Abstracts

Rationale: The mediodorsal thalamus (MDT) is an established part of the limbic seizure circuit. Its capacity to modulate seizures in animal models makes it a promising therapeutic target. We wished to determine whether focal infusion of GABA-A agonists into the MDT could suppress limbic seizures in two rat models: kindling and post-status epilepticus chronic limbic epilepsy. Methods: Bilateral MDT cannulas (Coordinates from bregma: AP:-2.0mm, RL: +/- 0.75mm, Depth: 5.4mm below dura) and bilateral hippocampal twist electrodes (AP:-4.9mm, RL: +/- 5.3mm, Depth: 5.5mm from dura) were placed in male 350-400g Sprague-Dawley rats and secured with dental acrylic. Kindling: Animals were kindled according to previously published protocols. Freely moving, fully kindled animals received continuous bilateral intraMDT infusion of 400mM Phenobarbital (PB) while on continuous video-EEG monitoring. Infusion began at 2.93 mg/day. The rate was increased by 0.02 µL/min every other day (preceding the next kindling session by 24 hours) until seizure activity was suppressed or a maximum of 0.10 µL/min (14.64 mg/day) was reached. Suprathreshold unilateral hippocampal electrical stimulation was delivered six times every other day. Animals with behavioral seizure scores (BSS) below 2 at a given infusion rate (considered responders) underwent a washout phase. Afterdischarge duration (ADD) recordings were obtained independently from each hippocampus at baseline, each PB rate and during washout. Spontaneous Seizures: Animals underwent continuous hippocampal stimulation to induce epileptogenesis (methods previously published). Animals which developed epilepsy underwent cannula and electrode placement as described above a minimum of three months following status epilepticus. Freely moving epileptic animals were placed on continuous 450mM Phenobarbital infusion at 0.01 µL/min while maintained on continuous video-EEG recording. Results: Kindling: Eight rats completed the infusion protocol, of which six demonstrated BSS response. Among responders, bilateral hippocampal ADD and BSS were significantly reduced by MDT PB infusion (ADD per cent of baseline duration: mean .48, range 0.1-.94; average BSS: mean 0.69, range 0.17-1.0) and normalized during washout (p value=.015 ipsilateral to stimulation, p<.001 contralateral to stimulation). There was clear dose response effect for both BSS and ADD. Spontaneous Seizures: Four animals have completed the protocol as of this writing, and demonstrated mean 72% (range 50-100%) reduction in seizure frequency. Conclusions: Our results demonstrate that focal PB infusion in the MDT reduces the duration and behavioral severity of kindled seizures, as well as the frequency of spontaneous hippocampal seizures. These data support the MDT as a potential therapeutic target for pharmacologic treatment of limbic epilepsy.