FUS-mediated BBB opening leads to transient perfusion decrease and inflammation without acute or chronic brain lesion.

Impact: The permeabilization of the BBB to deliver therapeutics with MR-guided FUS redefines therapeutic strategies as it improves patient outcomes. To ensure the best translation towards clinical treatment, the evaluation of hemodynamic modifications in the CNS is necessary to refine treatment parameters. Methods: MR-guided FUS was applied at 1.5 MHz with a 50 ms burst every 1 s to open the BBB. CBF, BVf and ADC parameters were monitored with MRI. Cavitation was monitored with a PCD during the FUS sequence and classified with the IUD index into three cavitation levels. We distinctly applied the FUS in the cortex or the striatum. After the BBB permeabilization, neuroinflammation markers were quantified longitudinally. Results: The BBB was successfully opened in all animals in this study and only one animal was classified as "hard" and excluded from the rest of the study. 30 min after FUS-induced BBB opening in the cortex, we measured a 54% drop in CBF and a 13% drop in BVf compared to the contralateral side. After permeabilization of the striatum, a 38% drop in CBF and a 15% drop in BVf were measured. CBF values rapidly returned to baseline, and 90 min after BBB opening, no significant differences were observed. We quantified the subsequent neuroinflammation, noting a significant increase in astrocytic recruitment at 2 days and microglial activation at 1 day after FUS. After 7 days, no more inflammation was visible in the brain. Conclusion: FUS-induced BBB opening transiently modifies hemodynamic parameters such as CBF and BVf, suggesting limited nutrients and oxygen supply to the CNS in the hour following the procedure.

Introduction

Purpose Drug delivery with BBB opening

Study Objective To measure and compare changes in brain perfusion over time following focused ultrasound-mediated blood-brain barrier permeabilization.

Animal model / Human subject Rattus norvegicus (rat), Wistar Han strain, 7 weeks old, male

Disease model healthy

MRI or image guidance method MR-guided FUS using axial and coronal T1-weighted (FLASH) and T2 TurboRARE MRI to establish transducer position (computed offline with ThermoGuide®); electronic steering of the transducer to place/adjust the focal point.

Targeted brain region(s) Striatum

Target coordinates not provided

Cargo name and characteristics Gd-DOTA (DOTAREM) — small-molecule gadolinium-based MRI contrast agent, dose 200 µmol/kg; USPIO nanoparticles (Synomag‑D, Micromod) — ultrasmall superparamagnetic iron oxide nanoparticles ~50 nm, used at 200 µmol Fe/kg (for BVf measurements)

Route of administration intravenous (tail vein catheter)

Outcomes and Safety

Summary of Outcomes MR‑guided focused ultrasound (1.5 MHz, 50 ms bursts every 1 s, mechanical index ≈0.5) with lipid microbubbles reliably opened the BBB (all but one 'hard' case) and produced transient hypoperfusion (CBF reduced ~54% in cortex, ~38% in striatum) and BVf reductions (~13–15%) that normalized within ~90 min–24 h and elicited transient microglial (peak day 1) and astrocytic (peak days 2–3) activation resolving by 7 days.

Duration of biological effect 1 hour

Safety-related matter One animal showed haemorrhage with erythrocyte extravasation and was excluded; otherwise 95% of procedures resulted in neither oedema nor bleeding by MRI and H&E. FUS caused transient hypoperfusion (CBF decreased up to ~54% in cortex and ~38% in striatum; BVf reduced ~13–15%) lasting ~90 min and transient neuroinflammation (microglial activation at day 1, astrocytic recruitment peaking days 2–3) that resolved by 7 days, with no persistent tissue lesions under the reported settings.

Brain Region

Ultrasound Parameters

Ultrasound instrument Dedicated MR-guided FUS system (Image Guided Therapy, Pessac, France); seven-concentric-elements transducer (Imasonic, Voray-sur-l'Ognon, France); center frequency 1.5 MHz; radius of curvature 20.01 mm; focal length 20 mm; transducer aperture/diameter: None

FUS Frequency 1.5 MHz (FUS center frequency); 2 MHz (passive cavitation detector central frequency); hydrophone ±3 dB frequency range 0.25–40 MHz; 50 kHz bandwidth for harmonic/ultraharmonic analysis

FUS Pressure 0.6 MPa

FUS Mode pulsed

Pulse duration 50 ms

Duration of a single FUS session 60 s

Focal Characteristics focal depth: 6.6 mm; focal length: 20 mm; aperture size: None

Treatment frequency single session

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