Table Info

Table 2.

Summary of the technical parameters of the tVNS studies

Authors (year)	Condition/study	Participants	tVNS device	Stimulation side	Stimulation site	Sham control	Pulse width (µs)	Intensity (mA)	Frequency (Hz)	Duty cycle/time
Keute, et al. (2019) [36]	Visual bistable perception	34	DS7, Digitimer	L	Cymba concha	Sham stimulation 25 Hz on ear lobe	200.0	3.0	25.0	30 s on, 30 s off for 40 min
Zhao, et al. (2019) [37]	Post-stroke insomnia	1	-	L, R	Concha	-	1,000.0	4.0–6.0	20.0	30 min twice a day for 4 weeks
Badran, et al. (2018) [38]	Improving oromotor function in newborns	5	DS7AH, Digitimer	L	Tragus	-	500.0	0.1	25.0	Max 2 min or less per dose, paired with newborn feeding, stops when newborn stops sucking, up to 30 min a day over 10–22 days
Badran, et al. (2018) [39]	Neuro-physiologic effects of tVNS	17	DS7A, Digitimer	L	Tragus	Sham stimulation 25 Hz on ear lobe	500.0	-	25.0	Each round consisted of a baseline period of 90 seconds, stimulation period of 60 seconds, and recovery period of 180 seconds
Colzato, et al. (2018) [40]	Divergent thinking	80	NEMOS®, Cerbomed GmbH	L	Concha	Sham stimulation 25 Hz on ear lobe	-	0.5	25.0	30 s on, 30 s off for 40 min
Fischer, et al. (2018) [41]	Conflict-triggered adjustment of cognitive control	21	CM02, Cerbomed	L	Cymba concha	Sham stimulation 25 Hz on ear lobe	200.0–300.0	1.3	25.0	Continuously for 36 min
Jongkees, et al. (2018) [42]	Response selection during sequential action	40	CM02, Cerbomed	L	Tragus	Sham stimulation 25 Hz on ear lobe	200.0–300.0	0.5	25.0	30 s on, 30 s off for 45 min
Keute, et al. (2018) [43]	Ergic modulation of GABA	16	DS7, Digitimer	L	Concha	Sham stimulation 25 Hz on ear lobe	200.0	8.0	25.0	30 s on, 30 s off for 25 min
Liu, et al. (2018) [44]	Epilepsy	17	TENS-sm device, Suzhou Medical Audio Supplies	L, R	Cymba concha and outer ear canal	-	200.0	-	10.0	20 min three times a day for 6 months
Yakunina, et al. (2018) [45]	Tinnitus	36	Custom-made	L	Inner tragus and cymba concha	Sham stimulation 25 Hz on ear lobe	500.0	0.1	25.0	Each location was stimulated in two runs with 30 s of stimulation followed by 30 s of rest; this cycle was repeated five times in a run
Assenza, et al. (2017) [46]	Epilepsy	1	NEMOS®, Cerbomed GmbH	L	External acoustic meatus	Sham stimulation on right ear lobe	-	-	-	4 h
Fang, et al. (2017) [47]	Depression	38	VN stimulator developed in cooperation with Suzhou Medical Appliance Factory	-	Concha	Sham stimulation 20 Hz delivered to superior scapha	200.0	4.0–6.0	20.0	Continuously for 30 min twice a day, 5 days a week for 4 weeks
Yu, et al. (2017) [48]	Disorders of consciousness	1	-	L, R	Concha	-	1,000.0	4.0–6.0	20.0	30 min twice a day for 4 weeks
Bauer, et al. (2016) [49]	Epilepsy	76	NEMOS®, Cerbomed GmbH	L	Cymba concha	Active control 1 Hz stimulation	250.0	-	1.0 or 25.0	30 s on 30 s off for 4 h
Burger, et al. (2016) [50]	Fear extinction in health volunteers	38	NEMOS®, Cerbomed GmbH	L	Cymba concha	Sham stimulation 25 Hz on ear lobe	-	0.5	25.0	30 s on 30 s off
