Table 2.
Summary of previous tVNS clinical trials and studies.
| References | Condition/Study | Participants | tVNS device | Electrode type | Stimulation Side |
Stimulation Site |
Sham control | Pulse width (ms) | Intensity (mA) | Freq (Hz) | Duty cycle/Time | Brain activation |
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Keute et al. (2019) | Visual bistable perception | 34 | Digitimer DS7 | Ag/AgCl | L | Cymba Concha | Sham stimulation 25 Hz on ear lobe | 0.2 ms | 3 mA | 25 Hz | 30 s on, 30 s off for 40 min | Inferred—tVNS has null effect on dynamics of visual bistable perception; perhaps there is a slight effect of GABA transmission in motor but not in the visual cortex |
| Zhao et al. (2019) | Post-stroke insomnia | 1 | NS | NS | L, R | Concha | NS | <1 ms | 4-6 mA | 20 Hz | 30 min twice a day for 4 weeks | Measured—Bold fMRI showed a decrease in functional connectivity between posterior cingulate cortex and other nodes of default mode network but a decrease in functional connectivity between posterior cingulate cortex, lingual gyrus, and cortex surrounding calcarine fissure due to tVNS |
| Badran et al. (2018b) | Improving oromotor function in newborns | 5 | Digitimer DS7AH | Custom ear electrode | L | Tragus | NS | 0.5 ms | 0.1 mA below perception threshold | 25 Hz | 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 | NS |
| Badran et al. (2018a) | Neuro-physiologic effects of tVNS | 17 | Digitimer DS7 | Ag/AgCl | L | Tragus | Sham stimulation 25 Hz on ear lobe | 0.5 ms | 200 % of perception threshold | 25 Hz | 3 × 60 s over 6 min | Measured—Bold fMRI showed active stimulation produced significantly greater increases in the right caudate, bilateral anterior cingulate, cerebellum, left prefrontal cortex, and mid-cingulate than in sham stimulation |
| Colzato et al. (2018) | Divergent thinking | 80 | NEMOS, Cerbomed | Titanium* | L | Concha | Sham stimulation 25 Hz on ear lobe | 0.2–0.3 ms | 0.5 mA | 25 Hz | 30 s on, 30 s off for 40 min | Inferred—tVNS enhances creativity in selective ways, increased divergent thinking which may be attributed to possible increase in GABA concentration |
| Fischer et al. (2018) | Conflict-triggered adjustment of cognitive control | 21 | CM02, Cerbomed | Two titan electrodes | L | Cymba Concha | Sham stimulation 25Hz on ear lobe | 0.2–0.3 ms | Below pain threshold (average 1.3 mA) | 25 Hz | Continuously for 36 min | Measured—EEG showed tVNS increasing behavioral and electrophysiological markers of conflict adaptation |
| Jongkees et al. (2018) | Response selection during sequential action | 40 | CM02, Cerbomed | Two titan electrodes | L | Tragus | Sham stimulation 25 Hz on ear lobe | 0.2–0.3 ms | 0.5 mA | 25 Hz | 30 s on, 30 s off for 45 min | Inferred—tVNS improves response selection, possibly due to tVNS increasing GABA concentration, which facilitates action control |
| Keute et al. (2018) | GABAergic modulation | 16 | Digitimer DS7 | Ambu Neuroline | L | Concha | Sham stimulation 25 Hz on ear lobe | 0.2 ms | 8 mA (or below pain threshold if not tolerable) | 25 Hz | 30 s on, 30 s off for 25 min | Measured—EEG demonstrated direct GABAergic effects of tVNS, shows direct effect on electrophysiology after single session of tVNS and suggests non-linear relationship between tVNS and GABA transmission |
| Liu et al. (2018) | Epilepsy | 17 | TENS-sm device, Suzhou Medical Audio Supplies | Ear clip | L, R | Cymba Concha and outer ear canal | NS | 200 s† | 4 mA (increased by 2 mA each week until patient could not tolerate or seizures were completely controlled) | 10 Hz | 3 × 20 min daily for 6 months | Measured—tVNS reduced the number of epileptic seizures and reduced abnormal wave changes shown on electroencephalogram (EEG) monitoring. The EEG changes followed the reduction in the frequency of seizures |
