Animal models of transcranial direct current stimulation: Methods and mechanisms.
The objective of this review is to summarize the contribution of animal research using direct current stimulation (DCS) to our understanding of the physiological effects of transcranial direct current stimulation (tDCS). We comprehensively address experimental methodology in animal studies, broadly classified as: (1) transcranial stimulation; (2) direct cortical stimulation in vivo and (3) in vitro models. In each case advantages and disadvantages for translational research are discussed including dose translation and the overarching "quasi-uniform" assumption, which underpins translational relevance in all animal models of tDCS. Terminology such as anode, cathode, inward current, outward current, current density, electric field, and uniform are defined. Though we put key animal experiments spanning decades in perspective, our goal is not simply an exhaustive cataloging of relevant animal studies, but rather to put them in context of ongoing efforts to improve tDCS. Cellular targets, including excitatory neuronal somas, dendrites, axons, interneurons, glial cells, and endothelial cells are considered. We emphasize neurons are always depolarized and hyperpolarized such that effects of DCS on neuronal excitability can only be evaluated within subcellular regions of the neuron. Findings from animal studies on the effects of DCS on plasticity (LTP/LTD) and network oscillations are reviewed extensively. Any endogenous phenomena dependent on membrane potential changes are, in theory, susceptible to modulation by DCS. The relevance of morphological changes (galvanotropy) to tDCS is also considered, as we suggest microscopic migration of axon terminals or dendritic spines may be relevant during tDCS. A majority of clinical studies using tDCS employ a simplistic dose strategy where excitability is singularly increased or decreased under the anode and cathode, respectively. We discuss how this strategy, itself based on classic animal studies, cannot account for the complexity of normal and pathological brain function, and how recent studies have already indicated more sophisticated approaches are necessary. One tDCS theory regarding "functional targeting" suggests the specificity of tDCS effects are possible by modulating ongoing function (plasticity). Use of animal models of disease are summarized including pain, movement disorders, stroke, and epilepsy.
Department of Biomedical Engineering, The City College of The City University of New York, NY, USA.
Mark P
MP
Jackson
Department of Biomedical Engineering, The City College of The City University of New York, NY, USA.
Asif
A
Rahman
Department of Biomedical Engineering, The City College of The City University of New York, NY, USA.
Belen
B
Lafon
Department of Biomedical Engineering, The City College of The City University of New York, NY, USA.
Gregory
G
Kronberg
Department of Biomedical Engineering, The City College of The City University of New York, NY, USA.
Doris
D
Ling
Department of Biomedical Engineering, The City College of The City University of New York, NY, USA.
Lucas C
LC
