Dynamics of neuronal firing modulated by high-frequency electrical pulse stimulations at axons in rat hippocampus.

Objective. The development of electrical pulse stimulations in brain, including deep brain stimulation, is promising for treating various brain diseases. However, the mechanisms of brain stimulations are not yet fully understood. Previous studies have shown that the commonly used high-frequency stimulation (HFS) can increase the firing of neurons and modulate the pattern of neuronal firing. Because the generation of neuronal firing in brain is a nonlinear process, investigating the characteristics of nonlinear dynamics induced by HFS could be helpful to reveal more mechanisms of brain stimulations. The aim of present study is to investigate the fractal properties in the neuronal firing generated by HFS.Approach. HFS pulse sequences with a constant frequency 100 Hz were applied in the afferent fiber tracts of rat hippocampal CA1 region. Unit spikes of both the pyramidal cells and the interneurons in the downstream area of stimulations were recorded. Two fractal indexes-the Fano factor and Hurst exponent were calculated to evaluate the changes of long-range temporal correlations (LRTCs), a typical characteristic of fractal process, in spike sequences of neuronal firing.Mainresults. Neuronal firing at both baseline and during HFS exhibited LRTCs over multiple time scales. In addition, the LRTCs significantly increased during HFS, which was confirmed by simulation data of both randomly shuffled sequences and surrogate sequences.Conclusion. The purely periodic stimulation of HFS pulses, a non-fractal process without LRTCs, can increase rather than decrease the LRTCs in neuronal firing.Significance. The finding provides new nonlinear mechanisms of brain stimulation and suggests that LRTCs could be a new biomarker to evaluate the nonlinear effects of HFS.

Simulation Study of Intermittent Responses of Neuronal Populations to Axonal High-Frequency Stimulation.

Deep brain stimulation (DBS) have shown a promising future for treating various brain disorders. Studies have indicated that the high frequency stimulation (HFS) used in DBS could cause a partial block in axons thereby attenuating the responses of axon fibers to the pulses of HFS. The attenuated response of axons might play a desynchronization role in modulating activity of neuronal populations. To investigate the detail behavior of individual axons under HFS, we created a computational model of neuronal populations including 1250 neurons. Each neuron consisted of a myelinated axon, an axonal initial segment, a soma and dendrites. A 10-s HFS sequence with 100 Hz pulses was applied to the axon layer by a bipolar stimulation electrode. The membrane potentials and the extracellular potassium concentration [K+]o at axons and at somata during the stimulation were investigated. The results showed that the simulation model with a mechanism of potassium accumulation could reproduce the attenuated responses of neuronal populations to persistent axonal HFS in rat experiments. The elevation of [K+]o during HFS resulted in an increase of basic membrane potentials and then generated a depolarization block in the axonal membrane thereby attenuating the responses of neuronal populations. The depolarization block in axons included both complete block (~26%) and intermittent block (~74%), which generated desynchronized firing among axons in fibers and travelled to the cell bodies to induce desynchronized firing in somata. The simulation results may provide important information for revealing the modulation mechanisms of axonal HFS in the therapy of brain stimulation.

Simulation Study of Intermittent Axonal Block and Desynchronization Effect Induced by High-Frequency Stimulation of Electrical Pulses.

Deep brain stimulation (DBS) has been successfully used in treating neural disorders in brain, such as Parkinson's disease and epilepsy. However, the precise mechanisms of DBS remain unclear. Regular DBS therapy utilizes high-frequency stimulation (HFS) of electrical pulses. Among all of neuronal elements, axons are mostly inclined to be activated by electrical pulses. Therefore, the response of axons may play an important role in DBS treatment. To study the axonal responses during HFS, we developed a computational model of myelinated axon to simulate sequences of action potentials generated in single and multiple axons (an axon bundle) by stimulations. The stimulations are applied extracellularly by a point source of current pulses with a frequency of 50-200 Hz. Additionally, our model takes into account the accumulation of potassium ions in the peri-axonal spaces. Results show that the increase of extracellular potassium generates intermittent depolarization block in the axons during HFS. Under the state of alternate block and recovery, axons fire action potentials at a rate far lower than the frequency of stimulation pulses. In addition, the degree of axonal block is highly related to the distance between the axons and the stimulation point. The differences in the degree of block for individual axons in a bundle result in desynchronized firing among the axons. Stimulations with higher frequency and/or greater intensity can induce axonal block faster and increase the desynchronization effect on axonal firing. Presumably, the desynchronized axonal activity induced by HFS could generate asynchronous activity in the population of target neurons downstream thereby suppressing over-synchronized firing of neurons in pathological conditions. The desynchronization effect generated by intermittent activation of axons may be crucial for DBS therapy. The present study provides new insights into the mechanisms of DBS, which is significant for advancing the application of DBS.

Novel Stimulation Paradigms with Temporally-Varying Parameters to Reduce Synchronous Activity at the Onset of High Frequency Stimulation in Rat Hippocampus.

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.

High frequency stimulation of afferent fibers generates asynchronous firing in the downstream neurons in hippocampus through partial block of axonal conduction.

