Pulsed focused ultrasound for seizure suppression: Mechanisms, models, and clinical translation.

Focused ultrasound (FUS) has emerged as a versatile, non-invasive therapeutic platform for drug-resistant epilepsy, offering both thermal effects for the permanent ablation of epileptogenic foci and non-thermal mechanical mechanisms for the reversible neuromodulation of neural activity, all without the need for surgical implantation. Pulsed focused ultrasound (pFUS) achieves seizure control through seizure suppression via non-thermal mechanical mechanisms. At the cellular level, pFUS modulates mechanosensitive ion channels, and may interrupt astrocyte-mediated excitatory signaling pathways. At the network level, pFUS normalizes pathological hypersynchrony, particularly in thalamus-hippocampus circuits, reduces functional hyper-connectivity, and restores excitation-inhibition balance. Preclinical laboratory studies consistently demonstrate acute epileptiform spikes and seizure suppression, reduced seizure frequency, prolonged seizure-free intervals, and long-term neuroprotective and behavioral benefits (reduced anxiety, improved cognition and motor function). Early human trials and first-in-human pilot studies confirm excellent safety of transcranial pFUS (no histological damage, reversible effects) and provide preliminary suggestions of significant reductions in seizure frequency and severity in patients with refractory focal epilepsy. This comprehensive review integrates historical foundations, mechanistic insights from cellular to network levels, extensive preclinical evidence across acute and chronic epilepsy models, and the latest clinical translation on pFUS as a reversible, tunable anti-seizure strategy.