Transcranial sonothrombolysis using high-intensity focused ultrasound: impact of increasing output power on clot fragmentation.
Authors: Ahadi G, Welch CS, Grimm MJ, Fisher DJ, Zadicario E, Ernström K, Voie AH, Hölscher T
The primary goal of this study was to investigate the relationship between increasing output power levels and clot fragmentation during high-intensity focused ultrasound (HIFU)-induced thrombolysis. A HIFU headsystem, designed for brain applications in humans, was used for this project. A human calvarium was mounted inside the water-filled hemispheric transducer. Artificial thrombi were placed inside the skull and located at the natural focus point of the transducer. Clots were exposed to a range of acoustic output power levels from 0 to 400 W. The other HIFU operating parameters remained constant. To assess clot fragmentation, three filters of different mesh pore sizes were used. To assess sonothrombolysis efficacy, the clot weight loss was measured. No evidence of increasing clot fragmentation was found with increasing acoustic intensities in the majority of the study groups of less than 400 W. Increasing clot lysis could be observed with increasing acoustic output powers. Transcranial sonothrombolysis could be achieved in vitro within seconds in the absence of tPA and without producing relevant clot fragmentation, using acoustic output powers of <400 W.
Introduction
Purpose
Sonothrombolysis
Study Objective
To investigate whether increasing HIFU acoustic output power levels increase clot fragmentation during HIFU-induced thrombolysis.
Animal model / Human subject
human skull
Disease model
Ischemic stroke (cerebral thrombosis)
MRI or image guidance method
Aligned to the HIFU system's natural focus (geometric center of the hemispheric transducer) using fixed X/Y/Z coordinates (0/0/150 mm); focus was electronically steered along the thrombus to nine locations (2 mm steps). No MRI or other image guidance reported.
Target coordinates
X/Y/Z = 0/0/150 mm; steered along longitudinal axis from -10/0/150 mm to +10/0/150 mm in 2.0 mm steps (nine locations)
Outcomes and Safety
Summary of Outcomes
Transcranial HIFU produced rapid, power‑dependent in vitro sonothrombolysis with statistically significant clot weight loss at acoustic output powers ≥125 W (125, 150, 200, 235, 270 and 400 W). Clot fragmentation was minimal (no significant fragmentation on 11 μm and 60 μm filters) and only showed a clinically relevant increase for the 180 μm filter at the highest power (400 W) (a 150 W signal was statistically significant but likely artifactual).
Duration of biological effect
within seconds
Safety-related matter
The authors report that transcranial HIFU sonothrombolysis produced no relevant clot fragmentation at acoustic output powers <400 W (though significant fragmentation was observed at 400 W and a likely measurement artefact at 150 W), and they emphasize safety concerns including clot-fragmentation–related distal emboli, secondary hemorrhage, cavitation and thermal effects, recommending in vivo studies to establish safety.
Brain Region
Ultrasound Parameters
Ultrasound instrument
ExAblate 4000 (InSightec, Inc., Tirat Carmel, Israel); hemispheric transducer; aperture/diameter: None
FUS Frequency
220 kHz
FUS Mode
pulsed
Pulse duration
200 ms
Duration of a single FUS session
30 s
Focal Characteristics
Focal depth: 150 mm; Focal length: None; Aperture size: None
Treatment frequency
single
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