Of the 2738 potentially eligible reports, our systematic review included 48 separate trials (27 RCTs, 21 single-arm trials; reported in 55 published articles), of which 12 were meta-analyzed (for included studies, see Table 2; for exclusions, with reasons for exclusion, see Supplementary Fig. 1 [PRISMA 2020 Flowchart] and Supplementary Table 1).
Of the 27 RCTs assessed via RoB 2.0, most (N = 17) were rated with “High” risk of bias, mainly due to poor blinding (Domain 4), or having “some concerns” primarily driven by a lack of clear pre-specified outcomes (N = 25) (Domain 5) or inadequate randomization (N = 12) (Domain 1; e.g., poor balance between groups at baseline; see Supplementary Fig. 2). Twenty-seven articles were published from the 21 single-arm trials. All articles were assessed via ROBINS-I and were judged to have “Serious” risk of bias owing to lack of blinding (Supplementary Fig. 2).
Systematic review results
Attention-deficit/hyperactivity disorder (ADHD)
One open-label trial (N = 21, children/adolescents with ADHD) reported significant improvement at 4 and 8 weeks of nightly eTNS relative to baseline in investigator-rated parent reports of ADHD symptoms (primary outcome), with most effects observed at 4 weeks; as well as in secondary outcomes of: investigator-rated parent reported subscores of inattention and hyperactivity/impulsivity symptoms; clinical global impression improvement scale; parent-rated severity of ADHD and related impairments; several subscales of sleep measures, and several subscores of behavioral executive functioning (with the strongest being working memory); self-rated dimensional measures of depression; and incongruent reaction time on the attention network task, a measure of interference inhibition. Self-rated measures of anxiety were unchanged as well as all other cognitive measures .
In a double-blind, parallel-arm RCT (N = 59 children and adolescents with ADHD), a significant group by time interaction indicated that 4 weeks of nightly real relative to sham eTNS significantly reduced clinician-rated total parent-reported symptoms of ADHD (primary outcome), and secondary outcomes of clinician-rated parent reports of subscores of inattentive and hyperactivity/impulsivity symptoms, and clinical global impression. There was no significant change in secondary outcomes of: parent- or teacher-rated severity of ADHD and related impairments; parent-rated sleep measures, and behavioral executive functioning; parent- or child-rated irritability symptoms, and symptoms of anxiety; clinician-rated symptoms of depression and suicidality; and spatial working memory or attention network task performance. In both groups, 1 week after stimulation cessation, there was a significant increase in clinician-rated parent reported ADHD total symptoms . Resting-state qEEG spectral power in right frontal (Delta, Theta, Beta, Gamma frequency bands) and frontal midline (Gamma frequency band) regions increased significantly immediately after real but not sham eTNS, with right frontal (Theta, Beta) and midline (Gamma) frequency band changes correlating with reduction in ADHD total and hyperactivity/impulsivity subscale ratings in the eTNS group. After trial completion, twenty sham participants received 4 weeks of nightly eTNS, which led to a significant group-by-time interaction, suggesting significantly improved parent-rated behavioral executive functioning immediately after stimulation in eTNS “responders” (N = 10, ADHD-RS Total Score <25%) compared to “non-responders” .
In summary, 4 weeks of eTNS has been shown to reduce core symptoms of ADHD, but in only one double-blind RCT . There is limited evidence of improvement in other ADHD-related impairments, behavioral executive functioning, symptoms of depression and anxiety, and task-based measures of neuropsychological functioning. Longer-term effects are yet to be explored.
Two double-blind parallel-arm RCTs in 24  or 40  adults with major depressive disorder (MDD) reported a significant group-by-time interaction, indicating significantly reduced self-rated dimensional measures of symptoms of depression immediately and one-month after 10 nights of real compared to sham eTNS (primary outcome measure) , with a significant improvement in response (>50% fewer depression symptoms) but not remission rates (<8 HDRS-17 score) . A significant group-by-time interaction showed that Montreal Cognitive Assessment (MoCA) scores were significantly improved one-month after real compared to sham eTNS in one trial , but MoCA and self-reported quality of life were unchanged in the other (secondary outcomes) .
Two open-label trials reported significant improvements from baseline in symptoms of depression [57, 58] and anxiety , immediately and one-month after 10 days of eTNS . MoCA remained unchanged . Two other open-label trials found significant improvement from baseline at 2, 4, 6, and 8 weeks of daily eTNS in clinician- or self-rated symptoms of depression [19, 59, 60], and at 8 weeks of eTNS in clinician-rated clinical global impression [59, 60] and self-rated quality of life [19, 59, 60].
In summary, eTNS has been shown to significantly improve depression symptoms at first end-point and one-month after stimulation cessation (with two double-blinded RCTs), with limited evidence of improvement in symptoms of anxiety, quality of life or MoCA.