Parra
Department of Biomedical Engineering, The City College of The City University of New York, NY, USA. Electronic address: bikson@ccny.cuny.edu.
Marom
M
Bikson
D000818:Animals; D006801:Humans; D017774:Long-Term Potentiation / Q000502:physiology; D008564:Membrane Potentials / Q000502:physiology; D023421:Models, Animal; D009415:Nerve Net / Q000502:physiology*; D009473:Neuronal Plasticity / Q000502:physiology*; D013569:Synapses / Q000502:physiology*; D065908:Transcranial Direct Current Stimulation / Q000379:methods*
Animal models; Galvanotropy; Long term potentiation; Noninvasive brain stimulation; Oscillations; Synaptic plasticity; Transcranial direct current stimulation
J Neurosci Methods. 2005 Feb 15;141(2):171-98
15661300
Exp Physiol. 1991 Jul;76(4):473-94
1910756
J Physiol. 1983 Feb;335:353-74
6875883
Nature. 1962 Jan 13;193:174-5
14449606
J In Vitro Fert Embryo Transf. 1989 Oct;6(5):290-3
2517295
Brain Stimul. 2014 Jul-Aug;7(4):499-507
25047826
Biophys J. 2000 Aug;79(2):670-9
10920001
J Neurosci. 2010 Aug 25;30(34):11476-85
20739569
Eur J Neurosci. 2010 Feb;31(4):704-9
20141528
Neuron. 2004 Sep 30;44(1):5-21
15450156
J Physiol. 1981 May;314:121-35
7310685
Neurol Res. 2013 Jul;35(6):602-7
23562065
J Neurophysiol. 1999 Nov;82(5):2262-70
10561404
Annu Int Conf IEEE Eng Med Biol Soc. 2007;2007:1715-8
18002306
Clin Neurophysiol. 2010 Dec;121(12):1976-8
21035740
Electroencephalogr Clin Neurophysiol. 1950 Nov;2(4):401-16
14793509
J Neurosci. 2000 Jan 1;20(1):470-84
10627623
Prog Brain Res. 2015;222:25-40
26541375
Nature. 1990 Sep 6;347(6288):69-72
1975639
Brain. 2002 Oct;125(Pt 10):2238-47
12244081
Neuroscience. 2011 Jun 30;185:161-5
21515340
Front Hum Neurosci. 2013 Sep 26;7:628
24133434
Clin Neurophysiol. 2009 Jun;120(6):1183-7
19423386
Anesth Analg. 2004 Mar;98(3):730-7, table of contents
14980928
Nat Neurosci. 2007 Nov;10(11):1387-94
17965659
J Neurobiol. 2000 Oct;45(1):30-8
10992254
J Physiol. 2013 May 15;591(10):2563-78
23478132
J Neurosci. 1990 Jan;10(1):247-55
2299395
Nat Commun. 2016 Mar 22;7:11100
27000523
Nature. 1968 Oct 26;220(5165):383-4
4300961
Neuron. 2005 Oct 6;48(1):109-21
16202712
Neuropsychopharmacology. 2014 Mar;39(4):981-8
24154668
J Neurosci. 2007 Mar 14;27(11):3030-6
17360926
Neuroimage. 2013 Jul 1;74:266-75
23370061
Epilepsy Res. 2011 Nov;97(1-2):142-5
21885255
J Trauma. 1988 Sep;28(9):1375-81
3262170
Clin Neurophysiol. 2011 Apr;122(4):637-8
21075048
Indian J Physiol Pharmacol. 1995 Jul;39(3):209-15
8550112
Nature. 1962 Nov 10;196:584-5
13968314
Exp Neurol. 2011 Feb;227(2):322-7
21147105
Proc Natl Acad Sci U S A. 1956 Sep;42(9):687-94
16589932
Br J Psychiatry. 1964 Nov;110:773-85
14211694
PLoS Comput Biol. 2013;9(2):e1002898
23459152
J Physiol. 2005 Oct 15;568(Pt 2):653-63
16037080
J Neurophysiol. 2000 Jul;84(1):274-80
10899202
Brain Stimul. 2012 Oct;5(4):435-53
22305345
Brain Res. 1966 Jan;1(1):109-13
5910705
Prog Brain Res. 2015;222:xv-xx
26541385
Anesth Analg. 1974 Jan-Feb;53(1):48-55
4204031
J Physiol. 2013 Jul 1;591(13):3381-99
23507876
Annu Int Conf IEEE Eng Med Biol Soc. 2011;2011:765-8
22254423
Prog Brain Res. 2015;222:1-23
26541374
Physiol Rev. 2005 Jul;85(3):943-78
