Abstract
Focused Ultrasound (FUS) coupled with intravenous administration of microbubbles (MB) is a non-invasive technique that has been shown to reliably open (increase the permeability of) the blood-brain barrier (BBB) in multiple in vivo models including non-human primates (NHP). This procedure has shown promise for clinical and basic science applications, yet the safety and potential neurological effects of long term application in NHP requires further investigation under parameters shown to be efficacious in that species (500kHz, 200–400 kPa, 4–5μm MB, 2 minute sonication). In this study, we repeatedly opened the BBB in the caudate and putamen regions of the basal ganglia of 4 NHP using FUS with systemically-administered MB over 4–20 months. We assessed the safety of the FUS with MB procedure using MRI to detect edema or hemorrhaging in the brain. Contrast enhanced T1-weighted MRI sequences showed a 98% success rate for openings in the targeted regions. T2-weighted and SWI sequences indicated a lack edema in the majority of the cases. We investigated potential neurological effects of the FUS with MB procedure through quantitative cognitive testing of’ visual, cognitive, motivational, and motor function using a random dot motion task with reward magnitude bias presented on a touchpanel display. Reaction times during the task significantly increased on the day of the FUS with MB procedure. This increase returned to baseline within 4–5 days after the procedure. Visual motion discrimination thresholds were unaffected. Our results indicate FUS with MB can be a safe method for repeated opening of the BBB at the basal ganglia in NHP for up to 20 months without any long-term negative physiological or neurological effects with the parameters used.
Highlights
The blood brain barrier (BBB) is a highly selective biological system that maintains brain homeostasis [1]
Food and water intake stayed consistent and the fluctuations were not significant when compared to a control non-human primates (NHP) not being used in the Focused Ultrasound (FUS) with MB procedures housed in the same facility
For the results reported from the experiments in this study, no NHP responded to the FUS with MB procedures with physical deficits as discussed above
Summary
The blood brain barrier (BBB) is a highly selective biological system that maintains brain homeostasis [1]. Our group and others have shown over the past decade that focused ultrasound (FUS) with microbubbles (MB) is an effective technique to open the BBB for multiple in vivo animal models [8],[9],[10],[11]. This technique is performed noninvasively and the opening closes within hours to days depending on the acoustic pressure used [12],[13]. FUS with MB is a promising technique for targeted drug delivery in the central nervous system, but before clinical application of this technique in humans can occur, the long term effects of the technique on behavioral and cognitive function must be further investigated
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