| Yakunina et al. (2018) | Tinnitus | 36 | Custom-made | NS | L | Inner tragus and cymba concha | Sham stimulation 25 Hz on ear lobe | 0.5 ms | 0.1 mA lower than pain threshold | 25 Hz | 30 s on, 30 s off for 6 × 5 min runs | Measured—fMRI showed tVNS via both the tragus and concha successfully suppressed the auditory, limbic, and other brain areas implicated in the mechanisms involved in the generation/perception of tinnitus via auditory and vagal ascending pathways |
| Assenza et al. (2017) | Epilepsy | 1 | NEMOS, Cerbomed | Titanium* | L | External acoustic meatus | Sham stimulation on right ear lobe | NS | Sensitive threshold | NS | 4 h | Inferred: tVNS engages same neural fibers as in invasive VNS |
| Fang et al. (2017) | Depression | 38 | Suzhou Medical Appliance Factory | Custom ear clip electrodes | Concha | Sham stimulation 20 Hz delivered to superior scapha | 0.2 ms | Tolerance threshold (typically between 4 and 6 mA) | 20 Hz | Continuously for 30 min twice a day, 5 days a week for 4 weeks | Measured—fMRI shows that tVNS targets left anterior insula, and activation of this region predicts the outcome of treatment for depression | |
| Yu et al. (2017) | Disorders of consciousness | 1 | NS | NS | L, R | Concha | NS | <1 ms | 4–6 mA | 20 Hz | 30 min twice a day for 4 weeks | Measured—fMRI shows that tVNS activated posterior cingulate/precuneus and thalamus and increased the functional connectivity between posterior cingulate/precuneus and hypothalamus, thalamus, ventral medial prefrontal cortex (vmPFC), superior temporal gyrus, yet decreased the functional connectivity between posterior cingulate/precuneus and the cerebellum |
| Bauer et al. (2016) | Epilepsy | 76 | NEMOS, Cerbomed | Titanium* | L | Cymba Concha | Active control 1 Hz stimulation | 0.25 ms | Tingling without pain | 25 or 1 Hz | 30 s on 30 s off for 4 h | NS |
| Burger et al. (2016) | Fear extinction in health volunteers | 38 | NEMOS, Cerbomed | Titanium* | L | Cymba Concha | Sham stimulation 25 Hz on ear lobe | NS | 0.5 mA | 25 Hz | 30 s on 30 s off | Inferred—tVNS improved extinction learning, increases in norepinephrine in the prefrontal cortex and limbic areas, such as the amygdala and hippocampus could be a possible working mechanism for the memory enhancing effects of VNS |
| Cha et al. (2016) | Sudden-onset vertigo | 1 | ES-420, Ito Company Ltd | Ball electrode | R | Cymba concha, cavum concha, and outer surface of tragus | NS | 0.2 ms | Discomfort threshold | 30 Hz | 4 min each site | Inferred—tVNS may normalize autonomic imbalance due to increased sympathetic response causing vertigo |
| Frokaer et al. (2016) | Pain threshold | 18 | NEMOS, Cerbomed | Titanium* | L | Concha | Sham stimulation 30 Hz on ear lobe | 0.25 ms | Tingling without pain | 30 Hz | 60 min | NS |
| Gaul et al. (2016) | Chronic cluster headache | 45 | NS | Stainless steel | R | Neck | NS | NS | 60 mA | 25 Hz | 1 ms on, 40 ms off for three doses of 2 min of stimulation twice a day | NS |
| Grazzi et al. (2016) | Menstrual related migraine | 51 | gammaCore electroCore LLC | Stainless Steel | L, R | Neck | NS | 0.2 ms | Up to 60 mA | 25 Hz | Burst (1 ms on, 50 ms off) for 2 min three times a day | NS |
| Lerman et al. (2016) | Peripheral immune system modulation in healthy humans | 20 | gammaCore electroCore LLC | Stainless steel | L, R | Neck | Active control 1 Hz stimulation | 0.2 ms | Tingling without pain | 25 Hz | Burst (1 ms on, 40 ms off) for 2 min | NS |
| Rong et al. (2016) | Major depressive disorder | 160 | NS | Ear clips | NS | Concha | Sham stimulation 20 Hz at superior scapha | 0.2 ms | Tolerance threshold (typically between 4 and 6 mA) | 20 Hz | Continuously for 30 min twice a day | NS |
| Silberstein et al. (2016a) | Migraine | 59 | gammaCore electroCore LLC | Stainless steel | R | Neck | Sham device that did not deliver electrical stimulation | NS | Set by the user (up to 60 mA) | NS | 2 × 2 min doses delivered 5–10 min apart three times a day | NS |
