Abstracts

Rationale: Neuromodulation with focused ultrasound (FUS) stimulation was discovered more than 60 years ago (Fry.F.J,et al,1958). Once fully characterized, FUS has the potential to be used as non-invasive therapy for many neurological disorders. While a few early studies have demonstrated FUS seizure suppression in a model of acute focal epilepsy, chronic models have not been investigated. We sought to test the ability of FUS to noninvasively produce a focal lesion to suppress seizures in a chronic, focal model of epilepsy. Methods: Three Sprague-Dawley rats were used (all male, 280-350 g, Charles River Laboratories) in accordance to a UMN IACUC approved protocol to create a focal model of epilepsy with kainic acid (KA). The animals were divided into two groups: KA + US (N=2), KA(N=1). For the chronic model, KA (450 ng KA in 200 nL saline) was injected focally and unilaterally into the left dentate gyrus of the hippocampus (2 mm lateral, 3.5 caudal and 3.7 mm below bregma) on anesthetized rats under isoflurane. Continuous video monitoring was analyzed to assess seizure frequency. If severe epileptiform activity persisted beyond 24 hours post injection then Lorazepam (2 mg/kg) was administered. After 1 week of recovery, rats generally seized spontaneously. A concave, 32-element, 3.2 MHz dual-mode ultrasound array (DMUA) transducer was used for imaging and delivering ablative therapy transcranially. The DMUA was attached to a 3-axis positioner, which allowed for stereotaxic placement of the tFUS focal spot at the target and perform localized thermal coagulation within a small volume 0.5 X 0.7 X 2 mm3.When seizure frequency plateaued for 2-3 days, we used the DMUA to apply high intensity tFUS to produce thermal lesions around the site of KA injection. Five (5) lesions were formed within a volume approximately 2 X 2 X 2 mm3 centered at the injection site.Behavior was monitored post lesion to detect seizures. If no behavioral seizures were observed for two weeks following the US therapy, a bipolar tungsten electrodes (60 μm in diameter, with 0.5‐mm vertical tip separation) was implanted contralaterally to the injection site to monitor spontaneous seizure activity and to preserve the lesion site. We measured local field potentials and 24 hour video monitoring for 6-7 days to detect any subclinical seizure activity. Results: Two rats treated by US had severe seizures after US lesioning. However, after 24h and 4 days after US, both rats became seizure free. We monitored them for 2 weeks and found no further behavioral seizures with video recording or through LFP recordings in the contralateral hippocampus. The untreated animal had seizures that persisted regularly for two months after induction. Conclusions: Lesioning of a KA induced seizure focus with high intensity US stopped seizures in two animals. Immediately following the lesioning, seizures were observed for 24 hours, which we attribute to lysing of neurons causing them to release potassium inducing seizures. Upon recovery, animals became seizure free for the duration of experimental observation. Funding: National Institute of Health: R01 NS098781