One double-blind, parallel-arm RCT (N = 42, with drug resistant, partial-onset epilepsy) reported significant improvements immediately after 18 weeks of daily 120 Hz versus 2 Hz eTNS based on change scores (baseline-endpoint) in ratings of symptoms of depression (secondary outcome), but not seizure frequency or response rates (i.e., >50% reduction in seizures relative to baseline), and time to the fourth seizure (primary outcomes) . After trial completion, thirty-five participants (19 from eTNS group; 16 from active control group) received 12 months of daily unblinded eTNS. Seizure frequency was significantly reduced at 6 months versus baseline and at 12 months versus 6 months, but only in participants who previously received eTNS in the blinded RCT .
One parallel-arm, unblinded RCT in adults with drug-resistant epilepsy (N = 40 with temporal or frontal epilepsy unsuitable for surgery) reported significant improvement at 6 and 12 but not at 3 months of daily eTNS compared to treatment-as-usual (TAU) in primary outcomes of response rates (≥50% reduction in seizure frequency), and in secondary outcomes of changes from baseline (i.e., baseline—endpoint) in seizure frequency and quality of life scores. At 12 months, response rates and changes from baseline in seizure frequency were significantly improved in participants with temporal relative to frontal epilepsy. There was no group difference in changes from baseline in ratings of symptoms of depression and anxiety symptoms or task-based measures of logical memory, visual memory, auditory learning, cognitive flexibility, working memory, and naming . Another parallel-arm, unblinded RCT (N = 30 with drug-resistant epilepsy) compared 6 months of 120 Hz versus 20 Hz eTNS. Change scores (baseline—3 or 6 months of eTNS) showed a significant improvement in favor of 120 Hz versus 20 Hz eTNS in seizure severity and rates of depression (i.e., HRSD score ≥20) at 3 and 6 months, and seizure frequency and symptoms of depression at 6 months, but not 3 months .
One open-label trial reported significant improvement from baseline in daily seizures at 3 but not 6 or 12 months of eTNS [65,66,67,68], or self-rated quality of life and symptoms of depression, but not sleep measures, immediately after 18 weeks of eTNS (M = 42, adults with drug-resistant epilepsy) . Another open label trial observed but did not test a 35% response rate in seizure frequency at 6 and 12 months and 14% at 48 months of eTNS .
In summary, eTNS has been shown to reduce seizure frequency, symptoms of depression, and quality of life, in people with epilepsy, but the evidence is based on mostly unblinded studies with only one unblinded RCT showing no effects on seizure frequency .
One double-blind, parallel-arm RCT (N = 52 adults with trigeminal neuralgia) combined real or sham eTNS with carbamazepine over 6-weeks. The mean dose of carbamazepine prescribed to participants was significantly reduced immediately, 6-weeks, 12-weeks, but not 3-months, after real stimulation compared to sham, while pain intensity and its effect on everyday functioning remained unchanged. No group-by-time interaction was conducted . One parallel-arm, unblinded head-to-head trial (N = 31 adults with trigeminal neuralgia) reported improvement in pain intensity with constant or theta-burst eTNS, for 3 weeks, but without statistical analyses .
In summary, evidence supporting the clinical relevance of eTNS in trigeminal neuralgia is limited with only one double-blind RCT, but there are initial indicators of improvement regarding medication intake and pain intensity.
Four parallel-arm (three unblinded, one double-blinded) RCTs applied 3 months of daily eTNS. One double-blind RCT (N = 67 adults with migraine) reported significant group difference favoring 60 versus 1 Hz eTNS in all primary outcomes (i.e., responders [>50% reduction from baseline in monthly migraines], and baseline—endpoint change in migraine days) and secondary outcomes (i.e., baseline—endpoint change in migraine attacks, headache days, and anti-migraine drug intake), but migraine severity was unchanged [41, 73]. In one RCT (N = 124 adults with migraine), change scores (i.e., baseline—post-assessment immediately after stimulation) based on measures of headache severity, duration, frequency, response rates (i.e., >25% reduction in headache frequency and duration), and quality of life showed significant improvement 8 weeks after twice-weekly daytime eTNS plus flunarizine relative to flurazine alone . In another RCT (N = 76 adults with migraine, measures of headache pain, frequency, duration, and response rates (i.e., >25% reduction in headache frequency and duration) were significantly reduced immediately after 12 weeks of twice-weekly daytime eTNS plus nimodipine versus nimodipine alone; however, baseline scores were not included in the analysis and the difference might hence be due to chance . Finally, one head-to-head RCT (N = 90 adults with migraine) found significant improvement versus baseline in migraine/headache symptoms and anti-migraine drug-use, but not accompanying symptoms, immediately after eTNS or mastoid electrical stimulation versus baseline only, while change scores (baseline—endpoint) of the impact of headaches daily functioning significantly improved with eTNS versus mastoid electrical stimulation. Symptoms accompanying migraine were unaffected .
