Focused Ultrasound in the Treatment of Epilepsy: Current Applications and Future Directions.

Introduction: Epilepsy is the fourth most common neurological disorder, affecting nearly 1% of the global population. Despite recent advancements in medical therapies, approximately one-third of patients remain refractory to treatment, necessitating consideration of surgical intervention. Historically, epilepsy surgery has been invasive and maximalist in nature, involving extensive brain resections with significant risk for morbidity. However, emerging approaches offer promising, less-invasive alternatives. One such technique is focused ultrasound (FUS), a rapidly evolving, incisionless, image-guided therapy that allows physicians to precisely target specific brain regions with ultrasonic energy to achieve a range of therapeutic effects.

Methods: Systematic methods were implemented to define the scope of preclinical and clinical applications of FUS to treat epilepsy. Inclusion criteria included preclinical experiment, case study, case series, cohort studies, and clinical trials involving therapeutic application of FUS for treatment of epilepsy of any etiology. The primary exclusion criterion was FUS for indications other than treatment of epilepsy.

Results: Forty-six published articles and 9 ongoing clinical trials were included for a total of 55 studies. For ablative therapies, 10 studies were identified, of which 2 were preclinical studies, 1 was a clinical proof-of-concept study, 3 were clinical case reports, 1 was a completed clinical pilot study, and 3 were ongoing Phase I-Phase II clinical trials. For neuromodulatory FUS, 30 studies were identified, of which 19 were preclinical studies, 1 was a clinical case report, 4 were clinical pilot studies, and 6 were ongoing Phase I-Phase II clinical trials. Lastly, with respect to FUS-mediated blood-brain barrier (BBB) opening studies, 15 were identified, all of which were preclinical studies.

Discussion: Currently, FUS has been clinically applied for targeted brain ablation (high intensity [HIFU]) and neuromodulation (low intensity [LIFU]), with recent basic science applications of sonogenetics and targeted drug delivery through the BBB (Precise Intracerebral Noninvasive Guided, or PING, Surgery) offering new opportunities for clinical translation. This review summarizes preclinical and clinical applications of FUS for epilepsy treatment, addresses challenges to implementation, and explores key areas for future research.