Focused ultrasound combined with drug-loaded microbubbles suppresses ictal spikes in kainic acid-induced epileptic animals

Current epilepsy treatments include anti-seizure medications (ASMs), surgical interventions, and neuromodulation. However, achieving precise, non-invasive seizure control continues to pose a significant clinical challenge. Transcranial-focused ultrasound (FUS) combined with microbubbles (MBs) has been employed to enhance localized chemotherapy drug delivery for brain tumors, yet its potential for improving ASMs delivery and modulating epileptic excitability has yet to be investigated. This study proposes a novel epilepsy treatment strategy using FUS with ASM- lacosamide-loaded MBs (L-MBs). Our results show that the accumulation of Lacosamide was significantly enhanced 8-fold in the targeted brain region (left CA1) in kainic acid-induced epileptic rats with L-MBs + 1-MHz FUS at 500 kPa, while heart tissue concentration was reduced by 55.6 % compared to direct IV administration. The most pronounced suppression of epileptic spikes was achieved at 500 kPa, resulting in a 91.5 % reduction in spike count within the initial 60 minutes post-treatment. This suppressive effect persisted for up to 180 minutes, with reductions of 82.2 % and 77.2 % observed during the 61-120 and 121-180 minutes intervals, respectively. Gamma power was significantly decreased in epileptic rats under 500 kPa FUS + L-MBs accompanied by the spike reduction. This minimally invasive, targeted delivery platform provides a promising alternative for managing drug-resistant focal epilepsy by enhancing focal ASM bioavailability and minimizing systemic adverse effects. Further preclinical and clinical studies are warranted to advance this strategy toward therapeutic application.