Table 1.
Clinical trials investigating the effects of vagal neuromodulation on pain and cognition. – indicates value unspecified; n refers to intervention/control. AF, atrial fibrillation; CABG, coronary artery bypass grafting; LVEDV, left ventricular end diastolic volume; LVEF, left ventricular ejection fraction; LVESV, left ventricular end systolic volume; PCI, percutaneous coronary intervention; PMID, PubMed Identification Number; STEMI, ST elevation myocardial infarction; taVNS, transcutaneous auricular vagus nerve stimulation; tcVNS, transcutaneous cervical vagus nerve stimulation; VNS, vagus nerve stimulation.
| Authors, ref. no., year (PMID) | Study design | Subjects (n) | Age (yr) | Sex (% female) | Intervention | Start of intervention | Stimulation parameters |
Control | Outcome measured | Outcome time point | ||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| On/off period (s) | Duration (min) | Pulse width (μs) | Pulse frequency (Hz) | Intensity (mA) | ||||||||||
| Pain | ||||||||||||||
| Lerman and colleagues27 2019 (30759089) | RCT | Volunteer (15/15) | 18–54 | 36.7 | tcVNS | 9.5 min before pain challenge | 120 | – | 1000 | 25 | 24 V | Sham | Numerical Pain Rating Scale (0–10); time to peak response from each noxious thermal stimulus (s) | 16.8 min |
| Tassorelli and colleagues32 2018 (29907608) | RCT | Migraine (122/126) | 18–75 | 25 | tcVNS | 20 min before pain assessment | 120 | – | 200 | 25 | 60 | Sham | Pain-free without using rescue medication (% of subjects) | 30, 60, 120 min |
| Janner and colleagues28 2018 (29337730) | RCT, crossover | Volunteer (49/group) | 22–28 | 51 | taVNS | 20 min before pain challenge | – | – | 200 | 100 | – | Sham and no (separate control arms) | Numeric pain scale (0–100) | 48 h |
| De Icco and colleagues33 2018 (29154689) | RCT, crossover | Volunteer (10/group) | 24–29 | 50 | tcVNS | 30 and 5 min before assessment | 120 | – | 200 | 25 | 0–60 | Sham | Nociceptive withdrawal reflex threshold (mA) | 30 min |
| Frøkjaer and colleagues34 2016 (26728182) | RCT, crossover | Volunteer (18/group) | 40–57 | 44.4 | taVNS | 5 min before assessment | – | 20 | 250 | 30 | 0.1–10 | Sham | Thresholds to bone pain (kPa) | 0, 144 h |
| Laqua and colleagues35 2014 (25135040) | Non-RCT, crossover | Volunteer (22/group) | 22–28 | – | taVNS | 15 min before assessment | – | 30 | 200 | 2–100 | – | No | Pain threshold (mA) | 35 min |
| Busch and colleagues36 2013 (22621941) | RCT, crossover | Volunteer (48/group) | – | – | taVNS | 48 h before assessment | – | 60 | 250 | 25 | 0.25–10 | No | Submodalities of pain thresholds (heat, pressure) (rating, kPa) | 60 min |
| Napadow and colleagues29 2012 (22568773) | RCT, crossover | Chronic pelvic pain (14/group) | 21–64 | 100 | taVNS | 15 min before assessment | – | – | 450 | 2 | – | No | Visual Analog Scale (0–100) | 0, 15 min |
| Kutlu and colleagues30 2020 (32190684) | RCT | Fibromyalgia (30/30) | 18–50 | 100 | taVNS | Unclear | – | 30 | 500 | 10 | – | No | Visual Analog Scale (0–100) | 168 h |
