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Journal of Integrative Neuroscience  2019, Vol. 18 Issue (1): 33-41    DOI: 10.31083/j.jin.2019.01.18
Original Research Previous articles | Next articles
High-frequency stimulation of afferent axons alters firing rhythms of downstream neurons
Weijian Ma1, Zhouyan Feng1, *(), Zhaoxiang Wang1, Wenjie Zhou1
1Key Laboratory of Biomedical Engineering of Education Ministry, College of Biomedical Engineering & Instrument Science, Zhejiang University, Hangzhou, Zhejiang 310027, China
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Deep brain stimulation is an emerging treatment for brain disorders. However, the mechanisms of high-frequency brain stimulation are unclear. Recent studies have suggested that high-frequency stimulation might produce therapeutic effects by eliminating pathological rhythms in neuronal firing. To test the hypothesis, the present study investigated whether stimulation of axonal afferent fibers might alter firing rhythms of downstream neurons in in-vivo experiments with Sprague-Dawley rats. Stimulation trains of 100 Hz with one minute duration were applied to the Schaffer collaterals of hippocampus Area CA1 in anaesthetized rats. Spikes of single interneurons and pyramidal neurons in the downstream region were analyzed. The spike rhythms before, during, and after the stimulations were evaluated by analyzing the power spectrum density of autocorrelograms of the spiking sequences. The rhythms of local field potentials were also evaluated by power spectrum density. During baseline recordings, theta rhythms were obvious in the spiking sequences of both types of neuron and in the local field potentials of the stratum radiatum. However, these theta rhythms were all suppressed significantly during the stimulations. Additionally, the results of Pearson's correlation analysis showed that 20-30% variation in the theta rhythms of neuronal firing could be explained by changes of the theta rhythms in local field potentials. High-frequency axonal stimulation might prevent the original rhythmic excitation in afferent fibers and generate new excitation by stimulation pulses per se, thereby suppressing the theta rhythms of individual neuron firing and of local field potentials in the region downstream from stimulation. The results provide new evidence to support the hypothesis that high-frequency stimulation can alter the firing rhythms of neurons, which may underlie the therapeutic effects of deep brain stimulation.

Key words:  Deep brain stimulation      high frequency stimulation      unit spike      theta rhythm      local field potential      autocorrelogram      power spectrum density      axonal block      hippocampus area CA1     
Submitted:  23 January 2018      Accepted:  28 March 2019      Published:  30 March 2019     
  • 30970753/National Natural Science Foundation of China
  • 2018DG0ZX01/Major Scientific Project of Zhejiang Lab
*Corresponding Author(s):  Zhouyan Feng     E-mail:

Cite this article: 

Weijian Ma, Zhouyan Feng, Zhaoxiang Wang, Wenjie Zhou. High-frequency stimulation of afferent axons alters firing rhythms of downstream neurons. Journal of Integrative Neuroscience, 2019, 18(1): 33-41.

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Figure 1.  Spontaneous theta rhythms of neuronal firing in hippocampus Area CA1 of anaesthetized rats. (A) Left: Schematic diagram of the rat hippocampus and electrode location. Recording electrode (RE) and stimulating electrode (SE) were respectively located in hippocampus Area CA1 and in the upstream Schaffer collaterals. Arrow indicates direction of stimulus-induced excitation. Electrical signals in the pyramidal layer (Pyr. layer) and in the stratum radiatum (S. rad.) were collected by two recording sites in the RE array (separated by 0.4 mm). Right: Typical waveforms of the population spike (PS) and field excitatory postsynaptic potential (fEPSP) evoked by a stimulus and recorded in Pyr. and S. rad. layers, respectively. Inverted triangles: Truncated stimulus artifacts. (B) Left: Segment of raw recording in the Pyr. layer together with associated local field potential (LFP) in theta range and multiple unit activity (MUA). Middle: Autocorrelation profile of the sequence of unit spikes extracted from the MUA. Right: Corresponding LFP-power spectrum density (top: LFP-PSD) and unit spike-power spectrum density (bottom: unit-PSD). (C) Left: Recording from S. rad. corresponding to the segment in (B) with its LFP in theta range. Right: Corresponding LFP-power spectrum density. Shaded area: Theta range (2-5 Hz).

Figure 2.  Changes in the multiple unit activity and local field potential evoked by stimulation (one minute, 100 Hz). (A) Example recording from Pyr. layer and associated multiple unit activity and local field potential in theta range. Typical spike waveforms of interneurons and pyramidal neurons are given in the two expanded insets. (B) Corresponding recording from S. rad. layer. Shaded area: High-frequency stimulation period, stimulus artifacts removed.

