Small Changes in Inter-Pulse-Intervals Can Cause Synchronized Neuronal Firing During High-Frequency Stimulations in...

Deep brain stimulation (DBS) traditionally utilizes electrical pulse sequences with a constant frequency, i.e., constant inter-pulse-interval (IPI), to treat certain brain disorders in clinic. Stimulation sequences with varying frequency have been investigated recently to improve the efficacy of existing DBS therapy and to develop new treatments. However, the effects of such sequences are inconclusive. The present study tests the hypothesis that stimulations with varying IPI can generate neuronal activity markedly different from the activity induced by stimulations with constant IPI. And, the crucial factor causing the distinction is the relative differences in IPI lengths rather than the absolute lengths of IPI nor the average lengths of IPI. In rat experiments in vivo, responses of neuronal populations to applied stimulation sequences were collected during stimulations with both constant IPI (control) and random IPI. The stimulations were applied in the efferent fibers antidromically (in alveus) or in the afferent fibers orthodromically (in Schaffer collaterals) of pyramidal cells, the principal cells of hippocampal CA1 region. Amplitudes and areas of population spike (PS) waveforms were used to evaluate the neuronal responses induced by different stimulation paradigms. During the periods of both antidromic and orthodromic high-frequency stimulation (HFS), the HFS with random IPI induced synchronous neuronal firing with large PS even if the lengths of random IPI were limited to a small range of 5-10 ms, corresponding to a frequency range 100-200 Hz. The large PS events did not appear during control stimulations with a constant frequency at 100, 200, or 130 Hz (i.e., the mean frequency of HFS with random IPI uniformly distributed within 5-10 ms). Presumably, nonlinear dynamics in neuronal responses to random IPI might cause the generation of synchronous firing under the situation without any long pauses in HFS sequences. The results indicate that stimulations with random IPI can generate salient impulses to brain tissues and modulate the synchronization of neuronal activity, thereby providing potential stimulation paradigms for extending DBS therapy in treating more brain diseases, such as disorders of consciousness and vegetative states.