Table 1.

Main neuroprotective and neuroregenerative effects of transcranial electric stimulation in experimental research.

Model	Stroke stage	Technique	Types of protocol	Cortical effects	Neurogenesis	Neuroprotection	Neural plasticity	Neuroinflammation	Angiogenesis	Oxidative stress	Neurotransmitter metabolism	BBB permeability	Clinical results	Possible signalling pathway	Data
Healthy animals		C-tDCS or A-tDCS	Continuous administration of C-tDCS or A-tDCS for 15 min at 500 μA using a constant current stimulator to a charge density of 128.571 C/m2, daily, for 5 consecutive days, followed by a tDCS-free interval of 3 days and another 5 days of electrical stimulation for only half of the animals	Inflammatory modulation through IBA1+ cells, increased ICAM1+ and BrdU+ cells	P	P		P	P				Not analysed	—	Rueger et al., [23]
			1 mA current, for 15 min, the inter-tDCS interval longer than 2 h. At the onset and offset of stimulation, the current was slowly ramped up and ramped down over ∼15 s to avoid sudden current change. S-, A-, and C-tDCS were performed in order and repeated for six cycles in each cat	A- and C-tDCS can selectively affect GABAergic and glutamatergic transmissions by reducing GABA and glutamate synthesis		P					P		Reduced glutamate excitotoxicity; A- and C-tDCS can, respectively, enhance and suppress neuronal excitability	Selectively affect GABAergic and glutamatergic transmissions	Zhao et al., [161]
		A-tDCS	3 different doses of weak direct current (0.1, 0.5, and 1 mA) for 20 min (including 30 s ramp up and 30 s ramp down), current density for each dosage being 0.8, 4.0, and 8.0 mA/cm2	Enhanced BBB dysfunction (transiently); could be used as a convenient, noninvasive, and selective approach for systemic drug delivery to the central nervous system via the BBB								P	BBB permeability modulation	Temporarily disrupting the structural components forming the paracellular pathway of the BBB	Shin DW et al., [114]
MCAO model	Acute/chronic	t-DCS	Subconvulsive train, 30 mA, 60 pulses/sec, 0.5 ms pulse width, 1 s duration and in total for 5 s at 7 and 24 days after stroke	Possibly reduced glutamate excitotoxicity (significantly downregulated genes Gria 3-glutamate receptor) increased the number of BrdU-labeled tubulin beta III cells in the infarct core of ES animals over controls	P	P							Significant beneficial effect on spatial long-term memory, no beneficial effect on complex sensorimotor skills, detrimental effect on the asymmetric sensorimotor deficit	Possibly AKT/mTOR and β-catenin signaling pathways	Balseanu et al., [24], Liu et al., [50]
	Acute		Continuous stimulation for 3 days or 1 week, with square-wave pulses at the duration of 1 ms constant current, with different electric current (0, 100, 200 μA) and frequency (0, 2, 10, 50 Hz). After the 1-week stimulation, the electric stimulation was discontinued	Phosphorylated Akt upregulation of BDNF, GDNF, and VEGF		P		P	P				Ameliorated behavioral impairment; reduced infarct volumes; increased cerebral blood flow through angiogenesis	Stimulation of PI3K/Akt/mTOR pathway	Baba et al., [17]
			Electric current of 20 Hz, 2 ms square biphasic pulse, 100 μA for 30 min, starting at 30 min after reperfusion	Inhibits proliferation and activation of microglia and astrocyte upregulation of BDNF		P		P					Attenuated infarction volume and improved functional recovery; neuroprotection	Stimulation of PI3K/Akt/mTOR pathway, autophagy P62-LC3B-related pathway	Wang et al., [166]
		A-tDCS	Early tDCS, 1 day after ischemia for 5 days and late tDCS, 1 week after ischemia for 5 days	Enhanced levels of MAP-2 and GAP-43 for dendritic and axonal regrowth			P						Improved Barnes maze performance; increased motor behavioral index scores and beam balance test	—	Yoon et al., [101]
Asphyxial model of cardiac arrest			1 mA A- tDCS for 0.5 h with a constant direct current generator, repeated for four sessions with a resting interval of 1 h	MAP2, GAP-43, PSD-95, and SYN dramatically higher levels			P						Improves quantitative electroencephalogram; neurological deficit score and 96 h survival	—	Dai C et al., [118]
