Seung-Schik Yoo, PhD: Non-Pharmacological Enhancement of Convective Clearance of Intracortical Solutes Using Transcranial Focused Ultrasound

SEUNG-SCHIK YOO, PHD

Director, Neuromodulation and Tissue Engineering Laboratory (NTEL)
Brigham and Women’s Hospital
Associate Professor of Radiology
Harvard Medical School

Abstract

Brain lymphatic clearance of undesirable metabolic waste is important for normal brain function, with critical implications in neurological disorders such as dementia and Alzheimer’s disease. Convective bulk flow of solutes in the cerebrospinal fluid (CSF) in the perivascular space (PVS), being coupled to the intracortical solute transport, is considered one of the important mechanisms behind the brain solute movement, before their ultimate drainage to the systemic lymphatic system. Acoustic pressure waves can impose radiation force on a medium in its path, inducing localized and directional fluidic flow, known as acoustic streaming. We transcranially applied low-intensity focused ultrasound (FUS) to rats that received an intracisternal injection of fluorescent CSF tracers (dextran and ovalbumin, having two different molecular weights- Mw). The sonication pulsing parameter was determined on the set that propelled the aqueous solution of toluidine blue O dye into a porous media at the highest level of infiltration. Fluorescence imaging of the harvested brain sections showed that application of FUS increased the uptake of ovalbumin at the sonicated plane, particularly around the ventricles, whereas the uptake of high-Mw dextran was unaffected. We also demonstrated that FUS enhanced the transport of intracortically injected fluorescent ovalbumin and dextran, yielding greater parenchymal tracer volume distribution compared to the unsonicated control group. FUS did not alter the animals’ behavior or disrupt the blood-brain barrier (BBB), while yielding normal brain histology. The sonication did not elicit tissue-level neuronal excitation, measured by an electroencephalogram, nor did it alter the Mw of the tracers. Numerical simulation showed that the effects of sonication were non-thermal. These findings suggest that nonthermal transcranial FUS can enhance advective transport of CSF/interstitial solutes and their subsequent removal in a completely non-invasive fashion, offering its potential non-pharmacological utility in facilitating clearance of waste from the brain.

Short Bio

Seung-Schik is an Associate Professor of Radiology at Harvard Medical School and the Director of the Neuromodulation and Tissue Engineering Laboratory (NTEL) at Brigham and Women’s Hospital. He also serves as a faculty member of the Mind Brain Behavior Initiative at Harvard University. Currently, Seung-Schik’s primary research focuses on exploring a new mode of non-invasive technology to control regional neural function or to promote brain lymphatic clearance using focused ultrasound (FUS). His research interests also extend to the development of three-dimensional bioprinting methods to produce artificial neural tissues and organoids, with potential applications in neural computing and theragnostics. Seung-Schik is an inducted fellow of the Academy for Radiology and Biomedical Imaging Research as well as the American Institute of Ultrasound in Medicine, a recipient of the Jolesz Memorial Award from the Focused Ultrasound Surgery Foundation.