15987799
Brain Res. 2012 Dec 13;1489:17-26
23063889
Brain Res. 1987 Jul 28;416(2):308-14
3620964
Epilepsia. 2008 Sep;49(9):1586-93
18397296
Radiat Prot Dosimetry. 2003;106(4):321-3
14690274
J Neurosci Methods. 2010 Jul 15;190(2):188-97
20488204
Acta Med Okayama. 1988 Oct;42(5):293-6
3223340
Nature. 2006 Nov 30;444(7119):610-3
17086200
Stem Cells. 2008 Aug;26(8):2193-200
18556511
Cell Commun Adhes. 2003 Jul-Dec;10(4-6):401-6
14681048
Eur J Neurosci. 2012 Jan;35(1):119-24
22211744
Brain Stimul. 2011 Jul;4(3):169-74
21777878
Front Psychiatry. 2012 Oct 22;3:91
23097644
J Neurosci. 2010 Feb 3;30(5):1925-36
20130201
Epilepsy Behav. 2010 Jan;17(1):6-22
19926525
Neurosci Lett. 2011 Mar 10;491(1):40-3
21215288
J Psychiatr Res. 2016 Mar;74:70-86
26765514
Neuron Glia Biol. 2006 May;2(2):93-103
18458757
J Physiol. 2007 Oct 15;584(Pt 2):369-70
17702811
Clin Neurophysiol. 2012 Oct;123(10):2006-9
22480602
J Physiol. 1999 Feb 15;515 ( Pt 1):203-7
9925889
J Physiol. 2007 Sep 1;583(Pt 2):555-65
17599962
Brain Res. 1995 Jul 3;684(2):206-8
7583224
Plast Reconstr Surg. 1988 Oct;82(4):573-9
3262226
Nature. 2014 Jan 16;505(7483):318-26
24429630
Neurosurgery. 1987 Jan;20(1):143-7
3808255
Neuroreport. 2004 Jun 7;15(8):1307-10
15167555
J Cell Biol. 1988 Oct;107(4):1397-408
3170634
J Physiol. 1988 Aug;402:751-71
3236254
Neurosci Lett. 2010 Jul 26;479(2):128-33
20493923
Clin Neurophysiol. 2009 Dec;120(12):2008-2039
19833552
PLoS One. 2012;7(8):e43776
22928032
Annu Int Conf IEEE Eng Med Biol Soc. 2014;2014:406-9
25569982
J Neurosci. 1997 Oct 15;17(20):7817-30
9315902
J Physiol. 1992 Nov;457:675-87
1297848
J Neurophysiol. 1997 Feb;77(2):579-86
9065831
Hippocampus. 1996;6(1):79-95
8878746
Brain Res. 1984 Jun 15;303(2):331-6
6744028
Rev Neurosci. 2011;22(4):471-81
21819264
J Neurophysiol. 2012 Apr;107(7):1881-9
22219028
Neurosci Res. 1994 Dec;21(2):169-72
7724068
J Physiol. 2003 Nov 15;553(Pt 1):293-301
12949224
Neuroimage. 2013 Jul 15;75:12-19
23473936
J Neurophysiol. 1965 Jan;28:166-85
14244793
Med Sci Sports Exerc. 2015 Sep;47(9):1788-97
25551405
J Neurosci. 2014 Sep 17;34(38):12837-49
25232119
J Neurosci. 1984 Dec;4(12):2939-47
6502213
Epilepsia. 2006 Jul;47(7):1216-24
16886986
Neuroscientist. 2011 Feb;17(1):37-53
21343407
Nature. 1968 Oct 26;220(5165):382-3
5684882
Br J Psychiatry. 1964 Nov;110:786-99
14211695
Annu Int Conf IEEE Eng Med Biol Soc. 2010;2010:1593-6
21096128
Neurosci Lett. 2006 May 1;398(1-2):85-90
16448754
Neuroimage. 2010 Oct 1;52(4):1268-78
20435146
Annu Int Conf IEEE Eng Med Biol Soc. 2012;2012:891-5
23366036
J Neurophysiol. 2012 Apr;107(7):1868-80
22236710
Methods Mol Biol. 2010;617:505-15
20336445
J Physiol. 2000 Sep 15;527 Pt 3:633-9
10990547
J Gen Physiol. 1957 Mar 20;40(4):565-77
13416531
Front Syst Neurosci. 2013 Apr 11;7:6
23596399
Biol Psychiatry. 2015 Jan 1;77(1):15-21
24650688
J Physiol. 1986 Feb;371:89-114
3701658
J Cell Biol. 1990 Nov;111(5 Pt 1):2029-39
2229185
Brain Res. 2010 Aug 19;1349:76-89
20599813
Neuron. 2010 Apr 29;66(2):198-204
20434997
Br J Psychiatry. 2012 Jan;200(1):52-9
22215866
J Physiol. 1954 Jun 28;124(3):586-604
13175201
J Neurosci. 2004 Nov 3;24(44):9985-92
15525784
