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

Po-Chun Chu; Hsiang-Yu Yu; Cheng-Chia Lee; Robert Fisher; Hao-Li Liu

doi:10.1007/s13311-022-01250-7

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

Neurotherapeutics. 2022 Jul;19(4):1368-1380. doi: 10.1007/s13311-022-01250-7. Epub 2022 May 17.

Authors

Po-Chun Chu¹, Hsiang-Yu Yu^{2

3}, Cheng-Chia Lee^{3

4}, Robert Fisher⁵, Hao-Li Liu⁶

Affiliations

¹ Department of Electrical Engineering, National Taiwan University, Taipei, Taiwan, 106.
² Department of Neurology, Taipei Veteran General Hospital, Taipei, Taiwan.
³ School of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan.
⁴ Department of Neurosurgery, Taipei Veteran General Hospital, Taipei, Taiwan.
⁵ Department of Neurology, Stanford Neuroscience Health Center, Stanford University School of Medicine, 213 Quarry Road, Room 4865, Palo Alto, CA, 94304-5979, USA. robert.fisher@stanford.edu.
⁶ Department of Electrical Engineering, National Taiwan University, Taipei, Taiwan, 106. hlliu@ntu.edu.tw.

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 (I_SPTA) 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, I_SPTA 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 I_SPTA 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.

Keywords: Focused ultrasound; Kainic acid model; Neuromodulation; Temporal lobe epilepsy.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Electroencephalography
Epilepsy* / chemically induced
Epilepsy* / therapy
Gliosis
Hippocampus
Inflammation
Kainic Acid* / toxicity
Male
Rats
Rats, Sprague-Dawley
Seizures / chemically induced
Seizures / therapy

Substances

Kainic Acid