Pulsed-Focused Ultrasound Provides Long-Term Suppression of Epileptiform Bursts in the Kainic Acid-Induced Epilepsy Rat Model

Abstract

Focused ultrasound (FUS) has potential utility for modulating regional brain excitability and possibly aiding seizure control; however, the duration of any beneficial effect is unknown. This study explores the efficacy and time course of a short series of pulsed FUS in suppressing EEG epileptiform spikes/bursts in a kainic acid (KA) animal model of temporal lobe epilepsy. Forty-four male Sprague–Dawley rats were recorded for 14 weeks with EEG while software calculated EEG numbers of epileptiform spikes and bursts (≥ 3 spikes/s). Four regimens of FUS given in a single session at week 7 were evaluated, with mechanical index (MI) ranging from 0.25 to 0.75, intensity spatial peak temporal average (ISPTA) from 0.1 to 2.8 W per cm2, duty cycle from 1 to 30%, and three consecutive pulse trains for 5 or 10 min each. Controls included sham injections in four and KA without FUS in eleven animals. Histological analysis investigated tissue effects. All animals receiving KA evidenced EEG spikes, averaging 10,378 ± 1651 spikes per 8 h and 1255 ± 199 bursts per 8 h by weeks 6–7. The KA-only group showed a 30% of increase in spikes and bursts by week 14. Compared to the KA-only group, spike counts were reduced by about 25%, burst counts by about 33%, and burst durations by about 50% with FUS. Behavioral seizures were not analyzed, but electrographic seizures longer than 10 s declined up to 70% after some FUS regimens. Repeated-measure ANOVA showed a significant effect of higher intensity and longer sonication duration FUS treatment using 0.75-MI, ISPTA 2.8 W/cm2, 30% duty cycle for 10-min sonications (group effect, F (4, 15) = 6.321, p < 0.01; interaction effect, F (44, 165) = 1.726, p < 0.01), with the hippocampal protective effect lasting to week 14, accompanied by decreased inflammation and gliosis effect. In contrast, spike and burst suppression were achieved using an FUS regimen with 0.25-MI ISPTA 0.5 W/cm2, 30% duty cycle for 10-min sonications. This regimen reduced inflammation and gliosis at weeks 8–14 and protected hippocampal tissue. This study demonstrates that low-intensity pulsed ultrasound can modulate epileptiform activity for up to 7 weeks and, if replicated in the clinical setting, might be a practical treatment for epilepsy.

Transcranial low-intensity ultrasound stimulation for treating central nervous system disorders: A promising therapeutic application

“…In these model mice, ultrasound delayed the onset of status epilepticus (SE) and inhibited acute seizure activity ( 65 ). Chu PC and colleagues found that, in the KA-induced epilepsy mouse model, LITUS could reduce the occurrence of seizures, and the effects lasted as long as 7 weeks ( 66 ).…”

Neuromodulatory Focused Ultrasound for Epilepsy: Are Animal Models Useful?

“…Chronic epilepsy animal models have consistently demonstrated that FUS session effectively suppresses epileptic signals in kainic acid (KA) models for up to seven weeks. 2 Duration of any therapeutic effect is of additional importance. Patients would not be likely to submit to daily sonications for an indefinite period of time.…”

“…Transcranial focused ultrasound (FUS) is a cutting-edge technology with the capability to precisely target deep brain tissue noninvasively while minimizing impact on adjacent regions . Recent studies have revealed that employing FUS to induce neuromodulatory effects holds promise in suppressing epileptiform discharges, thus offering potential for treating epilepsy . Several human clinical trials employing repeated FUS treatments for temporal lobe epilepsy (TLE) have been conducted, revealing promising therapeutic potential (see details in Supplementary Table 1).…”

“…While these interventions provide significant palliative benefits, their application is limited, and many patients may not meet the criteria for eligibility. 2 Transcranial focused ultrasound (FUS) is a cutting-edge technology with the capability to precisely target deep brain tissue noninvasively while minimizing impact on adjacent regions. 4 Recent studies have revealed that employing FUS to induce neuromodulatory effects holds promise in suppressing epileptiform discharges, thus offering potential for treating epilepsy.…”

“…4 Recent studies have revealed that employing FUS to induce neuromodulatory effects holds promise in suppressing epileptiform discharges, thus offering potential for treating epilepsy. 2 Several human clinical trials employing repeated FUS treatments for temporal lobe epilepsy (TLE) have been conducted, revealing promising therapeutic potential (see details in Supplementary Table 1). In 2021, Lee et al conducted a pilot study on FUS for epilepsy at the Taipei Veterans General Hospital (VGH), Taiwan, reporting a reduction in seizures within 72 h in 1/3 of the patients.…”