| Silberstein et al. (2016b) | Cluster headache | 150 | gammaCore electroCore LLC | Stainless steel | R | Neck | Sham device delivering 0.1 Hz biphasic pulse | 0.2 ms | Set by the user (up to 60 mA) | 25 Hz | Burst (1ms on, 40 ms off) for three consecutive 2 min stimulations 1 min apart | Inferred—stimulation of vagus nerve affects hypocretin and orexin pathway that affects pathophysiology of cluster headaches |
| Trevizol et al. (2016) | Depression | 12 | Ibramed Neurodyn II | Rubber electrodes | L, R | Mastoid process | NS | 0.25 ms | 12 mA | 120 Hz | 30 min a day 10 times over 2 weeks | NS |
| Fang et al. (2016) | Major depressive disorder | 34 | NS | Ear clip | L | Concha | Sham stimulation 20 Hz at superior scapha | <1 ms | Tolerance threshold (4–6 mA) | 20 Hz | 2 × 30 min daily, 5 days a week for 4 weeks | Measured—fMRI showed that after tVNS default mode network functional connectivity showed significant changes in brain regions involved in emotional modulation which is associated with depression severity |
| Frangos et al. (2015) | Bold fMRI effects of tVNS | 12 | NEMOS, Cerbomed | Titanium | L | Cymba Concha | Sham stimulation 25 Hz on ear lobe | 0.25 ms | Tingling but not painful (0.3–0.8 mA) | 25 HZ | Continuously for 14 min | Measured—fMRI shows tVNS significantly affects central projections of the vagus nerve. |
| Hyvärinen et al. (2015) | Tinnitus | 15 | Tinnoff Inc | Clip electrode | L | Tragus | Sham stimulation 25 Hz on ear lobe | 0.5 ms | Above sensory threshold (~0.5 mA) | 25 Hz | Continuously for 6 min | Measured—MEG showed tVNS modulates synchrony of tone-evoked brain activity, especially at the beta and gamma bands |
| Nesbitt et al. (2015) | Cluster headache | 19 | gammaCore electroCore LLC | Stainless steel* | L, R | Neck | NS | 1 ms | Self-controlled | 25 Hz | 2 min per dose, up to three doses twice daily | NS |
| Sellaro et al. (2015b) | Post-error slowing | 40 | CM02, Cerbomed | Two titan electrodes | L | Outer auditory canal | Sham stimulation 25 Hz on ear lobe | 0.2–0.3 ms | 0.5 mA | 25 Hz | 30 s on and 30 s off for 75 min | NS |
| Sellaro et al. (2015a) | Pro-social behavior | 24 | CM02, Cerbomed | Two titan electrodes | L | Outer auditory canal | Sham stimulation 25 Hz on ear lobe | 0.2–0.3 ms | 0.5 mA | 25 Hz | 30 s on and 30 s off for 26 min | Inferred—tVNS expected to enhance prosocial helping behavior due to activation in the insula and prefrontal cortex but this was not observed |
| Altavilla et al. (2015) | Migraine | 20 | gammaCore electroCore LLC | Stainless steel* | NS | Neck | NS | NS | NS | NS | Continuously for 90 s | NS |
| Barbanti et al. (2015) | Chronic Migraine | 50 | gammaCore electroCore LLC | Stainless steel* | R | Neck | NS | NS | NS | NS | 2 × 120 s doses 3 min apart per migraine | NS |
| Hasan et al. (2015) | Schizophrenia | 20 | CM02, Cerbomed | Two titan electrodes | L | Outer auditory canal | No electrical stimulation delivered | 0.25 ms | Above perception threshold | 25 Hz | 30 s on, 180 s off for up to 3 ×3 h a day | NS |
| Jacobs et al. (2015) | Associative memory in older individuals | 30 | TENSTem dental, Schwa-medico BV | Circular ear clip | L | External acoustic meatus on inner side of tragus | No electrical stimulation delivered | 0.2 ms | 5 mA | 8 Hz | Twice a day | Inferred—tVNS enhances memory performance by increasing locus coeruleus activity and noradrenalin levels to memory-relevant brain areas. |
| Kinfe et al. (2015a) | Cluster-Tic syndrome | 1 | gammaCore electroCore LLC | Stainless steel* | R | Neck | NS | 1 ms | 12–14 V | 25 Hz | Burst for 2 × 90 s doses 15 min apart | NS |
| Kinfe et al. (2015b) | Migraine and sleep disturbance | 20 | gammaCore electroCore LLC | Stainless steel* | L, R | Neck | NS | 1 ms | 0–24 V | 25 Hz | Burst for 2 × 2 min twice a day | Inferred—in patients with migraine, and tVNS may help to counteract the decline in thalamocortical activity |
