Cluster Neuronal Firing Induced by Uniform Pulses of High-Frequency Stimulation on Axons in Rat Hippocampus.

Objective: High-frequency stimulation (HFS) of electrical pulse sequences has been used in various neuromodulation techniques to treat certain disorders. Here, we test the hypothesis that HFS sequences with purely periodic pulses could directly generate non-uniform firing in directly stimulated neurons.

Methods: In vivo experiments were conducted in the rat hippocampal CA1 region. A stimulation electrode was placed on the alveus fibers, and a recording electrode array was inserted into the CA1 region upstream of the stimulation site. Antidromic-HFS (A-HFS) of 100 Hz pulses was applied to the alveus to antidromically activate the soma of pyramidal neurons around the recording site. By minimizing the interferences of population spikes, the evoked unit spikes of individual pyramidal neurons were obtained during A-HFS. Additionally, a computational model of pyramidal neuron was used to simulate the neuronal responses to A-HFS, revealing possible mechanisms underlying the different firing patterns.

Results: Of the total 54 pyramidal neurons recorded during 2-min 100 Hz A-HFS, 38 (70%) neurons fired in a cluster pattern with alternating periods of intensive spikes and silence. The remaining 16 (30%) neurons fired in a non-cluster pattern with regular spikes. Modeling simulations showed that under the situation of HFS-induced intermittent block, conduction failure and generation failure of action potentials along the axons resulted in the cluster and non-cluster firing.

Conclusion: Sustained axonal A-HFS with periodic pulses can induce non-uniform firing in directly stimulated neurons.

Significance: This finding provides new evidence for the nonlinear dynamics of neuronal firing, even under uniform stimulation.