Figure 3.  Axonal stimulation suppressed theta rhythms in neuronal firing. (A) Top to bottom: Examples of theta signal recorded from Pyr. layer, raster plots of unit spikes of an interneuron and a pyramidal neuron, and theta signal from S. rad. during the three periods of: before, during, and after high-frequency stimulation, respectively. (B) Example autocorrelation profiles and their unit-power spectrum densities (unit-PSD) for interneuron spikes during the three different periods. (C) Statistical power of theta rhythms in unit-PSD of interneurons during the three different periods. Paired $t$-test was used to compare mean power during stimulation and baseline mean power prior to stimulation (** p < 0.01, $n$ = 7). (D) and (E) Corresponding data for pyramidal neurons.

Figure 4.  Axonal stimulation suppressed theta rhythms in the local field potential. (A) and (B) Examples of local field potential-power spectrum densities in Pyr. layer (A) and S. rad. (B) for the three different periods: before, during, and after stimulation. (C) and (D) Statistical comparison of the power of theta rhythms (2-5 Hz) for the three different periods. $^{*}$p < 0.05, $^{**}$p < 0.01, paired $t$-test, $n$ = 7.

Figure 5.  Correlation between theta rhythm of neuronal firing and theta rhythm of local field potential. Scatter diagrams of theta power of unit spikes (A and C for interneurons, B and D for pyramidal neurons) against the corresponding theta power of local field potential (A and B for Pyr. Layer, C and D for S. rad.). Pearson's correlation coefficient (R) is shown above each plot together with the p-value. The data number ($N$ = 3 $\times$ 7 = 21) is the number of pooled data from the three different periods of before, during, and after stimulation within the seven experiments.

