Effect of Biphasic kHz Field Stimulation on CA1 Pyramidal Neurons in Slices

Main Article Content

Sergei Viktorovich Karnup William De Groat Jonathan Beckel Changfeng Tai

Abstract

Electrical stimulation in the kilohertz-frequency range has been successfully used for treatment of various neurological disorders. Nevertheless, the mechanisms underlying this stimulation are poorly understood. To study the effect of kilohertz-frequency electric fields on neuronal membrane biophysics we developed a reliable experimental method to measure responses of single neurons to kilohertz field stimulation in brain slice preparations. In the submerged brain slice pyramidal neurons of the CA1 subfield were recorded in the whole-cell configuration before, during and after stimulation with a biphasic charge balanced electric field at 2kHz, 5kHz or 10 kHz. The slice was placed in a 1 mm gap between two parallel 2 mm long platinum-iridium 0.1 mm diameter wire electrodes. Whole-cell recordings lasted for an hour or longer. Typically, a few 5-10 min long sessions of kHz-field stimulation (kHz-FS) with various frequency/amplitude combinations were applied to assess the type of neuronal response and possible changes of its membrane characteristics. It was found that kHz-field stimulation at all frequencies elicited reproducible excitatory neuronal responses lasting throughout stimulation period, but not after cessation of kHz-FS. During kHz-FS the rheobase usually decreased. In addition, spontaneous firing might be initiated in some silent neurons or became more intense in previously spontaneously active neurons. Response thresholds were in the range of 0.5-2 mA and were higher at higher frequencies. Blockade of glutamatergic synaptic transmission did not alter the magnitude of responses. Inhibitory synaptic input was not changed by kilohertz field stimulation. We conclude that kHz-frequency current applied in brain tissue has an excitatory effect on pyramidal neurons during stimulation. This effect is more prominent and occurs at a lower stimulus intensity at a frequency of 2kHz as compared to 5kHz and 10kHz.

Article Details

How to Cite
KARNUP, Sergei Viktorovich et al. Effect of Biphasic kHz Field Stimulation on CA1 Pyramidal Neurons in Slices. Medical Research Archives, [S.l.], v. 10, n. 8, aug. 2022. ISSN 2375-1924. Available at: <https://esmed.org/MRA/mra/article/view/2957>. Date accessed: 07 oct. 2022. doi: https://doi.org/10.18103/mra.v10i8.2957.
Section
Research Articles

