Ultrasonic Drug Uncaging
Today, the brain remains one of the most poorly understood organs in the human body in terms of quantitative physiology. For example, cardiac and pulmonary function have been quantitatively modeled to the point where we can practically replicate their function using external hardware for extended periods of time, such as with ECMO. Thanks to advances in electrophysiology, microscopy, and imaging, we have unprecedented ability to collect high-dimensional data about neural activity. However, the system remains underdetermined: without an easy way to perturb these neural circuits, the models and conclusions we can draw from the data are inherently limited in their scope. Clinically, methods for precise neuromodulation could help drastically change the way we think about treating neurologic or psychiatric disorders. Current methods for neuromodulation have several shortcomings:
They are invasive and/or require substantial gene therapy (e.g. optogenetics, deep brain stimulation)
They are nonspecific in the spatial or temporal domain: (e.g. transcranial magnetic stimulation, pharmaceuticals)
The mechanism of neuromodulation is poorly understood (e.g. direct ultrasound modulation)
My PhD thesis is centered around developing a method that utilizes nanoparticles that specifically drop their drug payload when placed in an ultrasound field. With transcranial focused ultrasound (FUS), we can precisely deliver medication to specific regions of the brain (volumes about 2-3 mm on a side). Effectively, this allows us to combine the precision and noninvasive nature of ultrasound with the potency and well-documented effects of psychoactive medication, without the addictive potential or side effects.
Delivering propofol to a specific brain region (marked with the black dotted circle, selectively anesthetizes the targeted brain region. After turning off sonication, brain activity returns back to normal within seconds.
Selectively silencing a region of the brain with targeted propofol delivery (marked with the asterisk) also silences distinct areas of the brain that are functionally connected to the primary target. This implies that ultrasonic drug uncaging can be used to map whole-brain networks that underlie general anesthesia.