| Stavrakis et al. (2015) | Atrial fibrillation | 40 | Grass S88, Natus Neurology Inc | Flat metal clip | R | Tragus | No electrical stimulation delivered | 1 ms | Discomfort threshold | 20 Hz | Continuously for 60 min following induction of atrial fibrillation | NS |
| Steenbergen et al. (2015) | Efficiency of action cascading processes in healthy humans | 30 | CM02, Cerbomed | Two titan electrodes | L | Outer auditory canal | Sham stimulation 25 Hz on ear lobe | 0.2–0.3 ms | 0.5 mA | 25 Hz | 30 s on, 30 s off for 45 min | Inferred—tVNS modulates efficiency of action cascading processes, likely via GABA and NE release |
| Straube et al. (2015) | Migraine | 46 | NEMOS, Cerbomed | Titanium* | L | Concha | Active control 1 Hz sham stimulation | 0.25 ms | Tingling but not painful | 1 or 25 Hz | 30 s on, 30 s off for 4 h a day for 12 weeks | Inferred—headache decreased more significantly in 1 Hz active control group, possibly due to suppression of nociceptive signaling and pain perception in spinal trigeminal nucleus.tVNS may also alter cortical excitability |
| Weise et al. (2015) | Parkinson's disease | 50 | NS | Custom made fine silver wires | L, R | Tragus | NS | 0.1 ms | 8 mA | 0.5 Hz | NS | Measured—scalp electrodes measured activation of brainstem after tVNS and observed somatosensory evoked potentials in the nerve which is believed to reflect neuronal activity |
| Mei et al. (2014) | Tinnitus | 32 | TENS-200, Suzhou Medical Supplies Co Ltd | NS | NS | Cavum Concha | NS | 1 ms | 1 mA | 20 Hz | 2 × 20 min daily for 8 weeks | NS |
| Aihua et al. (2014) | Epilepsy | 60 | TENS-200 | NS | L, R | Outer auditory canal and conchal cavity | Sham stimulation 20 Hz on ear lobe | 0.2 ms | Individual specific | 20 Hz | Continuously for 20 min three times a day | NS |
| Capone et al. (2015) | Cortical excitability in healthy volunteers | 10 | Twister, EBM | Ag/AgCl | L | External acoustic meatus at inner side of tragus | Sham stimulation 20 Hz on ear lobe | 0.3 ms | 8 mA | 20 Hz | 30 s on, 270 s off for 1 h | Measured—measurement of motor evoked potentials showed a GABA modulation in the motor cortex contralateral to the tVNS stimulation side |
| Clancy et al. (2014) | Sympathetic nerve activity in healthy humans | 48 | V-TENS PLUS, Body Clock Health Care Ltd | Modified surface electrodes | NS | Tragus | Disconnected electrodes for sham | 0.2 ms | Sensory threshold (10–50 mA) | 30 Hz | Continuously for 15 min | NS |
| Goadsby et al. (2014) | Acute Migraine | 30 | gammaCore electroCore LLC | Stainless steel* | R | Neck | NS | NS | NS | NS | 2 × 90 s doses 15 min apart after migraine onset | NS |
| Grazzi et al. (2014) | Migraine | 30 | gammaCore electroCore LLC | Stainless steel* | R | Neck | NS | NS | NS | NS | 90 s | NS |
| Huang et al. (2014) | Impaired glucose tolerance | 72 | Huatuo TENS-200, Suzhou | NS | NS | Concha | Sham stimulation 20 Hz applied at superior scapha | =1 ms | 1.0 (adjusted based on tolerance) | 20 Hz | 20 min twice daily for 12 weeks | NS |
| Kreuzer et al. (2014) | Tinnitus | 50 | Phase I: CM02, Cerbomed Phase II: NEMOS, Cerbomed | Two titan electrodes | NS | NS | NS | NS | 0.1–10 mA | 25 Hz | 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 | NS |
| Laqua et al. (2014) | Pain threshold in healthy humans | 22 | TNS SM 2 MF, Schwamedico GmbH | Anode: Silver disc Cathode: PECG electrode | L, R | Cavum Concha and Mastoid area | No electrical stimulation delivered | 0.2 ms | Perception threshold | 2 and 100 Hz | Burst 30 min | Inferred—tVNS produces both anti- and pro-nociceptive effects |
| Busch et al. (2013) | Pain perception in healthy volunteers | 48 | STV02, Cerbomed | Bipolar electrode | L | Concha at inner side of tragus | No electrical stimulation delivered | 0.25 ms | 0.25–10 mA | 25 Hz | Continuously for 1 h | Inferred—detailed analysis of different sub modalities of the somatosensory system suggest an impact of t-VNS on central pain processing rather than on peripheral nociceptor activity |
