Review Article

Mechanisms of Action of Noninvasive Brain Stimulation with Weak Non-Constant Current Stimulation Approaches


Objective: Non-constant current stimulation (NCCS) is a neuromodulatory method in which weak alternating, pulsed or random currents are delivered to the human head via scalp or earlobe electrodes. This approach is widely used in basic and translational studies. However, the underlying mechanisms of NCCS, which lead to biological and behavioral effects in the brain, remain largely unknown. In this review, we characterize NCCS techniques currently being utilized in neuroscience investigations, including transcranial alternating current stimulation (tACS), transcranial pulsed current stimulation (tPCS), transcranial random noise stimulation (tRNS), and cranial electrotherapy stimulation (CES).

Method: We unsystematically searched all relevant conference papers, journal articles, chapters, and textbooks on the biological mechanisms of NCCS techniques.

Results: The fundamental idea of NCCS is that these low-level currents can interact with neuronal activity, modulate neuroplasticity and entrain cortical networks, thus, modifying cognition and behavior. We elucidate the mechanisms of action for each NCCS technique. These techniques may cause microscopic effects (such as affecting ion channels and neurotransmission systems) and macroscopic effects (such as affecting brain oscillations and functional connectivity) on the brain through different mechanisms of action (such as neural entrainment and stochastic resonance).

Conclusion: The appeal of NCCS is its potential to modulate neuroplasticity noninvasively, along with the ease of use and good tolerability. Promising and interesting evidence has been reported for the capacity of NCCS to affect neural circuits and the behaviors under their control. Today, the challenge is to utilize this advancement optimally. Continuing methodological advancements with NCCS approaches will enable researchers to better understand how NCCS can be utilized for the modulation of nervous system activity and subsequent behaviors, with possible applications to non-clinical and clinical practices.

1. Khaleghi A, Mohammadi MR, Shahi K, Nasrabadi AM. Computational Neuroscience Approach to Psychiatry: A Review on Theory-driven Approaches. Clin Psychopharmacol Neurosci. 2022;20(1):26-36.
2. Khaleghi A, Zarafshan H, Vand SR, Mohammadi MR. Effects of Non-invasive Neurostimulation on Autism Spectrum Disorder: A Systematic Review. Clin Psychopharmacol Neurosci. 2020;18(4):527-52.
3. Khaleghi A, Pirzad Jahromi G, Zarafshan H, Mostafavi SA, Mohammadi MR. Effects of transcranial direct current stimulation of prefrontal cortex on risk-taking behavior. Psychiatry Clin Neurosci. 2020;74(9):455-65.
4. Mostafavi SA, Khaleghi A, Mohammadi MR. Noninvasive brain stimulation in alcohol craving: A systematic review and meta-analysis. Prog Neuropsychopharmacol Biol Psychiatry. 2020;101:109938.
5. Mostafavi SA, Khaleghi A, Mohammadi MR, Akhondzadeh S. Is transcranial direct current stimulation an effective modality in reducing food craving? A systematic review and meta-analysis. Nutr Neurosci. 2020;23(1):55-67.
6. Paulus W, Nitsche MA, Antal A. Application of transcranial electric stimulation (tDCS, tACS, tRNS): From motor-evoked potentials towards modulation of behaviour. Eur Psychol. 2016;21(1):4.
7. Helfrich RF, Schneider TR, Rach S, Trautmann-Lengsfeld SA, Engel AK, Herrmann CS. Entrainment of brain oscillations by transcranial alternating current stimulation. Curr Biol. 2014;24(3):333-9.
8. Vöröslakos M, Takeuchi Y, Brinyiczki K, Zombori T, Oliva A, Fernández-Ruiz A, et al. Direct effects of transcranial electric stimulation on brain circuits in rats and humans. Nat Commun. 2018;9(1):483.
9. Yaghmazadeh O, Vöröslakos M, Alon L, Carluccio G, Collins C, Sodickson DK, et al. Neuronal activity under transcranial radio-frequency stimulation in metal-free rodent brains in-vivo. Communications Engineering. 2022;1(1):1-13.