References

1. Voroslakos, M.; Takeuchi, Y.; Brinyiczki, K.; Zombori, T.; Oliva, A.; Fernandez-Ruiz, A.; Kozak, G.; Kincses, Z. T.; Ivanyi, B.; Buzsaki, G.; Berenyi, A., Direct effects of transcranial electric stimulation on brain circuits in rats and humans. Nat Commun 2018, 9 (1), 483.
2. Billet, B.; Hanssens, K.; De Coster, O.; Nagels, W.; Weiner, R. L.; Wynendaele, R.; Vanquathem, N., Wireless high-frequency dorsal root ganglion stimulation for chronic low back pain: A pilot study. Acta Anaesthesiol Scand 2018.
3. Finch, P.; Price, L.; Drummond, P., High-Frequency (10 kHz) Electrical Stimulation of Peripheral Nerves for Treating Chronic Pain: A Double-Blind Trial of Presence vs Absence of Stimulation. Neuromodulation 2019, 22 (5), 529-536.
4. Formento, E.; Minassian, K.; Wagner, F.; Mignardot, J. B.; Le Goff-Mignardot, C. G.; Rowald, A.; Bloch, J.; Micera, S.; Capogrosso, M.; Courtine, G., Electrical spinal cord stimulation must preserve proprioception to enable locomotion in humans with spinal cord injury. Nat Neurosci 2018, 21 (12), 1728-1741.
5. Litvak, L. M.; Smith, Z. M.; Delgutte, B.; Eddington, D. K., Desynchronization of electrically evoked auditory-nerve activity by high-frequency pulse trains of long duration. J Acoust Soc Am 2003, 114 (4 Pt 1), 2066-78.
6. Buzsaki, G.; Draguhn, A., Neuronal oscillations in cortical networks. Science 2004, 304 (5679), 1926-9.
7. Milosevic, L.; Kalia, S. K.; Hodaie, M.; Lozano, A. M.; Fasano, A.; Popovic, M. R.; Hutchison, W. D., Neuronal inhibition and synaptic plasticity of basal ganglia neurons in Parkinson's disease. Brain 2018, 141 (1), 177-190.
8. McIntyre, C. C.; Grill, W. M.; Sherman, D. L.; Thakor, N. V., Cellular effects of deep brain stimulation: model-based analysis of activation and inhibition. J Neurophysiol 2004, 91 (4), 1457-69.
9. Chiken, S.; Nambu, A., Mechanism of Deep Brain Stimulation: Inhibition, Excitation, or Disruption? Neuroscientist 2016, 22 (3), 313-22.
10. Chaieb, L.; Antal, A.; Paulus, W., Transcranial alternating current stimulation in the low kHz range increases motor cortex excitability. Restor Neurol Neurosci 2011, 29 (3), 167-75.
11. Antal, A.; Paulus, W., Transcranial alternating current stimulation (tACS). Front Hum Neurosci 2013, 7, 317.
12. Kapural, L.; Yu, C.; Doust, M. W.; Gliner, B. E.; Vallejo, R.; Sitzman, B. T.; Amirdelfan, K.; Morgan, D. M.; Brown, L. L.; Yearwood, T. L.; Bundschu, R.; Burton, A. W.; Yang, T.; Benyamin, R.; Burgher, A. H., Novel 10-kHz High-frequency Therapy (HF10 Therapy) Is Superior to Traditional Low-frequency Spinal Cord Stimulation for the Treatment of Chronic Back and Leg Pain: The SENZA-RCT Randomized Controlled Trial. Anesthesiology 2015, 123 (4), 851-60.
13. Harmsen, I. E.; Hasanova, D.; Elias, G. J. B.; Boutet, A.; Neudorfer, C.; Loh, A.; Germann, J.; Lozano, A. M., Trends in Clinical Trials for Spinal Cord Stimulation. Stereotact Funct Neurosurg 2021, 99 (2), 123-134.
14. Khadka, N.; Harmsen, I. E.; Lozano, A. M.; Bikson, M., Bio-Heat Model of Kilohertz-Frequency Deep Brain Stimulation Increases Brain Tissue Temperature. Neuromodulation 2020, 23 (4), 489-495.
15. Elias, G. J. B.; Loh, A.; Gwun, D.; Pancholi, A.; Boutet, A.; Neudorfer, C.; Germann, J.; Namasivayam, A.; Gramer, R.; Paff, M.; Lozano, A. M., Deep brain stimulation of the brainstem. Brain 2021, 144 (3), 712-723.
16. Miller, C. A.; Robinson, B. K.; Rubinstein, J. T.; Abbas, P. J.; Runge-Samuelson, C. L., Auditory nerve responses to monophasic and biphasic electric stimuli. Hear Res 2001, 151 (1-2), 79-94.
17. Kilgore, K. L.; Bhadra, N., Reversible nerve conduction block using kilohertz frequency alternating current. Neuromodulation 2014, 17 (3), 242-54; discussion 254-5.
18. Shapiro, K.; Guo, W.; Armann, K.; Pace, N.; Shen, B.; Wang, J.; Beckel, J.; de Groat, W.; Tai, C., Pudendal Nerve Block by Low-Frequency ( 19. Wen, H.; Hubbard, J. M.; Wang, W. C.; Brehm, P., Fatigue in Rapsyn-Deficient Zebrafish Reflects Defective Transmitter Release. J Neurosci 2016, 36 (42), 10870-10882.
