Abstracts

Animal studies and human case reports indicate that electrical stimulation of the anterior thalamic nucleus (ANT) may be anticonvulsant. Animal studies, however, have tested ANT stimulation against acute seizure models, not chronic epilepsy. We tested whether continuous ANT stimulation inhibits spontaneous seizures in chronically epileptic rats following kainic acid (KA) induced status epilepticus (SE).
Adult rats anesthetized with ketamine/xylazine were implanted with screw electrodes over frontal cortex bilaterally and depth electrodes at the level of the dentate gyrus in the dorsal hippocampus bilaterally. Concentric bipolar stainless steel stimulation electrodes were implanted in the ANT bilaterally, and rats were allowed to recover at least one week. Next, rats received KA intraperitoneally (10mg/kg) to induce SE. Rats began baseline monitoring 2-3 weeks after SE. Rats experiencing at least 3 spontaneous seizures over the 5-7 day baseline recording received chronic bilateral ANT stimulation for at least five days. Stimulation consisted of rectangular 100[mu]s pulses at a rate of 100-130 Hz applied either continuously or intermittently. In the latter case, stimulation cycles consisted of 20-30 seconds of stimulation followed by 5-15 minutes without stimulation. Initial experiments were done with constant currents of 50-400[mu]A per electrode. Later experiments were done using voltages of 0.5-4V when it was found that the initial stimulation paradigm was frequently associated with abcess formation at the electrode tip.
Approximately half of rats treated with KA developed sufficiently frequent seizures to test ANT stimulation. In half the rats, seizures were strongly clustered, i.e. several seizures occured in one day, followed by several days without seizures. To avoid the confounding effects of seizure clustering, stimulation was initiated only between clusters, and the duration of baseline and stimulation monitoring was extended to the time require for repetition of the cluster cycle (usually ~7days).
Stimulation intensities of 200[mu]A or higher were associated with 100% incidence of abcess formation (n=16), while stimulation intensities of 100[mu]A or lower were rare (1 of 13). Voltage stimulation produced fewer toxicities compared to current stimulation, though the mechanism is unclear. Chronic continuous or intermittent stimulation did not prevent spontaneous seizures at any cycle duration or intensity tested (n = 17). In most rats ANT stimulation resulted in an increase between 30-300% in seizure frequency. In many rats, seizures were triggered at the onset of stimulation. Electrographic seizure duration and behavioral severity were not affected by stimulation.
In KA-treated rats with spontaneous seizures, chronic ANT stimulation did not improve - and often worsened - seizure frequency. Moreover, stimulation at the highest current intensities tested was associated with brain abcess formation.
[Supported by: Medtronic Inc., NINDS K08-NS41340, Heffer Family Medical Foundation]