10. Anastassiou CA, Perin R, Markram H, Koch C. Ephaptic coupling of cortical neurons. Nat Neurosci. 2011;14(2):217-23.
11. Deans JK, Powell AD, Jefferys JG. Sensitivity of coherent oscillations in rat hippocampus to AC electric fields. J Physiol. 2007;583(Pt 2):555-65.
12. Vieira PG, Krause MR, Pack CC. tACS entrains neural activity while somatosensory input is blocked. PLoS Biol. 2020;18(10):e3000834.
13. Reato D, Rahman A, Bikson M, Parra LC. Effects of weak transcranial alternating current stimulation on brain activity-a review of known mechanisms from animal studies. Front Hum Neurosci. 2013;7:687.
14. Tavakoli AV, Yun K. Transcranial Alternating Current Stimulation (tACS) Mechanisms and Protocols. Front Cell Neurosci. 2017;11:214.
15. Pozdniakov I, Vorobiova AN, Galli G, Rossi S, Feurra M. Online and offline effects of transcranial alternating current stimulation of the primary motor cortex. Sci Rep. 2021;11(1):3854.
16. Reed T, Cohen Kadosh R. Transcranial electrical stimulation (tES) mechanisms and its effects on cortical excitability and connectivity. J Inherit Metab Dis. 2018;41(6):1123-30.
17. Fröhlich F. Endogenous and exogenous electric fields as modifiers of brain activity: rational design of noninvasive brain stimulation with transcranial alternating current stimulation. Dialogues Clin Neurosci. 2014;16(1):93-102.
18. Stonkus R, Braun V, Kerlin JR, Volberg G, Hanslmayr S. Probing the causal role of prestimulus interregional synchrony for perceptual integration via tACS. Sci Rep. 2016;6:32065.
19. Alagapan S, Schmidt SL, Lefebvre J, Hadar E, Shin HW, Frӧhlich F. Modulation of Cortical Oscillations by Low-Frequency Direct Cortical Stimulation Is State-Dependent. PLoS Biol. 2016;14(3):e1002424.
20. Violante IR, Li LM, Carmichael DW, Lorenz R, Leech R, Hampshire A, et al. Externally induced frontoparietal synchronization modulates network dynamics and enhances working memory performance. elife. 2017;6.
21. Liu A, Vöröslakos M, Kronberg G, Henin S, Krause MR, Huang Y, et al. Immediate neurophysiological effects of transcranial electrical stimulation. Nat Commun. 2018;9(1):5092.
22. Reato D, Rahman A, Bikson M, Parra LC. Low-intensity electrical stimulation affects network dynamics by modulating population rate and spike timing. J Neurosci. 2010;30(45):15067-79.
23. Fröhlich F, McCormick DA. Endogenous electric fields may guide neocortical network activity. Neuron. 2010;67(1):129-43.
24. Bergmann TO. Brain State-Dependent Brain Stimulation. Front Psychol. 2018;9:2108.
25. Nowak M, Hinson E, van Ede F, Pogosyan A, Guerra A, Quinn A, et al. Driving Human Motor Cortical Oscillations Leads to Behaviorally Relevant Changes in Local GABA(A) Inhibition: A tACS-TMS Study. J Neurosci. 2017;37(17):4481-92.
26. Weinrich CA, Brittain JS, Nowak M, Salimi-Khorshidi R, Brown P, Stagg CJ. Modulation of Long-Range Connectivity Patterns via Frequency-Specific Stimulation of Human Cortex. Curr Biol. 2017;27(19):3061-8.e3.
27. Gundlach C, Müller MM, Hoff M, Ragert P, Nierhaus T, Villringer A, et al. Reduction of somatosensory functional connectivity by transcranial alternating current stimulation at endogenous mu-frequency. Neuroimage. 2020;221:117175.
28. Kar K, Ito T, Cole MW, Krekelberg B. Transcranial alternating current stimulation attenuates BOLD adaptation and increases functional connectivity. J Neurophysiol. 2020;123(1):428-38.
