Oscillatory effects of ketamine using focused ultrasound sensitive liposomes

Abstract

The blood brain barrier (BBB) poses a significant challenge in the treatment of neurological disorders by preventing the diffusion of medications into the brain. Focused ultrasound (FUS) enables noninvasive modulation of the central nervous system by targeting millimeter-sized regions of the cortical and sub-cortical brain. We have synthesized ultrasound-sensitive nanoparticles (NPs) to encapsulate small, hydrophobic neuromodulators. Recent data has shown that our NPs deliver pharmacological drugs across the BBB when paired with FUS to the desired region of the brain with targeted accuracy. This method enables us to study the impact of small hydrophobic anesthetics across different regions of the brain. The aim of the study is to determine the electrophysiological effects of FUS neuromodulation in an awake small animal model. Specifically, we aim to understand the oscillatory effects of localized ketamine activity on the thalamocortical system. We hypothesized that localized delivery of ketamine in the central thalamus (CL) will induce slow-delta and gamma oscillations comparable to the recorded frequencies obtained from systemic delivery of ketamine. Using in-house electrocorticogram (ECoG) hardware, we recorded signals from the prefrontal cortex, CL, and visual cortex in awake-restraint rats. Preliminary results suggest that FUS-only neuromodulation of the brain induced undetectable oscillatory differences from baseline signals. We then investigated the electrophysiologic signatures of localized ketamine activity. Ketamine-loaded NPs were administered intravenously to rats via bolus injection and FUS was applied to the desired brain region for site-specific drug uncaging. Initial evidence indicated localized delivery of ketamine induced similar slow-delta and gamma oscillations in a smaller timeframe than those recorded after systemic ketamine administration. These results provide insight into the impacts of pharmacological modulation in relation to brain activity. Future directions include analyzing the thalamocortical system as a potential binding site for ketamine to induce anesthetic-specific oscillations.