Low‐intensity focused ultrasound neuromodulation for drug‐resistant epilepsy: A randomized, sham‐controlled crossover trial

OBJECTIVE: This study was undertaken to evaluate the safety, feasibility, and efficacy of low-intensity focused ultrasound (LIFU) as a noninvasive neuromodulation technique in patients with drug-resistant epilepsy (DRE). METHODS: In this pilot, single-blind, randomized sham-controlled crossover trial, 12 patients with DRE underwent both LIFU and sham stimulation in a randomized sequence, targeting the seizure onset zone (SOZ), each followed by a 4-week observation period. Seizure frequency was analyzed as proportional change from baseline using linear mixed-effects models. An open-label extension phase evaluated longitudinal seizure outcomes following LIFU. Safety assessments included neurological examinations, magnetic resonance imaging (MRI), and neuropsychological and quality of life (QOL) measures. RESULTS: During the crossover phase, LIFU did not significantly reduce seizure frequency compared with sham (estimate = .49, 95% confidence interval [CI] = -.04 to 1.01, p = .068). No period or sequence effects were observed. Conversely, during the open-label extension phase, seizure frequency demonstrated a significant longitudinal reduction following LIFU (β = -14.0 percentage points per month, 95% CI = -22.2 to -5.8, p = .001). Post-LIFU MRI showed no structural lesions. No significant changes were observed in anxiety, depression, or QOL scores. There were only transient mild-to-moderate adverse events reported, without serious complications. SIGNIFICANCE: LIFU neuromodulation targeting the SOZ is safe and well tolerated. Although the primary crossover analysis did not demonstrate a statistically significant antiseizure effect, delayed seizure reduction during the extended follow-up suggests potential sustained neuromodulatory effects. Larger parallel-group trials with longer observation periods are warranted.