29. Wischnewski M, Engelhardt M, Salehinejad MA, Schutter D, Kuo MF, Nitsche MA. NMDA Receptor-Mediated Motor Cortex Plasticity After 20 Hz Transcranial Alternating Current Stimulation. Cereb Cortex. 2019;29(7):2924-31.
30. Guerra A, Suppa A, Bologna M, D'Onofrio V, Bianchini E, Brown P, et al. Boosting the LTP-like plasticity effect of intermittent theta-burst stimulation using gamma transcranial alternating current stimulation. Brain Stimul. 2018;11(4):734-42.
31. Elyamany O, Leicht G, Herrmann CS, Mulert C. Transcranial alternating current stimulation (tACS): from basic mechanisms towards first applications in psychiatry. Eur Arch Psychiatry Clin Neurosci. 2021;271(1):135-56.
32. Sohal VS, Rubenstein JLR. Excitation-inhibition balance as a framework for investigating mechanisms in neuropsychiatric disorders. Mol Psychiatry. 2019;24(9):1248-57.
33. Aspart F. Investigating the effects of weak extracellular fields on single neurons: a modelling approach: Technische Universitaet Berlin (Germany); 2018.
34. Antal A, Grossman N, Paulus W. Basic Mechanisms of Transcranial Alternating Current and Random Noise Stimulation. Transcranial Direct Current Stimulation in Neuropsychiatric Disorders: Springer; 2021. p. 21-8.
35. Jaberzadeh S, Bastani A, Zoghi M. Anodal transcranial pulsed current stimulation: A novel technique to enhance corticospinal excitability. Clin Neurophysiol. 2014;125(2):344-51.
36. Moreno-Duarte I, Gebodh N, Schestatsky P, Guleyupoglu B, Reato D, Bikson M, et al. Transcranial electrical stimulation: Transcranial direct current stimulation (tDCS), transcranial alternating current stimulation (tACS), transcranial pulsed current stimulation (tPCS), and transcranial random noise stimulation (tRNS). The stimulated brain: Elsevier; 2014. p. 35-59.
37. Thibaut A, Russo C, Morales-Quezada L, Hurtado-Puerto A, Deitos A, Freedman S, et al. Neural signature of tDCS, tPCS and their combination: Comparing the effects on neural plasticity. Neurosci Lett. 2017;637:207-14.
38. Ma Z, Du X, Wang F, Ding R, Li Y, Liu A, et al. Cortical Plasticity Induced by Anodal Transcranial Pulsed Current Stimulation Investigated by Combining Two-Photon Imaging and Electrophysiological Recording. Front Cell Neurosci. 2019;13:400.
39. Castillo Saavedra L, Morales-Quezada L, Doruk D, Rozinsky J, Coutinho L, Faria P, et al. QEEG indexed frontal connectivity effects of transcranial pulsed current stimulation (tPCS): A sham-controlled mechanistic trial. Neurosci Lett. 2014;577:61-5.
40. Dissanayaka T, Zoghi M, Farrell M, Egan G, Jaberzadeh S. The effects of a single-session cathodal transcranial pulsed current stimulation on corticospinal excitability: A randomized sham-controlled double-blinded study. Eur J Neurosci. 2020;52(12):4908-22.
41. Datta A, Dmochowski JP, Guleyupoglu B, Bikson M, Fregni F. Cranial electrotherapy stimulation and transcranial pulsed current stimulation: a computer based high-resolution modeling study. Neuroimage. 2013;65:280-7.
42. Luu P, Essaki Arumugam EM, Anderson E, Gunn A, Rech D, Turovets S, et al. Slow-Frequency Pulsed Transcranial Electrical Stimulation for Modulation of Cortical Plasticity Based on Reciprocity Targeting with Precision Electrical Head Modeling. Front Hum Neurosci. 2016;10:377.
43. Abe T, Miyaguchi S, Otsuru N, Onishi H. The effect of transcranial random noise stimulation on corticospinal excitability and motor performance. Neurosci Lett. 2019;705:138-42.