[1] Alhourani, A., McDowell, M. M., Randazzo, M. J., Wozny, T. A., Kondylis, E. D., Lipski, W. J., Beck, S., Karp, J. F., Ghuman, A. S. and Richardson, R. M. (2015) Network effects of deep brain stimulation. Journal of Neurophysiology 114, 2105-2117.
doi: 10.1152/jn.00275.2015 pmid: 26269552
[2] Barthó, P., Hirase, H., Monconduit, L., Zugaro, M., Harris, K. D. and Buzsáki, G. (2004) Characterization of neocortical principal cells and interneurons by network interactions and extracellular features. Journal of Neurophysiology 92, 600-608.
doi: 10.1152/jn.01170.2003 pmid: 15056678
[3] Bellinger, S. C., Miyazawa, G. and Steinmetz, P. N. (2008) Submyelin potassium accumulation may functionally block subsets of local axons during deep brain stimulation: a modeling study. Journal of Neural Engineering 5, 263-274.
doi: 10.1088/1741-2560/5/3/001 pmid: 18566505
[4] Birdno, M. J., Kuncel, A. M., Dorval, A. D., Turner, D. A., Gross, R. E. and Grill, W. M. (2012) Stimulus features underlying reduced tremor suppression with temporally patterned deep brain stimulation. Journal of Neurophysiology 107, 364-383.
doi: 10.1152/jn.00906.2010 pmid: 21994263
[5] Buzsáki, G . (2002) Theta oscillations in the hippocampus. Neuron 33, 325-340.
[6] Buzsáki, G. and Draguhn, A . (2004) Neuronal oscillations in cortical networks. Science 304, 1926-1929.
[7] Buzsáki, G. and Moser, E. I. (2013) Memory, navigation and theta rhythm in the hippocampal-entorhinal system. Nature Neuroscience 16, 130-138.
[8] Chiken, S. and Nambu, S. (2016) Mechanism of deep brain stimulation: inhibition, excitation, or disruption? Neuroscientist 22, 313-322.
doi: 10.1177/1073858415581986 pmid: 25888630
[9] Cury, R.G., Fraix, V., Castrioto, A., Perez, F. M., Krack, P., Chabardes, S., Seigneuret, E., Alho, E., Benabid, A. L. and Moro, E. (2017) Thalamic deep brain stimulation for tremor in Parkinson disease, essential tremor, and dystonia. Neurology 89, 1416-1423.
[10] Deniau, J. M., Degos, B., Bosch, C. and Maurice, N. (2010) Deep brain stimulation mechanisms: beyond the concept of local functional inhibition. European Journal of Neuroscience 32, 1080-1091.
doi: 10.1111/j.1460-9568.2010.07413.x pmid: 21039947
[11] Feng, Z., Zheng, X., Yu, Y. and Durand, D. M. (2013) Functional disconnection of axonal fibers generated by high frequency stimulation in the hippocampal CA1 region in-vivo. Brain Research 1509, 32-42.
[12] Feng, Z., Wang, Z., Guo, Z., Zhou, W., Cai, Z. and Durand, D. M. (2017) High frequency stimulation of afferent fibers generates asynchronous firing in the downstream neurons in hippocampus through partial block of axonal conduction. Brain Research 1661, 67-78.
doi: 10.1016/j.brainres.2017.02.008 pmid: 28213155
[13] Florence, G., Sameshima, K., Fonoff, E. T. and Hamani, C. (2016) Deep brain stimulation: more complex than the inhibition of cells and excitation of fibers. Neuroscientist 22, 332-345.
doi: 10.1177/1073858415591964 pmid: 26150316
[14] Guo, Z., Feng, Z., Wang, Y. and Wei, X. (2018) Simulation study of intermittent axonal block and desynchronization effect induced by high-frequency stimulation of electrical pulses. Frontiers in Neuroscience 22, 1-12.
[15] Herrington, T. M., Cheng, J. J. and Eskandar, E. N. (2016) Mechanisms of deep brain stimulation. Journal of Neurophysiology 115, 19-38.
doi: 10.1152/jn.00281.2015 pmid: 26510756
[16] Huh, C. Y., Goutagny, R. and Williams, S . (2010) Glutamatergic neurons of the mouse medial septum and diagonal band of Broca synaptically drive hippocampal pyramidal cells: relevance for hippocampal theta rhythm. Journal of Neuroscience 30, 15951-15961.
doi: 10.1523/JNEUROSCI.3663-10.2010 pmid: 21106833
[17] Iremonger, K. J., Anderson, T. R., Hu, B. and Kiss, Z. H. (2006) Cellular mechanisms preventing sustained activation of cortex during subcortical high-frequency stimulation. Journal of Neurophysiology 96, 613-621.
doi: 10.1152/jn.00105.2006 pmid: 16554516
[18] Jensen, A. L. and Durand, D. M. (2009) High frequency stimulation can block axonal conduction. Experimental Neurology 220, 57-70.
doi: 10.1016/j.expneurol.2009.07.023 pmid: 2761511
[19] Jiruska, P., Powell, A. D., Deans, J. K. and Jefferys, J. G. (2010) Effects of direct brain stimulation depend on seizure dynamics. Epilepsia 51, 93-97.
doi: 10.1111/j.1528-1167.2010.02619.x pmid: 20618410
[20] Kamondi, A., Acsady, L., Wang, X. J. and Buzsáki, G. (1998) Theta oscillations in somata and dendrites of hippocampal pyramidal cells in vivo: activity-dependent phase-precession of action potentials. Hippocampus 8, 244-261.
[21] Kitchigina, V., Kutyreva, E. and Brazhnik, E . (2003) Modulation of theta rhythmicity in the medial septal neurons and the hippocampal electroencephalogram in the awake rabbit via actions at noradrenergic alpha 2-receptors. Neuroscience 120, 509-521.
doi: 10.1016/S0306-4522(03)00331-2 pmid: 12890520
[22] Kitchigina, V., Popova, I., Sinelnikova, V., Malkov, A., Astasheva, E., Shubina, L. and Aliev, R. (2013) Disturbances of septohippocampal theta oscillations in the epileptic brain: reasons and consequences. Experimental Neurology 247, 314-327.
