On the Response of Brain Vasculature to focused Ultrasound and Microbubbles

The treatment of neuropathologies is complicated by many factors; common, however, to most afflictions is the inherent difficulty of delivering therapeutic agents from systemic circulation to brain parenchyma. Specialized cerebrovasculature regulates the passage of molecules, acting to preserve efficient neural function and to protect from infection and toxicity. While essential, the blood-brain barrier (BBB) hinders the development of effective treatment strategies. In combination with circulating microbubbles (MBs), focused ultrasound (FUS) can be used to transiently increase BBB permeability, providing an avenue for localized brain-drug delivery. There are, however, risks associated with perturbing homeostatic conditions by allowing substances to enter the brain that are excluded under physiological conditions. The work described in this thesis focuses on characterizing the impact of FUS+MB-mediated BBB permeability enhancement on brain vasculature and on providing a means to mitigate risk. To this end, a hypothesis-generating microarray analysis of gene expression changes in hippocampal microvasculature was performed in the acute stages following sonication. The principal finding of this study was differential gene expression indicative of acute inflammation 6 hours following sonication, a response that was present, but diminished, by 24 hours. This observation motivated a study of factors that contribute to sonication-induced inflammation, including MB dose and the degree of BBB permeability enhancement, both of which were found to influence the expression of several key proinflammatory markers. The pattern of gene expression changes detected in microarray analysis 24 hours following FUS+MB exposure also motivated the study of blood vessel growth. A modest increase in blood vessel density and newborn endothelial cell density was observed at 7- and 14-days following sonication, an effect that normalized by 21 days. Finally, to manage the risks associated with transiently increasing BBB permeability, the post-sonication administration of dexamethasone, a synthetic glucocorticoid, was studied. Dexamethasone was found to expedite the return of BBB integrity, as well as limit inflammation, astrocyte activation, and blood vessel growth following FUS+MB exposure. An in-depth description of these studies and their implications are discussed. The findings presented in this thesis have value in informing clinical cost-benefit analyses and may influence the design of novel brain therapies.Ph.D