Abstract
Focused ultrasound with microbubbles has been used to noninvasively and selectively deliver pharmacological agents across the blood-brain barrier (BBB) for treating brain diseases. Acoustic cavitation monitoring could serve as an on-line tool to assess and control the treatment. While it demonstrated a strong correlation in small animals, its translation to primates remains in question due to the anatomically different and highly heterogeneous brain structures with gray and white matteras well as dense vasculature. In addition, the drug delivery efficiency and the BBB opening volume have never been shown to be predictable through cavitation monitoring in primates. This study aimed at determining how cavitation activity is correlated with the amount and concentration of gadolinium delivered through the BBB and its associated delivery efficiency as well as the BBB opening volume in non-human primates. Another important finding entails the effect of heterogeneous brain anatomy and vasculature of a primate brain, i.e., presence of large cerebral vessels, gray and white matter that will also affect the cavitation activity associated with variation of BBB opening in different tissue types, which is not typically observed in small animals. Both these new findings are critical in the primate brain and provide essential information for clinical applications.
Highlights
To ensure an effective and safe blood-brain barrier (BBB) opening for drug delivery and treatment, cavitation associated with BBB opening could be monitored[19]
The acoustic cavitation emission were recorded and calculated in real time, where SCDh denotes stable cavitation dose with harmonics, SCDu for stable cavitation dose with ultraharmonics, and ICD for inertial cavitation dose. (G,H)
Quantified cavitation doses (SCDh: stable cavitation dose with harmonics, SCDu: stable cavitation dose with ultraharmonics, ICD: inertial cavitation dose) were correlated with the BBB opening outcomes
Summary
To ensure an effective and safe BBB opening for drug delivery and treatment, cavitation associated with BBB opening could be monitored[19]. Cavitation monitoring in NHP for assessing BBB opening was found to be highly variable[14] and was not correlated with the BBB opening outcome such as opening volume[33], unlike in small animals such as rodents that showed good correlation We hypothesized that this discrepancy may be due to the heterogeneous and gyrencephalic nature of the primate brain (i.e., gray and white matter, and large cerebral vessels) in primates or the targeting parameters. For the quantitative analysis of BBB opening volume and drug delivery efficiency, T1-weighted (T1w) imaging and variable flip-angle (VFA) T1 mapping in magnetic resonance imaging (MRI) were performed 1 h following BBB opening These opening outcomes were correlated with the acquired acoustic monitoring findings in order to assess the PCD predictability value among animals. The effect of the incidence angle with respect to the skull on cavitation monitoring was evaluated by varying the targeting angle with PCD calibration as well
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