44. Moret B, Donato R, Nucci M, Cona G, Campana G. Transcranial random noise stimulation (tRNS): a wide range of frequencies is needed for increasing cortical excitability. Sci Rep. 2019;9(1):15150.
45. Gao Y, Cavuoto L, Schwaitzberg S, Norfleet JE, Intes X, De S. The Effects of Transcranial Electrical Stimulation on Human Motor Functions: A Comprehensive Review of Functional Neuroimaging Studies. Front Neurosci. 2020;14:744.
46. Ambrus GG, Paulus W, Antal A. Cutaneous perception thresholds of electrical stimulation methods: comparison of tDCS and tRNS. Clin Neurophysiol. 2010;121(11):1908-14.
47. Inukai Y, Saito K, Sasaki R, Tsuiki S, Miyaguchi S, Kojima S, et al. Comparison of Three Non-Invasive Transcranial Electrical Stimulation Methods for Increasing Cortical Excitability. Front Hum Neurosci. 2016;10:668.
48. Terney D, Chaieb L, Moliadze V, Antal A, Paulus W. Increasing human brain excitability by transcranial high-frequency random noise stimulation. J Neurosci. 2008;28(52):14147-55.
49. Harty S, Cohen Kadosh R. Suboptimal Engagement of High-Level Cortical Regions Predicts Random-Noise-Related Gains in Sustained Attention. Psychol Sci. 2019;30(9):1318-32.
50. Fertonani A, Miniussi C. Transcranial Electrical Stimulation: What We Know and Do Not Know About Mechanisms. Neuroscientist. 2017;23(2):109-23.
51. Battaglini L, Contemori G, Fertonani A, Miniussi C, Coccaro A, Casco C. Excitatory and inhibitory lateral interactions effects on contrast detection are modulated by tRNS. Sci Rep. 2019;9(1):19274.
52. Battaglini L, Contemori G, Penzo S, Maniglia M. tRNS effects on visual contrast detection. Neurosci Lett. 2020;717:134696.
53. Pavan A, Ghin F, Contillo A, Milesi C, Campana G, Mather G. Modulatory mechanisms underlying high-frequency transcranial random noise stimulation (hf-tRNS): A combined stochastic resonance and equivalent noise approach. Brain Stimul. 2019;12(4):967-77.
54. Miniussi C, Harris JA, Ruzzoli M. Modelling non-invasive brain stimulation in cognitive neuroscience. Neurosci Biobehav Rev. 2013;37(8):1702-12.
55. Chaieb L, Antal A, Paulus W. Transcranial random noise stimulation-induced plasticity is NMDA-receptor independent but sodium-channel blocker and benzodiazepines sensitive. Front Neurosci. 2015;9:125.
56. Sánchez-León CA, Sánchez-López Á, Gómez-Climent MA, Cordones I, Cohen Kadosh R, Márquez-Ruiz J. Impact of chronic transcranial random noise stimulation (tRNS) on GABAergic and glutamatergic activity markers in the prefrontal cortex of juvenile mice. Prog Brain Res. 2021;264:323-41.
57. Sheffield JG, Raz G, Sella F, Kadosh RC. How can noise alter neurophysiology in order to improve human behaviour? A combined transcranial random noise stimulation and electroencephalography study. bioRxiv. 2020.
58. Brunyé TT, Patterson JE, Wooten T, Hussey EK. A Critical Review of Cranial Electrotherapy Stimulation for Neuromodulation in Clinical and Non-clinical Samples. Front Hum Neurosci. 2021;15:625321.
59. Wagenseil B, Garcia C, Suvorov AV, Fietze I, Penzel T. The effect of cranial electrotherapy stimulation on sleep in healthy women. Physiol Meas. 2018;39(11):114007.
60. Lee J, Lee H, Park W. Effects of cranial electrotherapy stimulation on electrocephalogram. J Int Acad Phys Ther Res. 2019;10(1):1687-94.