| Alt and colleagues31 2020 (32592516) | RCT, crossover | Volunteer (23/group) | 18–45 | 60.9 | tcVNS | 60, 30, 15, and 5 min before assessment | 120 | 10 | 200 | 25 | 0–24 V | Sham | Nociceptive flexor and pain thresholds (mA); Numerical Pain Rating Scale (0–10); Somatosensory evoked potentials (μV) | 5, 15, 30, 60 min |
| Cognition | ||||||||||||||
| Bretherton and colleagues37 2019 (31358702) | Non-RCT, crossover | Volunteer (14/group) | 68–71 | 35.7 | taVNS | N/A | – | 15 | 200 | 30 | 2–4 | Sham | Mood disturbance (Profile of Mood States (POMS) score, no units) | 168 h |
| Burger and colleagues,38 2019 (30710565) | RCT | Volunteer (48/49) | 18–25 | 80.4 | taVNS | 20 min before cognitive tests | 30 | 15 | 250 | 25 | 0.5 | Sham | Worry (time spent worrying during 5 min period, %) | 15 min |
| Fischer and colleagues,39 2018 (29693214) | RCT, crossover | Volunteer (21/group) | 19–22 | 85.7 | taVNS | 28 min before cognitive tests | – | – | 200–300 | 25 | 0.4–3.3 | Sham | Conflict-triggered adjustment of cognitive control (N2 and P3 event-related potential amplitude, μV) | – |
| Colzato and colleagues,40 2018 (29326067) | RCT | Volunteer (40/40) | 17–33 | 62.5 | taVNS | 15 min before cognitive tests | 30 | – | 200–300 | 25 | 0.5 | Sham | Creativity performance (Alternate Uses Task, Idea Selection Task, Remote Associates Test and Creative Problem Solving Task scores, no units) | 25 min |
| Colzato and colleagues41 II, 2018 (29128975) | RCT | Volunteer (40/40) | 17–33 | 62.5 | taVNS | 15 min before cognitive tests | 30 | – | 200–300 | 25 | 0.5 | Sham | Creativity performance (Alternate Uses Task, Idea Selection Task, Remote Associates Test and Creative Problem Solving Task scores, no units) | 25 min |
| Sellaro and colleagues,42 2015 (26226074) | RCT | Volunteer (20/20) | 18–30 | 87.5 | taVNS | 15 min before cognitive tests | 30 | – | 200–300 | 25 | 0.5 | Sham | Post-error slowing (Response times, ms; Accuracy, %) | – |
| Jacobs and colleagues,43 2015 (25805212) | RCT, crossover | Volunteer ‘older’ (30/group) | 58–63 | 50 | taVNS | 90 min before cognitive tests | – | 17 | 200 | 8 | 5 | Sham | Associative memory (Response and reaction times, ms) | 90 min |
| Wittbrodt and colleagues,44 2020 (32659483) | RCT | Volunteer without PTSD (11/8) | 18–65 | 47.4 | tcVNS | 5 min before neuroimaging | 120 | – | 40 | 25 | 0–60 | Sham | Emotional stress/fear memory (Brain activity by: size, number of voxels; site, Brodmann area/Talairach coordinates) | 5 h |
| Borges and colleagues,45 2020 (32523510) | RCT, crossover | Volunteer (32/group) | 19–27 | 28.1 | taVNS | 4 min before cognitive tests | 30 | 13 | 200–300 | 25 | 2.2 | Sham | Core executive functions (Reaction times, ms; Error, %) | 24, 48 h |
| Warren and colleagues,46 2020 (32630571) | Non-RCT, crossover | Volunteer (42/group) | 18–25 | 81.0 | taVNS | At least 15 min before cognitive tests | 30 | – | 200–300 | 25 | 0.5 | Sham | Attention-triggered processes (P3 event-related potential amplitude, μV) | – |
| Steenbergen and colleagues,47 2015 (25869158) | RCT, crossover | Volunteer (30/group) | 18–27 | 86.7 | taVNS | 20 min before cognitive tests | 30 | 55 | 200–300 | 25 | 0.5 | Sham | Action cascading (Reaction times, ms; Error rates, %) | 25 min |