Biophys J. 2009 May 6;96(9):3495-508
19413956
Clin Neurophysiol. 2009 Jun;120(6):1161-7
19403329
J Physiol. 2013 Aug 15;591(16):4027-42
23774279
Proc Natl Acad Sci U S A. 2008 Oct 14;105(41):16039-44
18843113
Learn Mem. 2003 Mar-Apr;10(2):86-98
12663747
J Gen Physiol. 1962 Jul;45:1181-93
13919241
J Neurophysiol. 2015 Mar 1;113(5):1334-41
25505103
J Neural Eng. 2010 Feb;7(1):16005
20075507
Brain Stimul. 2012 Jul;5(3):175-195
22037126
J Cell Comp Physiol. 1946 Jun;27:139-57
20992048
J Neural Eng. 2008 Jun;5(2):163-74
18441418
Curr Treat Options Neurol. 2008 Sep;10(5):377-85
18782510
J Neurosci. 1982 Apr;2(4):483-96
6279799
Trends Neurosci. 2010 Jan;33(1):17-26
19889466
Med Sci Monit. 2007 Apr;13(4):CR147-55
17392643
J Physiol. 1973 Jul;232(2):331-56
4727084
J Neurol Sci. 2014 Jul 15;342(1-2):146-51
24857352
Annu Int Conf IEEE Eng Med Biol Soc. 2009;2009:670-3
19964238
Neuroimage. 2010 Jul 15;51(4):1310-8
20350607
J Neurophysiol. 1996 Dec;76(6):4202-5
8985916
Proc Natl Acad Sci U S A. 2012 Apr 24;109(17):6710-5
22493252
Brain Stimul. 2013 Jul;6(4):704-5
23290681
Annu Int Conf IEEE Eng Med Biol Soc. 2010;2010:2073-6
21095946
Exp Neurol. 1962 Jun;5:436-52
13882165
Brain Stimul. 2013 Jan;6(1):1-13
22483681
Clin Neurophysiol. 2006 Jul;117(7):1623-9
16762592
Epilepsy Behav. 2013 Jan;26(1):42-50
23207516
Exp Brain Res. 1999 Aug;127(3):279-90
10452215
J Cell Biol. 1986 Apr;102(4):1384-99
2420807
Exp Brain Res. 2012 Aug;221(1):75-83
22752510
J Physiol. 1981;319:143-52
7320909
J Neurosci. 2003 Aug 13;23(19):7255-61
12917358
Brain Stimul. 2009 Oct;2(4):215-28, 228.e1-3
20161507
J Neurosci. 2015 Sep 16;35(37):12824-32
26377469
Exp Brain Res. 2005 Sep;166(1):23-30
15999258
Nat Neurosci. 2011 Sep 11;14(10):1276-84
21909085
Brain Res. 2008 Jul 7;1218:77-86
18533132
Diabetologia. 1990 Jan;33(1):62-3
2303174
J Physiol. 2003 Mar 1;547(Pt 2):427-34
12562909
J Neurosci Methods. 2013 Oct 15;219(2):297-311
23954780
J Neurosci. 2010 Nov 10;30(45):15067-79
21068312
J Physiol. 1962 Aug;163:115-37
14449605
Exp Neurol. 2007 Mar;204(1):462-6
17113079
Exp Neurol. 1987 Nov;98(2):222-32
3666075
J Physiol. 1964 Aug;172:369-82
14199369
Clin Neurophysiol. 2009 Jun;120(6):1033-4
19394269
Hippocampus. 1996;6(4):347-470
8915675
Brain Res. 2012 May 3;1452:61-72
22444278
J Neurosci. 2013 Jul 3;33(27):11262-75
23825429
PLoS One. 2011 Feb 14;6(2):e16905
21340034
Microvasc Res. 1997 Jul;54(1):74-80
9245647
Brain Stimul. 2012 Jul;5(3):201-207
22305346
J Physiol. 2004 May 15;557(Pt 1):175-90
14978199
Behav Brain Res. 2011 Feb 2;217(1):99-103
20826186
Ann Clin Transl Neurol. 2015 Aug;2(8):843-56
26339678
IEEE Trans Biomed Eng. 2015 Sep;62(9):2095-105
25910001
J Exp Zool. 1979 Jul;209(1):115-28
490126
Brain Stimul. 2009 Oct;2(4):201-7, 207.e1
20648973
J Cogn Neurosci. 2003 May 15;15(4):619-26
12803972
Nat Neurosci. 1998 Jul;1(3):230-4
10195148
J Korean Med Sci. 2010 Oct;25(10):1499-505
20890433
Epilepsy Behav. 2009 Jun;15(2):131-2
19269348
Neuron. 2010 Jul 15;67(1):129-43
20624597
J Physiol. 1986 Jun;375:55-69
3795068
Brain Stimul. 2015 Jul-Aug;8(4):784-6
25857398
Neurosci Lett. 2013 Mar 14;537:60-4
23370288
Int J Neuropsychopharmacol. 2014 Oct 31;18(2):
25522391