Published Works

Published Works

Title Suppression of neuronal firing following antidromic high-frequency stimulations on the neuronal axons in rat hippocampal CA1 region.
Category Research paper
Overview High-frequency stimulation (HFS) of electrical pulses has been used to treat certain neurological diseases in brain with commonly utilized effects within stimulation periods. Post-stimulation effects after the end of HFS may also have functions but are lack of attention. To investigate the post-stimulation effects of HFS, we performed experiments in the rat hippocampal CA1 region in vivo. Sequences of 1-min antidromic-HFS (A-HFS) were applied at the alveus fibers. To evaluate the excitability of the neurons, separated orthodromic-tests (O-test) of paired pulses were applied at the Schaffer collaterals in the period of baseline, during late period of A-HFS, and following A-HFS. The evoked potentials of A-HFS pulses and O-test pulses were recorded at the stratum pyramidale and the stratum radiatum of CA1 region by an electrode array. The results showed that the antidromic population spikes (APS) evoked by the A-HFS pulses persisted through the entire 1-min period of 100 Hz A-HFS, though the APS amplitudes decreased significantly from the initial value of 9.9 ± 3.3 mV to the end value of 1.6 ± 0.60 mV. However, following the cessation of A-HFS, a silent period without neuronal firing appeared before the firing gradually recovered to the baseline level. The mean lengths of both silent period and recovery period of pyramidal cells (21.9 ± 22.9 and 172.8 ± 91.6 s) were significantly longer than those of interneurons (11.2 ± 8.9 and 45.6 ± 35.9 s). Furthermore, the orthodromic population spikes (OPS) and the field excitatory postsynaptic potentials (fEPSP) evoked by O-tests at ∼15 s following A-HFS decreased significantly, indicating the excitability of pyramidal cells decreased. In addition, when the pulse frequency of A-HFS was increased to 200, 400, and 800 Hz, the suppression of neuronal activity following A-HFS decreased rather than increased. These results indicated that the neurons with axons directly under HFS can generate a post-stimulation suppression of their excitability that may be due to an antidromic invasion of axonal A-HFS to somata and dendrites. The finding provides new clues to utilize post-stimulation effects generated in the intervals to design intermittent stimulations, such as closed-loop or adaptive stimulations.
Title Bifurcations in the firing of neuronal population caused by a small difference in pulse parameters during sustained stimulations in rat hippocampus in vivo
Category Research paper
Overview Objective: The bifurcation of neuronal firing is one of important nonlinear phenomena in the nervous system and is characterized by a significant change in the rate or temporal pattern of neuronal firing on responding to a small disturbance from external inputs. Previous studies have reported firing bifurcations for individual neurons, not for a population of neurons. We hypothesized that the integrated firing of a neuronal population could also show a bifurcation behavior that should be important in certain situations such as deep brain stimulations. The hypothesis was verified by experiments of rat hippocampus in vivo.

Methods: Stimulation sequences of paired-pulses with two different inter-pulse-intervals (IPIs) or with two different pulse intensities were applied on the alveus of hippocampal CA1 region in anaesthetized rats. The amplitude and area of antidromic population spike (APS) were used as indices to evaluate the differences in the responses of neuronal population to the different pulses in stimulations.

Results: During sustained paired-pulse stimulations with a high mean pulse frequency such as ∼130 Hz, a small difference of only a few percent in the two IPIs or in the two intensities was able to generate a sequence of evoked APSs with a substantial bifurcation in their amplitudes and areas.

Conclusion: Small differences in the excitatory inputs can cause nonlinearly enlarged differences in the induced firing of neuronal populations.

