Noninvasive Ultrasonic Drug Uncaging Maps Whole-Brain Functional Networks

Abstract

Summary Being able to noninvasively modulate brain activity, where and when an experimenter desires, with an immediate path towards human translation is a long-standing goal for neuroscience. To enable robust perturbation of brain activity while leveraging the ability of focused ultrasound to deliver energy to any point of the brain noninvasively, we have developed biocompatible and clinically-translatable nanoparticles that allow ultrasound-induced uncaging of neuromodulatory drugs. Utilizing the anesthetic propofol together with electrophysiological and imaging assays, we show that the neuromodulatory effect of ultrasonic drug uncaging is limited spatially and temporally by the size of the ultrasound focus, the sonication timing, and the pharmacokinetics of the uncaged drug. Moreover, we see secondary effects in brain regions anatomically distinct from and functionally connected to the sonicated region, indicating that ultrasonic drug uncaging could noninvasively map the changes in functional network connectivity associated with pharmacologic action at a particular brain target.

Summary: Order and Disorder in Brains and Behavior

“…Kim Butts Pauly showed direct brain activation and drug delivery by disrupting the bloodbrain barrier. Even more revolutionary techniques, presented by Yanik and Butts Pauly, promise to ultrasonically uncage drugs deep in the brain (Wang et al 2018). These methods are likely to revolutionize neuroscience and enable circuit-specific pharmacology in humans, an incredible feat.…”

Non-invasive molecularly-specific millimeter-resolution manipulation of brain circuits by ultrasound-mediated aggregation and uncaging of drug carriers

“…Therefore, for use in chronic treatments of many brain disorders, it is vital to achieve FUS-mediated drug release without compromising BBB as we demonstrated here. Recent studies by Airan et al 24,54,55 suggested that FUSsensitive perfluoropentane (PFP) nanoemulsions (instead of the microbubbles+liposomes used here) can allow delivery of lipophilic-only compounds to the brain without opening BBB. While highly interesting, these methods require extremely large amounts of encapsulated drug to be injected to observe any effects (nanoemulsions containing 1 mg kg −1 propofol need to be injected to show similar effects to systemic injection of only 2 mg kg −1 propofol).…”

Neuromodulation Management of Chronic Neuropathic Pain in the Central Nervous System

“…This would enable the spatially targeted drug or gene delivery. [205] Another successful demonstration is that the low-intensity tFUS is able to uncage and activate potential anesthetic agents, like propofol, ketamine, etc., [206] which is expected to enhance our capability for managing the pain by integrating the pharmacological effects into the ultrasound neuromodulation framework. In fact, cumulating experimental evidence on animal models has shed light upon the tFUS opening the BBB for modulating brain functional dynamics and even changing behavioral outcome once integrating with microbubbles and drug delivery.…”