Deep brain stimulation (DBS) is effective for treating neurological disorders in clinic. However, the therapeutic mechanisms of high-frequency stimulation (HFS) of DBS have not yet been elucidated. Previous studies have suggested that HFS-induced changes in axon conduction could have important contributions to the DBS effects and desiderate further studies. To investigate the effects of prolonged HFS of afferent axons on the firing of downstream neurons, HFS trains of 100 and 200Hz were applied on the Schaffer collaterals of the hippocampal CA1 region in anaesthetized rats. Single unit activity of putative pyramidal cells and interneurons in the downstream region was analyzed during the late periods of prolonged HFS when the axonal conduction was blocked. The results show that the firing rates of both pyramidal cells and interneurons increased rather than decreased during the period of axon block. However, the firing rates were far smaller than the stimulation frequency of HFS. In addition, the firing pattern of pyramidal cells changed from typical bursts during baseline recordings into regular single spikes during HFS periods. Furthermore, the HFS produced asynchronous firing in the downstream neurons in contrast to the synchronous firing induced by single pulses. Presumably, the HFS-induced block of axonal conduction was not complete. During the period of partial block, individual axons could recover intermittently and independently, and drive the downstream neurons to fire in an asynchronous pattern. This axonal mechanism of HFS provides a novel explanation for how DBS could replace an original pattern of neuronal activity by a HFS-modulated asynchronous firing in the target region thereby generating the therapeutic effects of DBS.

[A new algorithm for automatically detecting epileptiform spikes and its application in epilepsy models].

Epilepsy is characterized by abnormally synchronized firing of neuronal populations, which is presented as epileptiform spikes in neural electrical signal recordings. In order to investigate the epileptiform spikes quantitatively, we designed a new window-based algorithm to automatically detect population spikes (PS) in acute epilepsy models in rat hippocampus CA1 region, and to calculate characteristic parameters of PS. Results show that the algorithm could recognize PS waveforms directly in wideband recording signals in epilepsy models induced by 4-aminopyridine (4-AP), a potassium channel blocker, or by picrotoxin (PTX), an antagonist of γ-aminobutyric acid A-type receptor. The PS detection ratios of the two epilepsy models were 94.2%±1.6% ( n=11) and 95.9%±1.9% ( n=12), respectively. The false positive ratios were 3.5%±2.3% ( n=11) and 4.8%±2.3% ( n=12), which were significantly lower than those of the conventional threshold method. Comparisons of the PS patterns between the 4-AP model and the PTX model showed that the PS of the 4-AP model had wider waveforms and fired more dispersedly with intervals mainly in the range of 100-700 ms. The PS of the PTX model fired as Burst with a higher firing rate and with intervals mainly in the range of 2-20 ms, resulting in a larger sum of spike amplitudes per second than the 4-AP model. Thus, the synchronous firing of neuronal populations in the PTX model was more intense than that in the 4-AP model. In conclusion, the new algorithm of PS detection can correctly detect and analyze epileptiform population spikes. It provides a useful tool of data analysis for investigating the underlying mechanism of seizure generation and for evaluating new therapeutics of epilepsy.

Modulation of local field potentials by high-frequency stimulation of afferent axons in the hippocampal CA1 region.

Modulation of the rhythmic activity of local field potentials (LFP) in neuronal networks could be a mechanism of deep brain stimulation (DBS). However, exact changes of LFP during the periods of high-frequency stimulation (HFS) of DBS are unclear because of the interference of dense stimulation artifacts with high amplitudes. In the present study, we investigated LFP changes induced by HFS of afferent axons in the hippocampal CA1 region of urethane-anesthetized rats by using a proper algorithm of artifact removal. Afterward, the LFP changes in the frequency bands of [Formula: see text], [Formula: see text], [Formula: see text], [Formula: see text] and [Formula: see text] rhythms were studied by power spectrum analysis and coherence analysis for the recorded signals collected in the pyramidal layer and in the stratum radiatum of CA1 region before, during and after 1-min long 100 and 200[Formula: see text]Hz HFS. Results showed that the power of LFP rhythms in higher-frequency band ([Formula: see text] rhythm) increased in the pyramidal layer and the power of LFP rhythms in lower-frequency bands ([Formula: see text], [Formula: see text] and [Formula: see text] rhythms) decreased in the stratum radiatum during HFS. The synchronization of [Formula: see text] rhythm decreased and the synchronization of [Formula: see text] rhythm increased during HFS in the stratum radiatum. These results suggest that axonal HFS could modulate LFP rhythms in the downstream brain areas with a plausible underlying mechanism of partial axonal blockage induced by HFS. The study provides new evidence to support the mechanism of DBS modulating rhythmic activity of neuronal populations.

High frequency stimulation extends the refractory period and generates axonal block in the rat hippocampus.

BACKGROUND: The therapeutic mechanisms of deep brain stimulations (DBS) are not fully understood. Axonal block induced by high frequency stimulation (HFS) has been suggested as one possible underlying mechanism of DBS. OBJECTIVE: To investigate the mechanism of the generation of HFS-induced axonal block. METHODS: High frequency pulse trains were applied to the fiber tracts of alveus and Schaffer collaterals in the hippocampal CA1 neurons in anaesthetized rats at 50, 100 and 200 Hz. The amplitude changes of antidromic-evoked population spikes (APS) were measured to determine the degree of axonal block. The amplitude ratio of paired-pulse evoked APS was used to assess the changes of refractory period. RESULTS: There were two distinct recovery stages of axonal block following the termination of HFS. One frequency-dependent faster phase followed by another frequency-independent slower phase. Experiments with specially designed temporal patterns of stimulation showed that HFS produced an extension of the duration of axonal refractory period thereby causing a fast recovery phase of the axonal block. Thus, prolonged gaps inserted within HFS trains could eliminate the axonal block and induced large population spikes and even epileptiform activity in the upstream or downstream regions. CONCLUSIONS: Extension of refractory period plays an important role on HFS induced axonal block. Stimulation pattern with properly designed pauses could be beneficial for different requirements of excitation or inhibition in DBS therapies.