Abstracts

RATIONALE: High frequency electrical stimulation of the deep structures of the brain (DBS) has been effective at controllling abnormal neuronal activity in Parkinson patients and is now being applied for the treatment of pharmacologically intractable epilepsy. The mechanisms underlying the suppression of the abnormal neural activity with DBS are not understood. Of particular interest is the response of neurons around the electrodes to the high frequency stimulation applied extracellularly.
METHODS: Experiments were carried using in-vitro hippocampal slices. Two stimulation methods were applied: 1) Sinusoidal uniform electric fields were generated in the hippocampal slices with two large electrodes at a frequency of 50Hz. 2) Localized fields were applied with monopolar electrodes located in the stratum pyramidale with either a sinusoidal (50Hz) or pulse waveforrm (140Hz, 120us). Extracellular, intracellular recording electrodes as well as potassium selective electrodes were used to measure the response of the tissue to the stimulation. Filtering was used to remove the large stimulation artifact.Three animal models of epielspy were used: High potassium (8.5mM), low-calcium (0.2mM) and picrotoxin.
RESULTS: Using both uniform and localized fields, sinusoidal stimulation waveforms could completely suppress epileptiform activity in all three models of epilepsy tested (low calcium, high potassium and picrotoxin). Suppression was associated with 1) an increase extracellular potassium concentration (~ 2.5 mM) and 2) a tonic (~19 mV) depolarization of individual CA1 neurons and a suppression of neuronal firing. The threshold for suppression was not affected by cell orientation relative to the applied field. Experiments carried out with monopolar electrodes using pulsed stimulation protocols closely related to those used clinically also showed that high frequency stimulation can directly inhibit neuronal firing (n=21). The threshold for local suppression using monopolar stimulation ( ~90 uA for sinusoidal, ~300uA for pulsed ) was significantly lower than for field stimulation (~1 mA). Using monopolar (but not uniform field) stimulation, suppresssion could be localized to the stimulation region.
CONCLUSIONS: High frequency stimulation can completely suppress neuronal firing in three different models of epilepsy.
The mechanism of the suppression is most likely a depolarization block generated by an increased potassium concentration around neurons.
The suppression is independant of the stimulation waveform and sinusoidal as well as pulse waveform with low duty cycle can be used.
The suppression by monopolar electrodes is independant of the orientation of the tissue and localized around the stimulation electrode.
These experiments suggest a possible mechanism for DBS-mediated suppression of neuronal activity and role for high frequency stimulation in epilepsy.
[Supported by: TheWhitaker Foundation and by NIH grant #R01 NS40785-01]