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. 2018 Oct 24;12:783.
doi: 10.3389/fnins.2018.00783. eCollection 2018.

Axonal Stimulations With a Higher Frequency Generate More Randomness in Neuronal Firing Rather Than Increase Firing Rates in Rat Hippocampus

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Axonal Stimulations With a Higher Frequency Generate More Randomness in Neuronal Firing Rather Than Increase Firing Rates in Rat Hippocampus

Zhaoxiang Wang et al. Front Neurosci. .
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Abstract

Deep brain stimulation (DBS) has been used for treating many brain disorders. Clinical applications of DBS commonly require high-frequency stimulations (HFS, ∼100 Hz) of electrical pulses to obtain therapeutic efficacy. It is not clear whether the electrical energy of HFS functions other than generating firing of action potentials in neuronal elements. To address the question, we investigated the reactions of downstream neurons to pulse sequences with a frequency in the range 50-200 Hz at afferent axon fibers in the hippocampal CA1 region of anesthetized rats. The results show that the mean rates of neuronal firing induced by axonal HFS were similar even for an up to fourfold difference (200:50) in the number and thereby in the energy of electrical pulses delivered. However, HFS with a higher pulse frequency (100 or 200 Hz) generated more randomness in the firing pattern of neurons than a lower pulse frequency (50 Hz), which were quantitatively evaluated by the significant changes of two indexes, namely, the peak coefficients and the duty ratios of excitatory phase of neuronal firing, induced by different frequencies (50-200 Hz). The findings indicate that a large portion of the HFS energy might function to generate a desynchronization effect through a possible mechanism of intermittent depolarization block of neuronal membranes. The present study addresses the demand of high frequency for generating HFS-induced desynchronization in neuronal activity, which may play important roles in DBS therapy.

Keywords: desynchronization; electrical energy; firing rate; high frequency stimulation; randomness; unit spikes.

Figures

FIGURE 1
FIGURE 1
Changes of evoked potentials in the downstream region during HFS of afferent fibers in the rat hippocampal CA1 region. (A) Schematic diagram of the locations of recording electrode array (RE) and orthdromic stimulation electrode (SE) in the CA1 region. Two contacts on the recording array separated 0.2 mm were used to collect the potentials in the pyramidal layer (Pyr.) and stratum radiatum (S. rad.), respectively. Typical evoked potentials (PS and fEPSP) by a single pulse are showed on the right. (B–D) Neuronal responses to 1-min HFS trains with 50, 100, and 200 Hz pulse frequencies (denoted by the bars). Large PS and fEPSP were evoked by the first stimulation pulse at the onset of HFS. However, in the late HFS period, no more PS potentials appeared in the pyramidal layer and only small oscillations paced pulses in the stratum radiatum. Nevertheless, unit spikes (indicated by hollow arrow heads in the expanded plots) persisted. (E) Comparison of the oscillation amplitudes among HFS with different pulse frequencies of 50, 100, and 200 Hz. With similar amplitudes at the onset of HFS (denoted by A1 and listed on the bottom), the mean oscillation amplitudes at the end of HFS (denoted by A2) were suppressed more by higher frequencies. The A2 values were calculated by superposing and averaging the inter-pulse signals in the last 1 s of HFS. See the insets at the lower right of plots (B–D). The green waveforms are superposed signals, and the black curves are average waveforms. Two repeated inter-pulse intervals are drawn for clarity. The solid arrow heads (with dot lines) over the waveforms indicate the removed stimulation artifacts.
FIGURE 2
FIGURE 2
Increase of multiple unit activity (MUA) in the CA1 region during HFS of afferent axons. (A) A typical example of neuronal responses to a 1-min train of 200 Hz HFS. The high-pass filtered signal (>500 Hz) shows that the MUA increased during the late period of HFS that was absent of obvious PS activity. (B) Comparisons of MUA firing rates between baseline recordings and during late 30-s periods of 1-min HFS with 50, 100, and 200 Hz pulse frequencies. No significant differences existed among the firing rates of the baseline recordings and during HFS, respectively, for the three groups with different frequencies (ANOVA F < 1.1, P > 0.34).
FIGURE 3
FIGURE 3
Changes of the PSTH distributions of MUA firing by HFS with various pulse frequencies. (A) Making mimic PSTH of MUA firing from 30-s baseline recording for control. Left: a typical baseline MUA signal (30 s) was divided by virtual intervals of 10 ms (100 Hz). Right: superimposed signals of all 10 ms segments in the 30-s MUA (up) and the corresponding mimic PSTH (down). The blue line denotes the mean value of PSTH. (B) Typical plots of MUA PSTH during late 30-s HFS with 50, 100, and 200 Hz pulse frequencies. Up: superimposed signals of all inter-pulse intervals. Down: PSTH plots. In the PSTH plots, the red lines and blue lines denote the self-mean values (Cave) and the baseline mean values, respectively. ΔtextitC is the difference between the peak value and the self-mean. The pink bins of PSTH are with values greater than the baseline mean values (termed as excitatory bins). (C) Comparisons of the PSTH distributions under the identical time duration of 20 ms by dividing the PSTH of 100 and 200 Hz into two and four same portions, respectively. (D,E) Comparisons of the peak coefficient (ΔC/Cave) and the percentage of excitatory bins (i.e., duty ratio of excitatory phase) among HFS with stimulation frequencies of 50, 100, and 200 Hz.
FIGURE 4
FIGURE 4
Changes of the PSTH distributions of SUA firing. (A) Examples of raster plots and PSTH plots of an interneuron’s firing with HFS of 50, 100, and 200 Hz frequencies. Top: raster plots of spikes in baseline before HFS (–30 to 0 s) in mimic interval 20 ms. Middle: raster plots of spikes during the late 30-s period of HFS. Bottom: PSTH plots during the late period of HFS. The time spans of the three groups of plots were unified to 20 ms to facilitate the comparison of firing rates directly. The PSTH plots of 100 and 200 Hz are duplications of two and four same portions, respectively. (B,C) Comparisons of the peak coefficients (ΔC/Cave) and the duty ratio of excitatory phase of PSTH for individual interneurons and pyramidal cells during HFS with different stimulation frequency of 50, 100, and 200 Hz.

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