Significance: The novel dynamics and bifurcation of neuronal responses to electrical stimulations provide important clues for developing new paradigms to extend neural stimulations to treat more diseases.
Title Cathodic- and anodic-pulses can alternately activate different sub-populations of neurons during sustained high-frequency stimulation of axons in rat hippocampus.
Category Research paper
Overview Objective.Charge-balanced biphasic-pulses are commonly used in neural stimulations to prevent possible damages caused by charge accumulations. The lagging anodic-phases of biphasic-pulses may decrease the activation efficiency of stimulations by counteracting the depolarization effect of the leading cathodic-phases. However, a monophasic anodic-pulse alone can itself activate neurons by depolarizing neuronal membrane through a mechanism of virtual cathode. This study aimed to verify the hypothesis that the anodic-phases/pulses in charge-balanced stimulations could play an activation role during sustained high-frequency stimulations (HFSs).Approach.Two types of antidromic HFS (A-HFS) were applied on the alveus of hippocampal CA1 region of anesthetized rats: monophasic-pulse A-HFS of alternate opposite pulses and biphasic-pulse A-HFS with the same frequency of 100 or 200 Hz. The antidromically-evoked population spike was used as a biomarker to evaluate the activation effects of A-HFS pulses.Main results.Despite a significant difference in the initial abilities of anodic- and cathodic-pulses to activate neurons, an anodic-pulse was able to induce similar amount of neuronal firing as a cathodic-pulse during sustained monophasic-pulse A-HFS. Additionally, the amount of neuronal firing induced by the monophasic-pulse A-HFS was similar to that induced by the biphasic-pulse A-HFS consuming a double amount of electrical energy. Furthermore, the alternate cathodic- and anodic-pulses respectively activated different sub-populations of neurons during steady A-HFS.Significance.The anodic-phases/pulses in charge-balanced HFS at axons can play an activation role in addition to a role of charge balance. The study provides important information for designing charge-balanced stimulations and reveals new mechanisms of neural stimulations.
Title Adjust neuronal reactions to pulses of high-frequency stimulation with designed inter-pulse-intervals in rat hippocampus in vivo.
Category Research paper
Overview Sequences of electrical pulses have been applied in the brain to treat certain disorders. In recent years, altering inter-pulse-interval (IPI) regularly or irregularly in real time has emerged as a promising way to modulate the stimulation effects. However, algorithms to design IPI sequences are lacking. This study proposed a novel strategy to design pulse sequences with varying IPI based on immediate neuronal reactions. Firstly, to establish the correlationship between the neuronal reactions with varying IPIs, high-frequency stimulations with varying IPI in the range of 5-10 ms were applied at the alveus of the hippocampal CA1 region of anesthetized rats in vivo. Antidromically-evoked population spikes (APS) following each IPI were recorded and used as a biomarker to evaluate neuronal reactions to each pulse. A linear mapping model was established to estimate the varied APS amplitudes by the two preceding IPIs. Secondly, the mapping model was used to derive an algorithm for designing an IPI sequence that would be applied for generating a desired neuronal reaction pre-defined by a particular APS distribution. Finally, examples of stimulations with different IPI sequences designed by the algorithm were verified by rat experiments. The results showed that the designed IPI sequences were able to reproduce the desired APS responses of different distributions in the hippocampal stimulations. The novel algorithm of IPI design provides a potential way to obtain various stimulation effects for brain stimulation therapies.
Title Different effects of monophasic pulses and biphasic pulses applied by a bipolar stimulation electrode in the rat hippocampal CA1 region.
Category Research paper
Overview The results showed that orthodromically activating hippocampal neurons by HFS of monophasic pulses can induce the abnormal neuron activity of spreading depression, and antidromic activation can cause an attenuation of neuronal excitability persisting after HFS stimulations. The results suggest that HFS of monophasic pulses have a risk of tissue damage and can induce neuronal reactions different from HFS of biphasic pulses, which provide new information for appropriate usage of pulse stimulations in brain tissues either in clinic or in animal experiments.
Title Design and application of neural electrical stimulation system with time-varying parameters
Category Research paper
Overview Currently, commercial devices for electrical neural stimulations can only provide fixed stimulation paradigms with preset constant parameters, while the development of new stimulation paradigms with time-varying parameters has emerged as one of the important research directions for expanding clinical applications. To facilitate the performance of electrical stimulation paradigms with time-varying parameters in animal experiments, the present study developed a well-integrated stimulation system to output various pulse sequences by designing a LabVIEW software to control a general data acquisition card and an electrical stimulus isolator. The system was able to generate pulse sequences with inter-pulse-intervals (IPI) randomly varying in real time with specific distributions such as uniform distribution, normal distribution, gamma distribution and Poisson distribution. It was also able to generate pulse sequences with arbitrary time-varying IPIs. In addition, the pulse parameters, including pulse amplitude, pulse width, interphase delay of biphasic pulse and duration of pulse sequence, were adjustable. The results of performance tests of the stimulation system showed that the errors of the parameters of pulse sequences output by the system were all less than 1%. By utilizing the stimulation system, pulse sequences with IPI randomly varying in the range of 5~10 ms were generated and applied in rat hippocampal regions for animal experiments. The experimental results showed that, even with a same mean pulse frequency of ~130 Hz, for neuronal populations, the excitatory effect of stimulations with randomly varying IPIs was significantly greater than the effect of stimulations with fixed IPIs. In conclusion, the stimulation system designed here may provide a useful tool for the researches and the development of new paradigms of neural electrical stimulations.