61. Vasquez A, Malavera A, Doruk D, Morales-Quezada L, Carvalho S, Leite J, et al. Duration Dependent Effects of Transcranial Pulsed Current Stimulation (tPCS) Indexed by Electroencephalography. Neuromodulation. 2016;19(7):679-88.
62. Feusner JD, Madsen S, Moody TD, Bohon C, Hembacher E, Bookheimer SY, et al. Effects of cranial electrotherapy stimulation on resting state brain activity. Brain Behav. 2012;2(3):211-20.
63. Gense de Beaufort D, Sesay M, Stinus L, Thiebaut R, Auriacombe M, Dousset V. Cerebral blood flow modulation by transcutaneous cranial electrical stimulation with Limoge's current. J Neuroradiol. 2012;39(3):167-75.
64. Morales-Quezada L, Cosmo C, Carvalho S, Leite J, Castillo-Saavedra L, Rozisky JR, et al. Cognitive effects and autonomic responses to transcranial pulsed current stimulation. Exp Brain Res. 2015;233(3):701-9.
65. Asamoah B, Khatoun A, Mc Laughlin M. tACS motor system effects can be caused by transcutaneous stimulation of peripheral nerves. Nat Commun. 2019;10(1):266.
66. Hopfinger JB, Parsons J, Fröhlich F. Differential effects of 10-Hz and 40-Hz transcranial alternating current stimulation (tACS) on endogenous versus exogenous attention. Cogn Neurosci. 2017;8(2):102-11.
67. Kasten FH, Herrmann CS. Transcranial Alternating Current Stimulation (tACS) Enhances Mental Rotation Performance during and after Stimulation. Front Hum Neurosci. 2017;11:2.
68. Brambilla M, Dinkelbach L, Bigler A, Williams J, Zokaei N, Cohen Kadosh R, et al. The Effect of Transcranial Random Noise Stimulation on Cognitive Training Outcome in Healthy Aging. Front Neurol. 2021;12:625359.
69. Saito K, Otsuru N, Inukai Y, Miyaguchi S, Yokota H, Kojima S, et al. Comparison of transcranial electrical stimulation regimens for effects on inhibitory circuit activity in primary somatosensory cortex and tactile spatial discrimination performance. Behav Brain Res. 2019;375:112168.
70. Morales-Quezada L, Leite J, Carvalho S, Castillo-Saavedra L, Cosmo C, Fregni F. Behavioral effects of transcranial pulsed current stimulation (tPCS): Speed-accuracy tradeoff in attention switching task. Neurosci Res. 2016;109:48-53.
71. Feng Y, Zhang J, Zhou Y, Bai Z, Yin Y. Noninvasive brain stimulation for patients with a disorder of consciousness: a systematic review and meta-analysis. Rev Neurosci. 2020.
72. Mohsen S, Mahmoudian S, Talebian S, Pourbakht A. Multisite transcranial Random Noise Stimulation (tRNS) modulates the distress network activity and oscillatory powers in subjects with chronic tinnitus. J Clin Neurosci. 2019;67:178-84.
73. Pellegrini M, Zoghi M, Jaberzadeh S. Cluster analysis and subgrouping to investigate inter-individual variability to non-invasive brain stimulation: a systematic review. Rev Neurosci. 2018;29(6):675-97.
74. Pellegrini M, Zoghi M, Jaberzadeh S. Biological and anatomical factors influencing interindividual variability to noninvasive brain stimulation of the primary motor cortex: a systematic review and meta-analysis. Rev Neurosci. 2018;29(2):199-222.
IssueVol 18 No 1 (2023) QRcode
SectionReview Article(s)
Neuroplasticity Review Literature Transcranial Electrical Stimulation Transcranial Alternating Current Stimulation Transcranial Random Noise Stimulation

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Nazarpoy Shirehjini S, Shahrabi Farahani M, Khaleel Ibrahim M, Mahmood Salman H, Motevalli S, Mohammadi MH. Mechanisms of Action of Noninvasive Brain Stimulation with Weak Non-Constant Current Stimulation Approaches. Iran J Psychiatry. 2022;18(1):72-82.