State of the art on microbubble cavitation monitoring and feedback control for blood-brain-barrier opening using focused ultrasound
Paul Mondou,
Sébastien Mériaux,
Florent Nageotte
et al.
Abstract:Focused ultrasound is a non-invasive and highly promising method for targeted and reversible blood-brain barrier permeabilization. Numerous preclinical studies aim to optimize this localized drug delivery method in rodents and non-human primates. A few clinical trials have been initiated to treat various brain diseases in humans using simultaneous BBB permeabilization and drug injection. This review presents the state of the art of in vitro and in vivo cavitation control algorithms for BBB permeabilization usi… Show more
“…MRI of gadolinium in the brain parenchyma is used (Hynynen et al 2001) to verify the extent of BBBO because the gadolinium compounds used as contrast agents in MRI do not cross the undisturbed BBB. Acoustic monitoring is used in FUS-BBBO to minimize damage because inertial and non-inertial cavitation have particular backscatter signatures which are used to distinguish and quantify them (Mondou et al 2023). Acoustic mapping approaches use a multi-element imaging transducer to receive scattered signals during FUS sonication and beamform maps of the acoustic activity.…”
Objective – Linking cavitation and anatomy was found to be important for predictable outcomes in Focused-Ultrasound Blood-Brain-Barrier-Opening and requires high resolution cavitation mapping. However, cavitation mapping techniques for planning and monitoring of therapeutic procedures either 1) do not leverage the full resolution capabilities of ultrasound imaging or 2) place strong constraints on the length of the therapeutic pulse. This study aimed to develop a high-resolution technique that could resolve vascular anatomy in the cavitation map. 
Approach – Herein, we develop BP-ETACI, derived from bandpass sampling and dual-frequency contrast imaging at 12.5 MHz to produce cavitation maps prior and during blood-brain barrier opening with long therapeutic bursts using a 1.5-MHz focused transducer in the brain of C57BL/6 mice. 
Main Results – The BP-ETACI cavitation maps were found to correlate with the vascular anatomy in ultrasound localization microscopy vascular maps and in histological sections. Cavitation maps produced from non-blood-brain-barrier disrupting doses showed the same cavitation-bearing vasculature as maps produced over entire blood-brain-barrier opening procedures, allowing use for 1) monitoring FUS-BBBO, but also for 2) therapy planning and target verification. 
Significance – BP-ETACI is versatile, created high resolution cavitation maps in the mouse brain and is easily translatable to existing FUS-BBBO experiments. As such, it provides a means to further study cavitation phenomena in FUS-BBBO.
“…MRI of gadolinium in the brain parenchyma is used (Hynynen et al 2001) to verify the extent of BBBO because the gadolinium compounds used as contrast agents in MRI do not cross the undisturbed BBB. Acoustic monitoring is used in FUS-BBBO to minimize damage because inertial and non-inertial cavitation have particular backscatter signatures which are used to distinguish and quantify them (Mondou et al 2023). Acoustic mapping approaches use a multi-element imaging transducer to receive scattered signals during FUS sonication and beamform maps of the acoustic activity.…”
Objective – Linking cavitation and anatomy was found to be important for predictable outcomes in Focused-Ultrasound Blood-Brain-Barrier-Opening and requires high resolution cavitation mapping. However, cavitation mapping techniques for planning and monitoring of therapeutic procedures either 1) do not leverage the full resolution capabilities of ultrasound imaging or 2) place strong constraints on the length of the therapeutic pulse. This study aimed to develop a high-resolution technique that could resolve vascular anatomy in the cavitation map. 
Approach – Herein, we develop BP-ETACI, derived from bandpass sampling and dual-frequency contrast imaging at 12.5 MHz to produce cavitation maps prior and during blood-brain barrier opening with long therapeutic bursts using a 1.5-MHz focused transducer in the brain of C57BL/6 mice. 
Main Results – The BP-ETACI cavitation maps were found to correlate with the vascular anatomy in ultrasound localization microscopy vascular maps and in histological sections. Cavitation maps produced from non-blood-brain-barrier disrupting doses showed the same cavitation-bearing vasculature as maps produced over entire blood-brain-barrier opening procedures, allowing use for 1) monitoring FUS-BBBO, but also for 2) therapy planning and target verification. 
Significance – BP-ETACI is versatile, created high resolution cavitation maps in the mouse brain and is easily translatable to existing FUS-BBBO experiments. As such, it provides a means to further study cavitation phenomena in FUS-BBBO.
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