| He et al. (2013) | Pediatric epilepsy | 14 | TENS-200 | Conductive rubber | L, R | Concha | NS | NS | 0.4–1.0 mA depending on tolerance | 20 Hz | 3 × 30 min a day | Inferred—afferent projections from the ABVN to the nucleus tractus solitarius rather than to the spinal trigeminal nucleus may explain anti-seizure effect |
| Lehtimäki et al. (2013) | Tinnitus | 10 | Tinoff pulse generator | Clip electrode | L | Tragus | No electrical stimulation delivered | NS | Above sensory threshold (usually around 0.8 mA) | 25 Hz | 7 × 45/60 min sessions delivered over 10 days | Measured—MEG shows tVNS can modulate auditory cortical activation |
| Kraus et al. (2013) | Effects of sham-controlled transcutaneous electrical stimulation | 16 | Digitimer DS7A | Silver | L | Group I: Anterior wall of ear canal Group II: posterior side of ear canal | Sham stimulation 8 Hz on ear lobe | 0.02 ms | Non-painful | 8 Hz | 4 × 30 s on, 60 s off | Measured—fMRI shows activations and deactivations of certain brain regions, especially frontal and limbic areas depending on area of stimulation, and showed more activation than in sham stimulation |
| Hein et al. (2012) | Depression | 37 | Study1: TENS-NET 2000, Auri-Stim Medical Inc Study 2: TENS-NET 1000, Auri-Stim Medical Inc | Headset (4 electrodes placed crosswise) | L, R | Outer auditory canal | No electrical stimulation delivered electrodes unplugged | NS | Study 1: Perception threshold Study 2: 130 μ A | 1.5 Hz | Study 1: 1 × 15 min 5 days a week Study 2: 2 × 15 min 5 days a week | NS |
| Napadow et al. (2012) | Chronic pelvic pain | 15 | Cefar Acus II, Cefar Medical | Modified press-tack electrode | L | Cymba Concha and slope between antihelix and cavum concha | Sham stimulation 30 Hz on ear lobe | 0.45 ms | Strong, non-painful | 30 Hz | 0.5 s on, matched to respiration for 30 min | NS |
| Stefan et al. (2012) | Epilepsy | 10 | NS | NS | L | Tragus | NS | 0.3 ms | Tolerance threshold | 10 Hz | 3 × 1 h a day over 9 months | NS |
| Schulz-Stübner and Kehl (2011) | Hiccups | 1 | NMS 300, Xavant Technology | NS | L | Neck | NS | NS | 6 mA | 1 Hz | 30 s | Inferred—Unclear whether hiccups were stopped due to interference with reflex arches at different neuronal levels |
| Dietrich et al. (2008) | Bold fMRI | 4 | Cerbomed | Silver | L | Tragus | NS | 0.25 ms | 4–8 mA | 25 Hz | 50 s on, 100 s off for 700 s | Measured—Bold fMRI showed tVNS elicited a robust activation in the left locus coeruleus, a brainstem nucleus related to clinical depression as well as bilateral activation of the thalamus |
| Kraus et al. (2007) | Bold fMRI | 22 | EMP2 Expert, Schwa-medico GmbH | Silver | L | Tragus | Sham stimulation 8 Hz on ear lobe | 0.02 ms | Perception threshold | 8 Hz | 30 s on, 120 s off three times over 2 days | Measured—fMRI shows tVNS leads to prominent changes in cerebral activation patterns, with marked deactivation in limbic and temporal brain areas |
| Fallgatter et al. (2003) | Vagus sensory evoked potentials | 6 | NS | Bipolar electrode | NS | Tragus and acoustic meatus | NS | 0.1 ms | 8 mA | NS | 2 s interstimulus interval | Measured—Evoked potential recordings are far field potentials of post-synaptic brainstem activity from vagus nerve nuclei that can be elicited on electrical stimulation |
| Johnson et al. (1991) | Pain threshold and autonomic function | 24 | Microtens 7757 | Ag/AgCl and rubber | R | Concha | No electrical stimulation delivered | 0.5 ms | Discomfort threshold | 2.3 Hz | Burst for 15 min | NS |
NS, not stated. An asterisk indicates that an electrode type was not stated in the study but was assumed by us from the type of the device. A dagger indicates parameters as stated in the original paper but that are outside the normal range (possible typing error).