Cha, et al. (2016) [51]	Sudden-onset vertigo	1	ES-420, ITO Co., Ltd.	R	Cymba concha, cavum concha, and outer surface of tragus	-	200.0	-	30.0	4 min each site
Frøkjaer, et al. (2016) [52]	Pain threshold	18	NEMOS®, Cerbomed GmbH	L	Concha	Sham stimulation 30 Hz on ear lobe	250.0	-	30.0	60 min
Gaul, et al. (2016) [13]	Chronic cluster headache	45	-	R	Neck	-	-	60.0	25.0	Burst (1 ms on, 40 ms off) for three consecutive 2-minute stimulations, with a 1-minute interval in between
Grazzi, et al. (2016) [53]	Menstrual related migraine	51	gammaCore®, electroCore LLC	L, R	Neck	-	200.0	60.0	25.0	Burst (1 ms on, 50 ms off) for 2 min three times a day
Lerman, et al. (2016) [54]	Peripheral immune system modulation in healthy humans	20	gammaCore®, electroCore LLC	L, R	Neck	Active control 1 Hz stimulation	200.0	-	25.0	Burst (1 ms on, 40 ms off) for 2 min
Rong, et al. (2016) [55]	Major depressive disorder	160	-	-	Concha	Sham stimulation 20 Hz at superior scapha	200.0	4.0–6.0	20.0	Continuously for 30 min twice a day
Silberstein, et al. (2016) [15]	Migraine	59	gammaCore®, electroCore LLC	R	Neck	Sham device that did not deliver electrical stimulation	-	60.0	-	Each treatment consisted of two 2-minute self-administered stimulations delivered 5–10 min apart to the right side of the neck at 3 prespecified times every day
Silberstein, et al. (2016) [56]	Cluster headache	150	gammaCore®, electroCore LLC	R	Neck	Sham device delivering 0.1 Hz biphasic pulse	200.0	60.0	25.0	Burst (1 ms on, 40 ms off) for three consecutive 2 min stimulations 1 min apart
Trevizol, et al. (2016) [57]	Depression	12	Neurodyn II, IBRAMED	L, R	Mastoid process	-	250.0	12.0	120.0	30 min a day ten times over 2 weeks
Fang, et al. (2016) [58]	Major depressive disorder	34	-	L	Concha	Sham stimulation 20 Hz at superior scapha	1,000.0	4.0–6.0	20.0	2 times 30 min daily, 5 days a week for 4 weeks
Frangos, et al. (2015) [25]	Bold fMRI effects of tVNS	12	NEMOS®, Cerbomed GmbH	L	Cymba concha	Sham stimulation 25 Hz on ear lobe	250.0	0.3–0.8	25.0	Continuously for 14 min
Hyvärinen, et al. (2015) [59]	Tinnitus	15	Transcutaneous vagus nerve stimulator, Tinnoff Inc.	L	Tragus	Sham stimulation 25 Hz on ear lobe	500.0	0.5	25.0	Continuously for 6 min
Nesbitt, et al. (2015) [60]	Cluster headache	19	gammaCore®, electroCore LLC	L, R	Neck	-	1,000.0	-	25.0	2 min per dose, up to three doses twice daily
Sellaro, et al. (2015) [61]	Post-error slowing	40	CM02, Cerbomed GmbH	L	Outer auditory canal	Sham stimulation 25 Hz on ear lobe	200.0–300.0	0.5	25.0	30 s on and 30 s off for 75 min
Sellaro, et al. (2015) [62]	Pro-social behavior	24	CM02, Cerbomed GmbH	L	Outer auditory canal	Sham stimulation 25 Hz on ear lobe	200–300	0.5	25.0	30 s on and 30 s off for 26 min
Altavilla, et al. (2015) [63]	Migraine	20	gammaCore®, electroCore LLC	-	Neck	-	-	-	-	Continuously for 90 s
Barbanti, et al. (2015) [14]	Chronic migraine	50	gammaCore®, electroCore LLC	R	Neck	-	-	-	-	2 times 120 s doses 3 min apart per migraine