doi: 10.1016/j.expneurol.2013.01.029 pmid: 23384663
[23] Kloosterman, F., Peloquin, P. and Leung, L. S. (2001) Apical and basal orthodromic population spikes in hippocampal CA1 in vivo show different origins and patterns of propagation. Journal of Neurophysiology 86, 2435-2444.
[24] Kuncel, A. M., Cooper, S. E., Wolgamuth, B. R., Clyde, M. A., Snyder, S. A., Montgomery, E. J., Rezai, A. R. and Grill, W. M. (2006) Clinical response to varying the stimulus parameters in deep brain stimulation for essential tremor. Movement Disorders 21, 1920-1928.
doi: 10.1002/mds.21087 pmid: 16972236
[25] Lee, M. G., Chrobak, J. J., Sik, A., Wiley, R. G. and Buzsáki, G. (1994) Hippocampal theta activity following selective lesion of the septal cholinergic system. Neuroscience 62, 1033-1047.
[26] McConnell, G. C., So, R. Q., Hilliard, J. D., Lopomo, P. and Grill, W. M. (2012) Effective deep brain stimulation suppresses low-frequency network oscillations in the basal ganglia by regularizing neural firing patterns. Journal of Neuroscience 32, 15657-15668.
doi: 10.1523/JNEUROSCI.2824-12.2012 pmid: 23136407
[27] Mercer, L. J., Remley, N. R. and Gilman, D. P. (1978) Effects of urethane on hippocampal unit activity in the rat. Brain Research Bulletin 3, 567-570.
doi: 10.1016/0361-9230(78)90089-8 pmid: 122723
[28] Pereira, E. A., Green, A. L., Stacey, R. J. and Aziz, T. Z. (2012) Refractory epilepsy and deep brain stimulation. Journal of Clinical Neuroscience 19, 27-33.
doi: 10.1016/j.jocn.2011.03.043 pmid: 22172283
[29] Ranck, J. J. (1975) Which elements are excited in electrical stimulation of mammalian central nervous system: a review. Brain Research 98, 417-440.
[30] Rosenbaum, R., Zimnik, A., Zheng, F., Turner, R. S., Alzheimer, C., Doiron, B. and Rubin, J. E. (2014) Axonal and synaptic failure suppress the transfer of firing rate oscillations, synchrony and information during high frequency deep brain stimulation. Neurobiology of Disease 62, 86-99.
doi: 10.1016/j.nbd.2013.09.006 pmid: 24051279
[31] Rutishauser, U., Ross, I. B., Mamelak, A. N. and Schuman, E. M. (2010) Human memory strength is predicted by theta-frequency phase-locking of single neurons. Nature 464, 903-907.
doi: 10.1038/nature08860 pmid: 20336071
[32] Sankar, T., Chakravarty, M. M., Bescos, A., Lara, M., Obuchi, T., Laxton, A. W., McAndrews, M. P., Tang-Wai, D. F., Workman, C. I., Smith, G. S. and Lozano, A. M. (2015) Deep brain stimulation influences brain structure in Alzheimer's disease. Brain Stimulation 8, 645-654.
doi: 10.1016/j.brs.2014.11.020 pmid: 25814404
[33] Singh, A., Mewes, K., Gross, R. E., DeLong, M. R., Obeso, J. A. and Papa, S. M. (2016) Human striatal recordings reveal abnormal discharge of projection neurons in parkinson's disease. Proceedings of the National Academy of Sciences of the United States of America 113, 9629-9634.
doi: 10.1073/pnas.1606792113 pmid: 27503874
[34] So, R. Q., Kent, A. R. and Grill, W. M. (2012) Relative contributions of local cell and passing fiber activation and silencing to changes in thalamic fidelity during deep brain stimulation and lesioning: a computational modeling study. Journal of Computational Neuroscience 32, 499-519.
doi: 10.1007/s10827-011-0366-4 pmid: 3288232
[35] Tass, P., Smirnov, D., Karavaev, A., Barnikol, U., Barnikol, T., Adamchic, I., Hauptmann, C., Pawelcyzk, N., Maarouf, M., Sturm, V., Freund, H. J. and Bezruchko, B. (2010) The causal relationship between subcortical local field potential oscillations and parkinsonian resting tremor. Journal of Neural Engineering 7, 1-16.
[36] Taghva, A. S., Malone, D. A. and Rezai, A. R. (2013) Deep brain stimulation for treatment-resistant depression. World Neurosurgery 80, S17-S27.
doi: 10.1016/j.wneu.2012.11.074 pmid: 15748841
[37] Udupa, K. and Chen, R. (2015) The mechanisms of action of deep brain stimulation and ideas for the future development. Progress in Neurobiology 133, 27-49.
[38] Vargas-Irwin, C. and Donoghue, J. P. (2007) Automated spike sorting using density grid contour clustering and subtractive waveform decomposition. Journal of Neuroscience Methods 164, 1-18.
doi: 10.1016/j.jneumeth.2007.03.025 pmid: 2104515
[39] Vonck, K., Sprengers, M., Carrette, E., Dauwe, I., Miatton, M., Meurs, A., Goossens, L., Herdt, V., Achten, R., Thiery, E., Raedt, R., Roost, D. and Boon, P. (2013) A decade of experience with deep brain stimulation for patients with refractory medial temporal lobe epilepsy. International Journal of Neural Systems 23, 1-13.
[40] Wang, Z., Feng, Z. and Wei, X. (2018) Axonal stimulations with a higher frequency generate more randomness in neuronal firing rather than increase firing rates in rat hippocampus. Frontiers in Neuroscience 24, 1-11.
[41] Yu, Y., Feng, Z., Cao, J., Guo, Z., Wang, Z., Hu, N. and Wei, X. (2016) Modulation of local field potentials by high-frequency stimulation of afferent axons in the hippocampal CA1 region. Journal of Integrative Neuroscience 15, 1-17.
doi: 10.1142/S0219635216500011 pmid: 26490044
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