20. Deans, J. K.; Powell, A. D.; Jefferys, J. G., Sensitivity of coherent oscillations in rat hippocampus to AC electric fields. J Physiol 2007, 583 (Pt 2), 555-65.
21. Jahnsen, H.; Karnup, S., A spectral analysis of the integration of artificial synaptic potentials in mammalian central neurons. Brain Res 1994, 666 (1), 9-20.
22. Miller, K. D.; Troyer, T. W., Neural noise can explain expansive, power-law nonlinearities in neural response functions. J Neurophysiol 2002, 87 (2), 653-9.
23. Lesperance, L. S.; Lankarany, M.; Zhang, T. C.; Esteller, R.; Ratte, S.; Prescott, S. A., Artifactual hyperpolarization during extracellular electrical stimulation: Proposed mechanism of high-rate neuromodulation disproved. Brain Stimul 2018, 11 (3), 582-591.
24. Esmaeilpour, Z.; Jackson, M.; Kronberg, G.; Zhang, T.; Esteller, R.; Hershey, B.; Bikson, M., Limited Sensitivity of Hippocampal Synaptic Function or Network Oscillations to Unmodulated Kilohertz Electric Fields. eNeuro 2020, 7 (6).
25. Zhao, S.; Yang, G.; Wang, J.; Roppolo, J. R.; de Groat, W. C.; Tai, C., Conduction block in myelinated axons induced by high-frequency (kHz) non-symmetric biphasic stimulation. Front Comput Neurosci 2015, 9, 86.
26. Wang, Z.; Pace, N.; Cai, H.; Shen, B.; Wang, J.; Roppolo, J. R.; de Groat, W. C.; Tai, C., Poststimulation Block of Pudendal Nerve Conduction by High-Frequency (kHz) Biphasic Stimulation in Cats. Neuromodulation 2020, 23 (6), 747-753.
27. Yang, G.; Xiao, Z.; Wang, J.; Shen, B.; Roppolo, J. R.; de Groat, W. C.; Tai, C., Post-stimulation block of frog sciatic nerve by high-frequency (kHz) biphasic stimulation. Med Biol Eng Comput 2017, 55 (4), 585-593.
28. De Carolis, G.; Paroli, M.; Tollapi, L.; Doust, M. W.; Burgher, A. H.; Yu, C.; Yang, T.; Morgan, D. M.; Amirdelfan, K.; Kapural, L.; Sitzman, B. T.; Bundschu, R.; Vallejo, R.; Benyamin, R. M.; Yearwood, T. L.; Gliner, B. E.; Powell, A. A.; Bradley, K., Paresthesia-Independence: An Assessment of Technical Factors Related to 10 kHz Paresthesia-Free Spinal Cord Stimulation. Pain Physician 2017, 20 (4), 331-341.
29. Kamal, A.; Artola, A.; Biessels, G. J.; Gispen, W. H.; Ramakers, G. M., Increased spike broadening and slow afterhyperpolarization in CA1 pyramidal cells of streptozotocin-induced diabetic rats. Neuroscience 2003, 118 (2), 577-83.
30. Staff, N. P.; Jung, H. Y.; Thiagarajan, T.; Yao, M.; Spruston, N., Resting and active properties of pyramidal neurons in subiculum and CA1 of rat hippocampus. J Neurophysiol 2000, 84 (5), 2398-408.
31. Franke, M.; Bhadra, N.; Bhadra, N.; Kilgore, K., Direct current contamination of kilohertz frequency alternating current waveforms. J Neurosci Methods 2014, 232, 74-83.
32. Pena, E.; Pelot, N. A.; Grill, W. M., Non-monotonic kilohertz frequency neural block thresholds arise from amplitude- and frequency-dependent charge imbalance. Sci Rep 2021, 11 (1), 5077.
33. Ackermann, D. M.; Bhadra, N.; Gerges, M.; Thomas, P. J., Dynamics and sensitivity analysis of high-frequency conduction block. J Neural Eng 2011, 8 (6), 065007.
34. Kilgore, K. L.; Bhadra, N., Nerve conduction block utilising high-frequency alternating current. Med Biol Eng Comput 2004, 42 (3), 394-406.
35. Berger, R.; Garnier, Y., Perinatal brain injury. J Perinat Med 2000, 28 (4), 261-85.
36. Blankenburg, S.; Wu, W.; Lindner, B.; Schreiber, S., Information filtering in resonant neurons. J Comput Neurosci 2015, 39 (3), 349-70.
37. Carandini, M.; Mechler, F.; Leonard, C. S.; Movshon, J. A., Spike train encoding by regular-spiking cells of the visual cortex. J Neurophysiol 1996, 76 (5), 3425-41.
38. Koppenhofer, E.; Schumann, H., A method for increasing the frequency response of voltage clamped myelinated nerve fibres. Pflugers Arch 1981, 390 (3), 288-9.