Hasan, et al. (2015) [64]	Schizophrenia	20	CM02, Cerbomed GmbH	L	Outer auditory canal	No electrical stimulation delivered	250.0	-	25.0	30 s on, 180 s off for up to 3 times 3 h a day
Jacobs, et al. (2015) [65]	Associative memory in older individuals	30	TENStem dental, schwa-medico GmbH	L	External acoustic meatus on inner side of tragus	No electrical stimulation delivered	200.0	5.0	8.0	Twice a day
Kinfe, et al. (2015) [66]	Cluster-Tic syndrome	1	gammaCore®, electroCore LLC	R	Neck	-	1,000.0	12.0–14.0	25.0	Burst for 2 times 90 s doses 15 min apart
Kinfe, et al. (2015) [67]	Migraine and sleep disturbance	20	gammaCore®, electroCore LLC	L, R	Neck	-	1,000.0	0.0–24.0	25.0	Burst for 2 times 2 min twice a day
Stavrakis, et al. (2015)* [68]	Atrial fibrillation	40	Grass® S88, Natus Neurology Inc.	R	Tragus	No electrical stimulation delivered	1,000.0	-	20.0	Continuously for 60 min following induction of atrial fibrillation
Steenbergen, et al. (2015) [69]	Efficiency of action cascading processes in healthy humans	30	CM02, Cerbomed GmbH	L	Outer auditory canal	Sham stimulation 25 Hz on ear lobe	200.0–300.0	0.5	25.0	30 s on, 30 s off for 45 min
Straube, et al. (2015) [23]	Migraine	46	NEMOS®, Cerbomed GmbH	L	Concha	Active control 1 Hz sham stimulation	250.0	-	1.0 or 25.0	30 s on, 30 s off for 4 h a day for 12 weeks
Weise, et al. (2015) [70]	Parkinson’s disease	50	-	L, R	Tragus	-	100.0	8.0	0.5	-
Zhi, et al. (2014) [71]	Tinnitus	32	TENS-200, Suzhou Medical Supplies Co., Ltd.	-	Cavum concha	-	1,000.0	1.0	20.0	2 times 20 min daily for 8 weeks
Aihua, et al. (2014) [72]	Epilepsy	60	TENS-200, Hebei Huatuo Pharmaceutical Co., Ltd.	L, R	Outer auditory canal and conchal cavity	Sham stimulation 20 Hz on ear lobe	200.0	-	20.0	Continuously for 20 min three times a day
Capone, et al. (2015) [73]	Cortical excitability in healthy volunteers	10	Twister, EBM	L	External acoustic meatus at inner side of tragus	Sham stimulation 20 Hz on ear lobe	300.0	8.0	20.0	30 s on, 270 s off for 1 h
Clancy, et al. (2014) [74]	SNA in healthy humans	48	V-TENS Plus^TM, Body Clock Health Care Ltd.	-	Tragus	Disconnected electrodes for sham	200.0	10.0–50.0	30.0	Continuously for 15 min
Goadsby, et al. (2014) [75]	Acute migraine	30	gammaCore®, electroCore LLC	R	Neck	-	-	-	-	2 times 90 s doses 15 min apart after migraine onset
Grazzi, et al. (2014) [76]	Migraine	30	gammaCore®, electroCore LLC	R	Neck	-	-	-	-	90 s
Huang, et al. (2014) [77]	Impaired glucose tolerance	72	TENS-200, Hebei Huatuo Pharmaceutical Co., Ltd.	-	Concha	Sham stimulation 20 Hz applied at superior scapha	1,000.0	1.0	20.0	20 min twice daily for 12 weeks
Kreuzer, et al. (2014) [78]	Tinnitus	50	Phase I: CM02, Cerbomed GmbH; phase II: NEMOS®, Cerbomed GmbH	-	-	-	-	0.1–10.0	25.0	Phase I: 30 s on, 180 s off for 6 h per day; phase II: 30 s on, 30 s off for 4 h per day
Laqua, et al. (2014) [79]	Pain threshold in healthy humans	22	TNS SM 2 MF, schwa-medico GmbH	L, R	Cavum concha and mastoid area	No electrical stimulation delivered	200.0	-	2.0 and 100.0	Burst 30 min
