Low Intensity Focused Ultrasound for Epilepsy— A New Approach to Neuromodulation

Abstract

Patients with drug-resistant epilepsy (DRE) who are not surgical candidates have unacceptably few treatment options. Benefits of implanted electrostimulatory devices are still largely palliative, and many patients are not eligible to receive them. A new form of neuromodulation, low intensity focused ultrasound (LIFUS), is rapidly emerging, and has many potential intracranial applications. LIFUS can noninvasively target tissue with a spatial distribution of highly focused acoustic energy that ensures a therapeutic effect only at the geometric focus of the transducer. A growing literature over the past several decades supports the safety of LIFUS and its ability to noninvasively modulate neural tissue in animals and humans by positioning the beam over various brain regions to target motor, sensory, and visual cortices as well as frontal eye fields and even hippocampus. Several preclinical studies have demonstrated the ability of LIFUS to suppress seizures in epilepsy animal models without damaging tissue. Resection after sonication to the antero-mesial lobe showed no pathologic changes in epilepsy patients, and this is currently being trialed in serial treatments to the hippocampus in DRE. Low intensity focused ultrasound is a promising, novel, incisionless, and radiation-free alternative form of neuromodulation being investigated for epilepsy. If proven safe and effective, it could be used to target lateral cortex as well as deep structures without causing damage, and is being studied extensively to treat a wide variety of neurologic and psychiatric disorders including epilepsy.

Recent advances in epilepsy surgery

“…Focus ultrasound includes two main therapeutic mechanisms: thermal ablation of epileptogenic regions using high-intensity focus ultrasound (HIFU) or, neuromodulation of epileptogenic networks using lowintensity focus ultrasound (LIFU). Several preclinical studies have demonstrated that focus ultrasound can ablate or suppress epileptiform activity in animal epilepsy models [51]. Two anecdotal case reports have been published showing improvement in seizure control after HIFU tissue ablation in patients with hypothalamic hamartoma [52,53].…”

“…Two anecdotal case reports have been published showing improvement in seizure control after HIFU tissue ablation in patients with hypothalamic hamartoma [52,53]. Moreover, several human pilot studies have shown that LIFU is able to elicit cortical modulatory effects in several brain regions [51], with some studies showing alteration of EEG oscillations following LIFU [54]. A recent report has demonstrated that LIFU in presurgical patients with TLE resulted in no histological signs of tissue damage to the resected mesial temporal structures [55], conveying a well tolerated profile to LIFU for neuromodulation in DRE.…”

Emerging Trends in the Management of Cryptogenic Epilepsy

“…High-intensity FUS (~1000 W/cm 2 ) execute the thermoablation effect, while low-intensity mode (~3 W/cm 2 ) showed neuromodulatory effects and suppressive effects on the frequency of epileptic signal bursts. The proposed mechanism of action of low-intensity FUS included the following [78]:…”

Early-phase neuroplasticity induced by offline transcranial ultrasound stimulation in primates

“…There are ongoing clinical trials testing the efficacy of TUS for the treatment of drug-resistant epilepsy [45], after its safety has been established in animal models. In a penicillin-induced epilepsy model in two non-human primates, offline TUS decreased the seizure frequency and duration in both macaques for up to seven hours after TUS [46].…”