Abolition of spindle oscillations and 3-Hz absence seizurelike activity in the thalamus by using high-frequency stimulation: potential mechanism of action

Abstract

The mechanism of action whereby high-frequency stimulation (HFS) in the thalamus ameliorates tremor and epilepsy is unknown. The authors studied the effects of HFS on thalamocortical relay neurons in a ferret in vitro slice preparation to test the hypothesis that HFS abolishes synchronized oscillations by neurotransmitter release. Intracellular and extracellular electrophysiological recordings were made in thalamic slices. The neurons in the thalamic slice spontaneously generated spindle oscillations, and treatment with picrotoxin, a gamma-aminobutyric acid A receptor antagonist, resulted in 3- to 4-Hz absence seizurelike activity. High-frequency stimulation (stimulation parameters: 10-1000-microA amplitude; l00-microsec pulse width; 100-Hz frequency; 1-60 seconds) was applied using a concentric bipolar stimulating electrode placed adjacent to the recording electrodes. High-frequency stimulation within the thalamus generated inhibitory and excitatory postsynaptic potentials, membrane depolarization, an increase in action potential firing during the stimulation period, and abolished the spindle oscillations in the thalamocortical relay neurons. High-frequency stimulation applied to 20-microM picrotoxin-treated slices eliminated the 3- to 4-Hz absence seizurelike activity. High-frequency stimulation eliminates spontaneous spindle oscillations and picrotoxin-induced absence seizurelike activity in thalamic slices by synaptic neurotransmitter release; thus, HFS may abolish synchronous oscillatory activities such as those that generate tremor and seizures. Paradoxically, HFS, which is excitatory, and surgical lesions of the ventrointermedius thalamus, which are presumably inhibitory, both suppress tremors. This paradox is resolved by recognizing that HFS-mediated neurotransmitter release and thalamic surgery both disrupt the circuit generating tremor or seizure, albeit by different mechanisms.