Abstract
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.
Highlights
Deep brain stimulation (DBS) has been developed to treat brain disorders for decades, including Parkinson’s disease, essential tremor, dystonia, epilepsy, obsessive-compulsive disorder, addiction, depression, and Alzheimer’s disease (Fridley et al, 2012; Udupa and Chen, 2015; Wichmann and DeLong, 2016; Cury et al, 2017)
At the onset of A-high-frequency stimulation (HFS) with a constant pulse frequency (100 Hz), each stimulation pulse evoked a large antidromically evoked population spike (APS, ∼9 mV), indicating that synchronous action potentials propagated from the efferent fibers back to the somata of the neuronal populations in the upstream region of stimulation site (Figures 1A,B)
After tens of seconds of stimulation, the amplitudes of antidromically evoked population spikes (APS) stabilized to a low level (∼20% of the initial APS amplitude, Figures 1B,C), indicating that the neuronal responses transformed from a transient phase to a steady-state phase with regular small APS evoked by each stimulation pulse
Summary
Deep brain stimulation (DBS) has been developed to treat brain disorders for decades, including Parkinson’s disease, essential tremor, dystonia, epilepsy, obsessive-compulsive disorder, addiction, depression, and Alzheimer’s disease (Fridley et al, 2012; Udupa and Chen, 2015; Wichmann and DeLong, 2016; Cury et al, 2017). Despite the most successful application of the therapy for treating movement disorders such as Parkinson’s disease, DBS treatment for other diseases is not mature currently. New stimulation paradigms have been designed and tested for extending DBS therapy in treating more neurological and psychiatric disorders (Rizzone et al, 2001; Kuncel et al, 2006; Brocker et al, 2017). Irregular temporal patterns of stimulation with varying IPI or with pauses have been studied in animal experiments, computational models as well as in clinical treatments (Swan et al, 2016; Brocker et al, 2017; Cassar et al, 2017). Even if the mean frequency of varying stimulation is as high as constant stimulation, the effectiveness of varying stimulations may be still poorer than constant stimulations (Dorval et al, 2010; Birdno et al, 2012; Kuncel et al, 2012; McConnell et al, 2016)
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