Busch, et al. (2013) [80]	Pain perception in healthy volunteers	48	STV02, Cerbomed GmbH	L	Concha at inner side of tragus	No electrical stimulation delivered	250.0	0.3–10.0	25.0	Continuously for 1 h
He, et al. (2013) [81]	Pediatric epilepsy	14	TENS-200	L, R	Concha	-	-	0.4–1.0	20.0	3 times 30 min a day
Lehtimäki, et al. (2013) [82]	Tinnitus	10	Pulse generator, Tinnoff Inc.	L	Tragus	No electrical stimulation delivered	-	0.8	25.0	7 times 45/60 min sessions delivered over 10 days
Kraus, et al. (2013) [83]	Effects of sham-controlled transcutaneous electrical stimulation	16	DS7A, Digitimer	L	Group I: anterior wall of ear canal; group II: posterior side of ear canal	Sham stimulation 8 Hz on ear lobe	20.0	-	8.0	4 times 30 s on, 60 s off
Hein, et al. (2013) [9]	Depression	37	Study 1: TENS-NET 2000, Auri-Stim Medical Inc.; study 2: TENS-NET 1000, Auri-Stim Medical Inc.	L, R	Outer auditory canal	No electrical stimulation delivered electrodes unplugged	-	0.13	1.5	Study 1: 1 time 15 min 5 days a week; study 2: 2 times 15 min 5 days a week
Napadow, et al. (2012) [84]	Chronic pelvic pain	15	Cefar® Acus II, Cefar Medical	L	Cymba concha and slope between antihelix and cavum concha	Sham stimulation 30 Hz on ear lobe	450.0	-	30.0	0.5 s on, matched to respiration for 30 min
Stefan, et al. (2012) [1]	Epilepsy	10	-	L	Tragus	-	300.0	-	10.0	3 times 1 h a day over 9 months
Schulz-Stübner and Kehl (2011) [85]	Hiccups	1	NMS 300, Xavant Technology (Pty) Ltd.	L	Neck	-	-	6.0	1.0	30 s
Dietrich, et al. (2008) [86]	Bold fMRI	4	Specially designed MRI-compatible stimulation unit	L	Tragus	-	250.0	4.0–8.0	25.0	50 s on, 100 s off for 700 s
Kraus, et al. (2007) [87]	Bold fMRI	22	EMP2 Expert, schwa-medico GmbH	L	Tragus	Sham stimulation 8 Hz on ear lobe	20.0	-	8.0	30 s on, 120 s off three times over 2 days
Fallgatter, et al. (2003) [21]	Vagus sensory evoked potentials	6	-	-	Tragus and acoustic meatus	-	100.0	8.0	-	2 s interstimulus interval
Johnson, et al. (1991) [88]	Pain threshold and autonomic function	24	Microtens 7757	R	Concha	No electrical stimulation delivered	500.0	-	2.3	Burst for 15 min
Andreas (2019)* [89]	Electrocardiogram post atrial fibrillation	-	DUCEST Neurostimulator V, Biegler Medizinelektronik GmbH	-	Triangular fossa	Sham: same location, low-level stimulation	-	1.0	1.0	40 min on 20 min off
Stavrakis (2015)* [68]	Atrial fibrillation cycle length and duration, TNF-α, CRP		Grass® S88, Natus Neurology Inc.	R	Tragus	Placebo: no current, same location	1,000.0	-	20.0	-
Stavrakis, et al. (2020)* [90]	Atrial fibrillation burden	-	Parasym^TM clip, Parasym Health Inc.	R	Tragus	Sham: different amplitude (mean 19.9 mA), different location (right ear lobe)	200.0	16.8	20.0	-
Badran, et al. (2018)* [27]	HRV during stimulation	-	Custom clip	L	Tragus	Sham: at 100 μs pulse width: 6.57 ± 1.83 mA. At 200 μs pulse width: 3.64 ± 1.26 mA. At 500 μs pulse width: 1.97 ± 0.71 mA. Different location (ear lobe)	100.0 200.0 500.0	9.3 5.3 3.0	1.0 10.0 25.0	-
