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Deep brain stimulation (DBS) has shown wide applications for treating various disorders in the central nervous system by using high frequency stimulation (HFS) sequences of electrical pulses. However, upon the onset of HFS sequences, the narrow pulses could induce synchronous firing of action potentials among large populations of neurons and cause a transient phase of “onset response” that is different from the subsequent steady state. To investigate the transient onset phase, the antidromically-evoked population spikes (APS) were used as an electrophysiological marker to evaluate the synchronous neuronal reactions to axonal HFS in the hippocampal CA1 region of anesthetized rats. New stimulation paradigms with time-varying intensity and frequency were developed to suppress the “onset responses”. Results show that HFS paradigms with ramp-up intensity at the onset phase could suppress large APS potentials. In addition, an intensity ramp with a slower ramp-up rate or with a higher pulse frequency had greater suppression on APS amplitudes. Therefore, to reach a desired pulse intensity rapidly, a stimulation paradigm combining elevated frequency and ramp-up intensity was used to shorten the transition phase of initial HFS without evoking large APS potentials. The results of the study provide important clues for certain transient side effects of DBS and for development of new adaptive stimulation paradigms.

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J o u r n a l o f I n t e g r a t i v e N e u r o s c i e n c eThis is an open access article under the CC BY-NC 4.0 license (https://creativecommons.org/licenses/by-nc/4.0/) Deep brain stimulation is an emerging treatment for brain disorders. However, the mechanisms of high-frequency brain stimulation are unclear. Recent studies have suggested that high-frequency stimulation might produce therapeutic effects by eliminating pathological rhythms in neuronal firing. To test the hypothesis, the present study investigated whether stimulation of axonal afferent fibers might alter firing rhythms of downstream neurons in invivo experiments with Sprague-Dawley rats. Stimulation trains of 100 Hz with one minute duration were applied to the Schaffer collaterals of hippocampus Area CA1 in anaesthetized rats. Spikes of single interneurons and pyramidal neurons in the downstream region were analyzed. The spike rhythms before, during, and after the stimulations were evaluated by analyzing the power spectrum density of autocorrelograms of the spiking sequences. The rhythms of local field potentials were also evaluated by power spectrum density. During baseline recordings, theta rhythms were obvious in the spiking sequences of both types of neuron and in the local field potentials of the stratum radiatum. However, these theta rhythms were all suppressed significantly during the stimulations. Additionally, the results of Pearson's correlation analysis showed that 20-30% variation in the theta rhythms of neuronal firing could be explained by changes of the theta rhythms in local field potentials. High-frequency axonal stimulation might prevent the original rhythmic excitation in afferent fibers and generate new excitation by stimulation pulses per se, thereby suppressing the theta rhythms of individual neuron firing and of local field potentials in the region downstream from stimulation. The results provide new evidence to support the hypothesis that high-frequency stimulation can alter the firing rhythms of neurons, which may underlie the therapeutic effects of deep brain stimulation.