39. Spruston, N.; Jaffe, D. B.; Johnston, D., Dendritic attenuation of synaptic potentials and currents: the role of passive membrane properties. Trends Neurosci 1994, 17 (4), 161-6.
40. Rahman, A.; Reato, D.; Arlotti, M.; Gasca, F.; Datta, A.; Parra, L. C.; Bikson, M., Cellular effects of acute direct current stimulation: somatic and synaptic terminal effects. J Physiol 2013, 591 (10), 2563-78.
41. Thomson, A. M.; Radpour, S., Excitatory Connections Between CA1 Pyramidal Cells Revealed by Spike Triggered Averaging in Slices of Rat Hippocampus are Partially NMDA Receptor Mediated. Eur J Neurosci 1991, 3 (6), 587-601.
42. Bennett, M. V.; Pereda, A., Pyramid power: principal cells of the hippocampus unite! Brain Cell Biol 2006, 35 (1), 5-11.
43. Mercer, A.; Bannister, A. P.; Thomson, A. M., Electrical coupling between pyramidal cells in adult cortical regions. Brain Cell Biol 2006, 35 (1), 13-27.
44. Parra, P.; Gulyas, A. I.; Miles, R., How many subtypes of inhibitory cells in the hippocampus? Neuron 1998, 20 (5), 983-93.
45. Buhl, E. H.; Han, Z. S.; Lorinczi, Z.; Stezhka, V. V.; Karnup, S. V.; Somogyi, P., Physiological properties of anatomically identified axo-axonic cells in the rat hippocampus. J Neurophysiol 1994, 71 (4), 1289-307.
46. Buhl, E. H.; Szilagyi, T.; Halasy, K.; Somogyi, P., Physiological properties of anatomically identified basket and bistratified cells in the CA1 area of the rat hippocampus in vitro. Hippocampus 1996, 6 (3), 294-305.
47. Lee, K. Y.; Bae, C.; Lee, D.; Kagan, Z.; Bradley, K.; Chung, J. M.; La, J. H., Low-intensity, Kilohertz Frequency Spinal Cord Stimulation Differently Affects Excitatory and Inhibitory Neurons in the Rodent Superficial Dorsal Horn. Neuroscience 2020, 428, 132-139.
48. Lee, K. Y.; Lee, D.; Kagan, Z. B.; Wang, D.; Bradley, K., Differential Modulation of Dorsal Horn Neurons by Various Spinal Cord Stimulation Strategies. Biomedicines 2021, 9 (5).
49. Pelot, N. A.; Grill, W. M., In vivo quantification of excitation and kilohertz frequency block of the rat vagus nerve. J Neural Eng 2020, 17 (2), 026005.
50. Tai, C.; de Groat, W. C.; Roppolo, J. R., Simulation analysis of conduction block in unmyelinated axons induced by high-frequency biphasic electrical currents. IEEE Trans Biomed Eng 2005, 52 (7), 1323-32.
51. Taoufik, E.; Probert, L., Ischemic neuronal damage. Curr Pharm Des 2008, 14 (33), 3565-73.
52. Cuellar, J. M.; Alataris, K.; Walker, A.; Yeomans, D. C.; Antognini, J. F., Effect of high-frequency alternating current on spinal afferent nociceptive transmission. Neuromodulation 2013, 16 (4), 318-27; discussion 327.
53. Bhadra, N.; Lahowetz, E. A.; Foldes, S. T.; Kilgore, K. L., Simulation of high-frequency sinusoidal electrical block of mammalian myelinated axons. J Comput Neurosci 2007, 22 (3), 313-26.
54. Ackermann, D. M., Jr.; Bhadra, N.; Foldes, E. L.; Wang, X. F.; Kilgore, K. L., Effect of nerve cuff electrode geometry on onset response firing in high-frequency nerve conduction block. IEEE Trans Neural Syst Rehabil Eng 2010, 18 (6), 658-65.
55. Ackermann, D. M., Jr.; Foldes, E. L.; Bhadra, N.; Kilgore, K. L., Effect of bipolar cuff electrode design on block thresholds in high-frequency electrical neural conduction block. IEEE Trans Neural Syst Rehabil Eng 2009, 17 (5), 469-77.
56. Coenen, V. A.; Amtage, F.; Volkmann, J.; Schlapfer, T. E., Deep Brain Stimulation in Neurological and Psychiatric Disorders. Dtsch Arztebl Int 2015, 112 (31-32), 519-26.
57. Gaunt, R. A.; Prochazka, A., Transcutaneously coupled, high-frequency electrical stimulation of the pudendal nerve blocks external urethral sphincter contractions. Neurorehabil Neural Repair 2009, 23 (6), 615-26.
58. Merrill, D. R.; Bikson, M.; Jefferys, J. G., Electrical stimulation of excitable tissue: design of efficacious and safe protocols. J Neurosci Methods 2005, 141 (2), 171-98.