MCAO model	Acute+subacute	C-tDCS	15 min, once per day, 500 μA administrated for 5 days in the acute and 5 days in the subacute phase, at a corresponding charge density of 128,571 C/m2 (higher than the one used in clinical trials)	Promoted neural stem cell differentiation to oligodendrocytes and neurons	P		P						Improved locomotor activity and athletic endurance deficits; accelerated recovery of limping gait	Inhibited Notch1 signaling pathway activation (DLL1 and Jagged1 downregulation and NUMB upregulation)	Zhang et al., [99]
	Acute		1/2 group-C-tDCS alternating 15 min on and 15 min off starting 45 min after MCAO and lasting 4 h. 1/2 group-same protocol but starting soon after MCAO and lasting 6 h. A constant current intensity of 0.2 mA (current density of 2.86 mA/cm2)	Reduced oxidative stress		P				P			Decreased number of spreading depolarizations; reduced infarct volume and area	Possibly C-tDCS blocks, the origin and the repeatedly spontaneous cycling of peri-infarction depolarizations	Notturno et al., [22]
		A-tDCS or/and C-tDCS	15 min at 500 μA, starting 3 days after ischemia, for 10 days in total (A-tDCS or C-tDCS), with a pause of 2 days in the middle of sessions (5-2-5 days) and a charge density of 128,571 C/m2	Increased microglia polarization towards an M1 phenotype: iNOS-positive M1-polarized microglia	P		P	P					Accelerated functional recovery; only C-tDCS recruited oligodendrocyte precursors towards the lesion and supported M1-polarization of microglia	—	Braun et al., [113]
			20 min on–20 min off–20 min on of either C-tDCS or A-tDCS, starting after the first 30 min or at 4.5 hours after MCAO	C-tDCS, but not A-tDCS, reduced glutamate excitotoxicity		P		P			P	P	A-tDCS increased BBB permeability, but not C-tDCS; C-tDCS reduced the ischemic volume and brain edema; ameliorated functional deficits	Decrease of cortical glutamate synthesis and downregulation of NR2B NMDAR subunit	Peruzzotti-Jametti et al., [21]
			30 min daily, A-tDCS and C-tDCS 10 Hz, 0.1 mA, beginning 1 day after stroke for 3, 5, 7, 11, or 14 days	Reduced neuronal membrane permeability and ionic dysregulation			P						Early application of t-DCS from day 7 to day 14 after stroke may result in better motor function improvement than ultraearly intervention (within 3–5 days after stroke); also, it reduced the significantly increased hemichannel pannexin-1 mRNA expression on days 7 and 14	Ischemia may induce opening of the hemichannel pannexin-1 (protein family that forms large-pore nonselective channels in the plasma membrane of cells)	Jiang et al., [100]
4-vessel occlusion model			400 μA constant current applied for 15 min, once, during cerebral ischemia	C-tDCS significantly decreased the levels of IL-1β and TNF-α, MDA, and NOS, while increasing the level of SOD; caused a significant decrease in NMDAR level, Bax and caspase-3 expressions, while increasing the Bcl-2 expression; significantly lower DNA fragmentation and neuronal death		P		P		P	P		Improved learning and memory dysfunctions	Antiapoptotic pathway Bcl-2	Kaviannejad et al., [167]

tDCS: transcranial direct current stimulation; C-tDCS: cathodal transcranial direct current stimulation; A-tDCS: anodal transcranial direct current stimulation; ES: electrical stimulation; mTOR: mammalian target of rapamycin; BDNF: brain-derived neurotrophic factor; GDNF: glial cell line-derived neurotrophic factor; VEGF: vascular endothelial growth factor; PI3K: phosphoinositide 3-kinase; MAP-2: microtubule-associated protein 2; GAP-43: growth-associated protein 43; PSD-95: postsynaptic density protein; SYN: synaptophysin; BBB: blood-brain barrier; DLL1: delta-like 1; MCAO: middle cerebral artery occlusion; iNOS: inducible nitric oxide synthase; NMDAR: N-methyl-D-aspartate receptor; s-tDCS: sham transcranial direct current stimulation; GABA: γ-aminobutyric acid; MDA: malondialdehyde; NOS: nitric oxide synthase; SOD: superoxide dismutase.