Antonino (2017)* [91]	cBRS from systolic BP and RR interval HRV (low frequency/high frequency)	-	Ear clip electrodes	L, R	Tragus	Placebo 1 sham: same waveform (mA NR), different location (bilateral ear lobe)	200.0	10.0–50.0	30.0	-
Bretherton (2019)* [92]	HRV and baroreflex sensitivity	-	Custom TENS electrodes	-	Tragus	Placebo: same location (inner and outer tragus)	200.0	2.0–4.0	30.0	-
Clancy (2014)* [74]	HRV and sympathetic activity	-	V-TENS Plus^TM, Body Clock Health Care Ltd.	-	Tragus	Placebo: no current, same location	200.0	10.0–50.0	30.0	Continuous
De Couck, et al. (2017)* [93]	ECG with HRV	-	NEMOS®, Cerbomed GmbH	L, R	Cymba concha	Placebo: no current, same location	250.0	0.7	25.0	-
Tran, et al. (2019)* [94]	LV strain and autonomic tone	-	Parasym^TM earclip, Parasym Health Inc.	R	Tragus	Sham: different current (mean 21.8 mA), different location (right ear lobe)	200.0	22.6	20.0	-
Yu, et al. (2017)* [95]	Myocardial ischemia-reperfusion injury	-	Clip electrodes (S20 stimulator)	R	Tragus	Placebo: no current, same location (right tragus)	1,000.0	-	20.0	5 s on/off
Tobaldini (2019)* [96]	Orthostatic stress, HRV, low frequency/high frequency, systolic arterial BP variance, respiratory rate	-	NEMOS®, Cerbomed GmbH	L	Cymba concha	Placebo: no stimulation, same location	200.0	1.0–6.0	25.0	-
Fisher (2018)* [97]	Hypertension	-	-	L	Biphasic left cymba concha and beneath antihelix	Placebo: no current, same location	-	15.0	25.0	1 s duration (gated to exhalation)
Stowell (2019)* [98]	Hypertension	-	UROstim device, schwa-medico GmbH	L	Cymba concha	Placebo: no current, same location	300.0	-	2.0 10.0 25.0 100.0	1 s on/off
Zamotrinsky (2001)* [99]	Coronary artery disease	-	Ear clip electrodes	L, R	Tragus	Placebo 1 sham: same waveform (mA), different location (bilateral ear lobe)	200.0	10.0–50.0	30.0	-
Borges (2019)* [100]	Cardiac vagal activity, HRV	-	NEMOS®, Cerbomed GmbH	L	Cymba concha	Sham: same set stimulation, different strong sensory stimulation (2.76 ± 1.01 mA), different location (ear lobe)	200.0–300.0	12.5	25.0	30 s on/off

L: left ear; R: right ear; TNF: tumor necrosis factor; CRP: C-reactive protein; BP: blood pressure; HRV: heart rate variability; LV: left ventricular; GABA: gamma-aminobutyric acid; fMRI: functional MRI; SNA: sympathetic nerve activity; -: no description; *: ardiac related trials

Declarations

Author contributions

NF: Conceptualization, Investigation, Writing—original draft, Writing—review & editing. MN: Validation, Writing—review & editing. CYF: Conceptualization, Investigation, Validation, Writing—review & editing, Supervision. All authors have read and approved the submitted version.

Conflicts of interests

The authors declare that they have no conflicts of interest.

Ethical approval

Not applicable.

Consent to participate

Not applicable.

Consent to publication

Not applicable.

Availability of data and materials

Not applicable.

Funding

This work was funded by grant Deutsche Forschungsgemeinschaft [FO 315/5-1 to CYF]. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Copyright

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