The combination of
focused ultrasound (FUS) applied to the skull
and gas-filled microbubbles injected intravenously is
an emerging technique for delivering drugs to the brain. The microbubbles circulating in the bloodstream begin to oscillate (a phenomenon known as cavitation) under the effect of low-intensity pulsed ultrasound, inducing mechanical stress on the vascular walls. In response, the local permeability of cerebral capillaries increases for several hours, enabling the local delivery of therapeutic molecules injected simultaneously.
This technique requires precise control of the applied ultrasound pressure to ensure the efficacy, reproducibility, and safety of protocols. It must also be
tested and validated in preclinical studies, particularly
using large animal models, to obtain authorization for clinical trials. The use of non-human primate models is essential, as they are much closer to humans than rodents in terms of both the anatomical and functional complexity of the brain and the properties of the skull.
Researchers from the BioMaps laboratory (SHFJ) and BAOBAB (NeuroSpin) have already demonstrated the value of a method co-developed with MIRCen (CEA-Jacob). This method involves
a classic feedback loop algorithm that detects the signal returned by the bubbles during ultrasound pulses and adjusts the ultrasound pressure accordingly to prevent the harmful implosion of the bubbles (see the original article: doi: 10.1177/0271678X17753514 and the
2020 news link).
Distinguishing the components of cavitation to suppress one of them
However, specific characteristics of primate heads can complicate this feedback control. In large males, the temporal muscles are highly perfused and
fill with microbubbles,
inducing extracranial cavitation that masks the cavitation in the region of interest.
The researchers now propose an optimization of their initial strategy to distinguish intracranial cavitation from extracranial cavitation by analyzing the broadband noise recorded by passive cavitation detection sensors.
The skull acts as a filter: it allows low frequencies to pass through while attenuating high frequencies. This effect enables the differentiation of distinct frequency components, providing information about the origin of the cavitation:
- In animals with thin temporal muscles (~< 5 mm), the optimized algorithm detects no extracranial cavitation, and the "classic" algorithm is sufficient to ensure proper opening of the BBB.
- In animals with thicker muscles (> 15 mm), the optimized algorithm detects extracranial cavitation and filters this signal to retain only the signature of intracranial cavitation, functioning according to the principle of the initial algorithm.
The study was conducted on seven animals, both male and female, from two macaque species, in compliance with French and European regulations. A total of 17 BBB openings were performed.
Essential Academic-MedTech Collaboration
This study was conducted jointly with TheraSonic, a medtech startup resulting from 15 years of R&D by CEA teams. TheraSonic is developing a medical robot for delivering focused ultrasound to the brain without surgery or anesthesia, enabling drug delivery to the brain. To go further: https://www.therasonic.fr/
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