Blood-Brain Barrier Opening in Behaving Non-Human Primates via Focused Ultrasound with Systemically Administered Microbubbles.

Over the past fifteen years, focused ultrasound coupled with intravenously administered microbubbles (FUS) has been proven an effective, non-invasive technique to open the blood-brain barrier (BBB) in vivo. Here we show that FUS can safely and effectively open the BBB at the basal ganglia and thalamus in alert non-human primates (NHP) while they perform a behavioral task. The BBB was successfully opened in 89% of cases at the targeted brain regions of alert NHP with an average volume of opening 28% larger than prior anesthetized FUS procedures. Safety (lack of edema or microhemorrhage) of FUS was also improved during alert compared to anesthetized procedures. No physiological effects (change in heart rate, motor evoked potentials) were observed during any of the procedures. Furthermore, the application of FUS did not disrupt reaching behavior, but in fact improved performance by decreasing reaction times by 23 ms, and significantly decreasing touch error by 0.76 mm on average.

Introduction

Purpose Drug delivery with BBB opening

Study Objective To demonstrate that focused ultrasound with intravenously administered microbubbles can safely and effectively open the blood-brain barrier in the basal ganglia and thalamus of alert non-human primates performing a behavioral task.

Animal model / Human subject Two adult male Macaca fascicularis (no strain specified), ages 14 and 18 years; one Macaca mulatta (no strain specified), age 21 years, sex None.

MRI or image guidance method Stereotactic targeting using a 9-degrees-of-freedom stereotactic manipulator (David Kopf Instruments) with head fixation/partial stereotactic positioning (custom bite bar); post-procedure 3T MRI (T2, SWI, contrast-enhanced T1) used to verify BBB opening and safety.

Targeted brain region(s) Thalamus

Cargo name and characteristics Ketamine — small-molecule anesthetic/sedative (IM; doses described: 0.3 ml or 5 mg/kg) ; Gadodiamide (Omniscan) — gadolinium-based MRI contrast agent (small-molecule chelate, 0.2 ml/kg IV)

Route of administration intravenous

Outcomes and Safety

Summary of Outcomes Focused ultrasound with intravenously administered microbubbles (FUS+IV MB) safely and effectively opened the BBB in alert non‑human primates at basal ganglia/thalamus (≈86–89% success; ~28% larger opening volumes vs anesthetized), with fewer imaging signs of edema/microhemorrhage, no adverse physiological effects, and modest behavioral benefits (≈23 ms faster reaction time and ≈0.76 mm reduced touch error); the successful parameter condition was FUS + IV microbubbles performed in alert (no isoflurane) animals compared to anesthetized procedures.

Safety-related matter The study reports that FUS safely opened the BBB in alert non-human primates with no edema or MRI-detectable microhemorrhage in most cases, no gross physiological effects (heart rate, EMG, motor activity) and no seizures; one transient T2-hyperintense voxel (possible edema) occurred in a single animal and resolved within one week.

Brain Region

Ultrasound Parameters

Ultrasound instrument 500-kHz focused ultrasound transducer (H-107, Sonic Concepts, WA, USA); center core removed for hydrophone placement (Y-107, Sonic Concepts, WA, USA). Transducer aperture/diameter: None

FUS Frequency 500 kHz

FUS Pressure 0.3 MPa

Pulse duration 120 s

Duration of a single FUS session 130 seconds (2 minutes 10 seconds)

Focal Characteristics Focal depth: None; Focal length: None; Aperture size: None

Treatment frequency Multiple sessions

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