disruption may be useful for targeted drug delivery in the brain.