Targeting effects on the volume of the focused-ultrasound-induced blood-brain barrier opening in Non-Human Primates in vivo

Drug delivery to subcortical regions is susceptible to the blood-brain barrier (BBB) hindering the molecular exchange between the blood stream and the brain parenchyma. Focused ultrasound coupled with the administration of microbubbles has been proven to open the BBB locally, transiently and non-invasively both in rodents and in Non-Human-Primates (NHPs). The development of this disruption technique independent of MRI monitoring is of outstanding importance yet restrained to the targeting optimization. The current paper establishes the linear relationship of the incidence angle with the volume of BBB opening (V_BBB) and the applied pressure when sonicating the Caudate Nucleus and the Putamen region of five NHPs. In addition, the effect of central nervous system structures on the opening morphology is evaluated by identification of the gray-to-white-matter ratio at the opening site. Finally, the targeting accuracy is assessed by estimation of the geometric and angle shift of the opening from the targeted region. Interestingly, results prove a monotonic increase of the opening volume with close to normal incidence angles. Moreover, 80.35% of the opening lies on gray matter regions compared to only 19.41% attributed to the white matter. The BBB opening was found to be shifted axially, towards the transducer, and laterally with an average angle shift at 4.5°. Finally, we were able to reproduce our findings by employing the same stereotactic and ultrasonic parameters in different experiments and animals. This study documents the a priori prediction of the opening volume through manipulation of the angle and pressure establishing the predictability, accuracy and safety of the current technique on NHPs.