The Effect of Electrical Stimulation of the Subthalamic Nucleus on Seizures Is Frequency Dependent *§Fred A. Lado, *†§Libor Velíšek, and *†‡§Solomon L. Moshé Departments of *Neurology, †Neuroscience, and ‡Pediatrics, §Comprehensive Epilepsy Management Center, Albert Einstein College of Medicine and Montefiore Medical Center, Bronx, New York, U.S.A. Summary: Purpose: Animal studies and anecdotal human case reports have indicated that the subthalamic nucleus (STN) may be a site of anticonvulsant action. Methods: We tested the hypothesis that continuous electrical stimulation of the STN inhibits seizures acutely. We deter- mined the effects of three stimulation frequencies, 130 Hz, 260 Hz, and 800 Hz, on generalized clonic and tonic–clonic flurothyl seizures. Adult male rats were implanted with con- centric bipolar stimulating electrodes in the STN bilaterally. After recovery, rats underwent flurothyl seizures to compare the effects of each stimulation frequency on seizure threshold. Rats were tested 4 times, twice in the stimulated condition, and twice in the unstimulated condition. The order of trials was random, except that stimulation trials alternated with control trials. Flurothyl seizure thresholds under each stimulation con- dition were compared with control values from the same animal. Results: Bilateral stimulation of the STN at 130 Hz produced a significant increase in the seizure threshold for clonic fluro- thyl seizures, whereas stimulation at 260 Hz did not appear to have any effect on seizures. STN stimulation at 800 Hz sig- nificantly lowered seizure threshold for tonic–clonic seizures. Conclusions: We conclude that electrical stimulation of the STN can be anticonvulsant, but the effects appear to depend on the stimulation frequency and the type of seizure. Key Words: Seizures—Subthalamic nucleus—Deep brain stimulation— Rat—Male—Electrical stimulation. Generalized convulsive seizures are one of the most debilitating and life-threatening consequences of human epilepsy, particularly in cases of medically intractable epilepsy in which surgical therapy cannot be considered. Indeed, as outlined in the NINDS-CURE benchmarks for epilepsy research (http://www.ninds.nih.gov/ about_ninds/epilepsybenchmarks.htm), there is an urgent need for novel therapies that can prevent seizures with- out causing unacceptable side effects, as frequently de- velop in patients taking multiple antiepileptic medications (AEDs). The application of focal deep brain stimulation as a potential treatment for convulsive and nonconvulsive seizures has recently gained attention as a result of two factors. First, an emerging understanding of endogenous anticonvulsant subcortical networks has identifed potential targets where focal intervetion may result in widespread changes in seizure susceptibility. Second, the availability of devices for deep brain elec- trical stimulation offer a means of selectively altering activity in anticonvulsant circuits without lesioning large numbers of neurons. Over the past two decades, investigators have recog- nized the importance of subcortical and extrapyramidal motor pathways in the control of seizures. The subtha- lamic nucleus (STN), a small nucleus receiving major input from cortical and pallidal afferents and projecting to the substantia nigra pars reticulata (SNR) (1–4), has shown anticonvulsant activity in several animal seizure models, including flurothyl convulsions, kindled sei- zures, and genetic absence epilepsy (5–8). Focal injec- tion of muscimol, a -aminobutyric acid subtype A (GABA-A)-receptor agonist, into the STN reduced sus- ceptibility to flurothyl-induced generalized convulsions (5). Bilateral injections of muscimol into the STN de- creased by two thirds the number of rats with generalized convulsions produced by amygdala kindling (6), al- though focal seizures and electrographic discharges were not suppressed. Muscimol injections into the STN of GAERS rats (which experience frequent spontaneous absence-like seizures with synchronous bilateral spike– wave discharges and behavioral arrest) produced a dose- dependent inhibition of electrographic seizures (7). Bilateral excitotoxic lesions in the STN produced a simi- lar but less complete suppression of spontaneous absence seizures (8). Electrical stimulation of the STN bilaterally with 130-Hz pulse trains completely suppressed ongoing absence seizures at the onset of stimulation, but the effect Accepted September 2, 2002. Address correspondence and reprint requests to Dr. F. A. Lado at Department of Neurology, K313, Albert Einstein College of Medicine, 1410 Pelham Parkway South, Bronx, NY 10461, U.S.A. E-mail: flado@aecom.yu.edu Epilepsia, 44(2):157–164, 2003 Blackwell Publishing, Inc. © 2003 International League Against Epilepsy 157