Drug delivery to subcortical regions is susceptible to the blood-brain barrier (BBB) impeding 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 primordial importance yet restrained to the targeting optimization. The current paper establishes the linear relationship of the incidence angle with the volume of BBB opening (VBBB) and the Peak Negative Pressure (PNP) when sonicating the Caudate Nucleus and the Putamen region of five non-human-primates. 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 through 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 opening was found to be shifted axially, towards the transducer, and laterally with an average angle shift at 4.5°. Finally, we were capable of showing reproducibility of targeting accuracy with the same stereotactic and ultrasonic parameters. This study documents the a priori prediction of the opening volume through manipulation of the angle and pressure as well as establishing the predictability, accuracy and safety of FUS induced BBB opening in NHPs.
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