TABLE 2.

Stimulation location, parameters, and therapeutic effects for all studies of nVNS in rodent models of stroke.

Authors	Rodent models	Device	Initial time	Parameters	Stimulation side and sites	Stimulation duration	Effects	Results and conclusion
Zhao et al., 2022	Rat, I/R (right ICA)	taVNS, tcvns (Hanshi Electroacupuncture Instrument, Nanjing Hanshi Co. Ltd.)	24 h post-stroke	10 Hz, 1 mA, Pulse width (not described)	Bilateral concha auricularis region or rat tragus	30 min/session, 7 days	Levels of acetylcholine, IL-1β, IL-6, and TNF-α↓; Cx43 phosphorylation↓	Improves motor function
Li et al., 2020a	Rats, MCAO/R (right)	taVNS (Grass Model S48 stimulator, Grass Technologies, Warwick, United States)	30 min post-stroke	20 Hz, 0.5 mA, 0.5 ms, square wave	Left cavum concha	60 min/session, twice daily, 14 days, 28 days	PPAR-γ↓; BDNF, VEGF, P-eNOS↑	Decreases neurological deficit scores, neuronal damage, and infarct volume. Increases microvessel density and endothelial cell proliferation.
Lindemann et al., 2020	Rats, MCAO (left)	tcVNS, iVNS (External transcutaneous stimulator, electrocore Inc.)	30 min post-stroke	iVNS: 25 Hz, 0.5 mA, 0.3 ms tcVNS:25 Hz,1 ms, 5 kHz sine waves.	Left vagus nerve (ivns), left cervical vagus nerve (tcvns)	iVNS: 60 min; tcVNS: 2 min, repeated after 15 min	Spreading depolarizations frequency↓	Improves behavioral tests. Reduces infarct volume. Both iVNS and nVNS reduce the frequency of SDs.
Li et al., 2020b	Rats, MCAO/R (right)	taVNS (Grass Model S48 stimulator, Grass Technologies, Warwick, United States)	30 min post-stroke	20 Hz, 0.5 MA, 0.5 ms, square	Left cavum concha	60 min/session, twice daily,14 days, 28 days	α7nAchR expression↓; Activation of the BDNF/cAMP/PKA/p-CREB pathway	Enhance axonal plasticity through activation of the BDNF/cAMP/PKA/p-CREB pathway
Zhao X.-P. et al., 2019	Mice, MCAO/R (right)	tcVNS (gammacore; Lectrocore, LLC, Basking Ridge, NJ, United States)	1 d before MCAO	25 Hz, 1 ms, 5 kHz sinewaves average voltage of 15 V	Right cervical vagus nerve	60 min	M2 phenotype microglia : Arg-1+ cells↑; IL-17A↓; (TUNEL + NeuN+) cells↓	Reduces infarct volume. Improves neurological outcomes. Reduces neurons apoptosis. Promotes microglial M2 polarization.
Yang et al., 2018	Rats, MCAO (right)	taVNS (gammacore; Lectrocore, LLC, Basking Ridge, NJ, United States)	30 min post-stroke	25 Hz, 1 ms, 5 kHz sinewaves average voltage of 15 V	Left cervical vagus nerve	50 min	TJPs: ZO-1↑ BBB transfer rate, serum IgG leakage↓; MMP-2/9 ↓	Reduces infarct volume. Protects Blood-brain barrier.
Ma et al., 2016	Rats, MCAO/R (right)	taVNS (Grass Model S48 stimulator, Grass Technologies, Warwick, United States)	30 min post-stroke	20 Hz, 0.5 mA, 0.5 ms, square	Left cavum concha	60 min/session, twice daily,24 h, 3 days,7 days	upregulate cerebral GDF11 and downregulate splenic GDF11; increase expression of ALK5 in ECs; stimulate proliferation of ecs.	Prompts neuro behavioral recovery Stimulated proliferation of endothelial cells.
Jiang et al., 2016	Rats, MCAO/R (right)	taVNS (Grass Model S48 stimulator, Grass Technologies, Warwick, United States)	30 min post-stroke	20 Hz, 0.5 mA, 0.5 ms, square	Left cavum concha	60 min/session, 2–3 weeks	Microvessel density and endothelial cell proliferation↑; BDNF, eNOS and VEGFs↑	Prompts neuro behavioral recovery and angiogenesis. Reduces infarct volume.
Ay et al., 2016	Rats, MCAO (right)	tcVNS (gammacore; electrocore, LLC).	30 min post-stroke	25 Hz, 1 ms, 5 kHz, 12 V sine waves	Right vagus nerve in the neck	60 min	DecreaseIba-1, CD68, and TNF-α positive cells and increase the number of HMGB1 positive cells.	Reduces infarct volume. Improves neurological score. Inhibits ischemia-induced immune activation.