One double-blinded, parallel-arm RCT (N = 45 adults with chronic type tension headache) reported significantly improved headache pain and its impact on quality of life immediately after 8 weeks of daily eTNS plus physiotherapy versus analgesic medication or physiotherapy alone, but no group by time interaction was tested .
Four parallel-arm unblinded RCTs applied daily eTNS for one-month. One (N = 154 adults with migraine) reported significantly reduced migraine frequency, pain intensity, and anti-migraine rescue medication, and a higher number of responders (≧50% reduction of migraine frequency) immediately after eTNS plus flurazine versus flurazine or eTNS alone. Flurazine alone significantly improved change scores in migraine intensity only when compared to eTNS alone . A second RCT (N = 60 adults with migraine) found that – compared to rizatriptan benzoate alone or eTNS alone – eTNS plus rizatriptan benzoate led to significantly improved change scores (i.e., baseline—post-assessment) in headache frequency and pain intensity at 30-days but not 7 or 14 days after stimulation . A third RCT (N = 180 adults with migraine) reported significantly improved change scores (i.e., baseline—immediately after stimulation) in headache pain severity, quality of life, and sleep quality immediately after eTNS plus nimesulide relative to nimesulide alone, with a significant higher number of recurrence of headaches at 3 months in the nimesulide alone versus eTNS plus nimesulide group (34% versus 20%) . The fourth RCT (N = 74 adults with migraine) analyzed change scores (i.e., baseline—10, 20, or 30-days of stimulation), and found that twice-daily eTNS plus rizatriptan benzoate relative to rizatriptan benzoate alone significantly improved headache frequency at 10 days and pain at 10-, 20-days, and 30-days .
Three parallel-arm unblinded RCTs applied eTNS over several days. Significant improvements were reported in: migraine symptoms immediately after one-week of eTNS versus TAU  (N = 118 adults with migraine); time without headaches (but not pain or everyday functioning) immediately after 10 days of twice daily eTNS plus flunarizine hydrochloride versus  (N = 60 adults with migraine); and headache frequency and duration 1 month after 10 days of eTNS but not TAU compared to baseline and in change scores (baseline—endpoint) in pain intensity 1 month after eTNS versus TAU  (N = 91 with migraine or other primary headaches). In the latter, a subsample (N not reported) of high self-reported pain ratings immediately after eTNS showed a significantly greater reduction in primary headache pain 30-days after eTNS versus TAU .
One head-to-head unblinded RCT (N = 120 adults with chronic headache) compared two brands of eTNS devices, eTNS with the MK-MT11 device (Maikang Medical Instrument Company, Beijing) versus the Cefaly device (STX-Med Sprl, Belgium) and found that change scores (baseline—post-treatment) in the number of headache attacks and headache pain intensity did not significantly differ between the two eTNS devices .
Three double-blind, parallel-arm RCTs in adults with migraine [39, 40, 85] administered single session eTNS. A significant group-by-time interaction suggested significant improvements relative to baseline immediately and 100-minutes after eTNS but not sham stimulation (N = 78) . eTNS versus sham stimulation significantly predicted improvements in freedom from pain and pain relief immediately and 24 h after stimulation and in migraine-associated symptoms immediately after stimulation, but there was no change in anti-migraine rescue medication intake (N = 538) . Finally, a significant group difference in baseline—endpoint change in migraine pain and the proportion of pain-free participants was found immediately after 100 Hz versus 3 Hz eTNS, with the migraine pain reduction only persisting 2 and 24 h after eTNS (N = 106) .
One crossover, unblinded RCT reported but did not test reduced pain from baseline immediately after single-session eTNS over the trigeminal or occipital and trigeminal nerves, with greater reduction in the latter (N = 10) . One parallel-arm unblinded RCT (N = 108 adults with migraine) found significantly improved headache pain severity, and quality of life, immediately after eTNS versus non-specified nerve stimulation . Stimulation duration was not reported.
Across 11 open-label trials (N Mean 36, range 17–100), eTNS led to significant improvements compared to baseline, which are summarized as follows. Six trials found a significant migraine/headache reduction at 8 weeks (but not 4 weeks) of eTNS  and/or immediately after 1 [89, 90] and/or 3 months of eTNS [22, 88, 91, 92]. Three out of four trials reported a significant reduction in anti-migraine medication intake immediately after 1 month  or 3 months of eTNS [91, 93], while one trial found no effect on medication intake . Five out of seven trials found that pain intensity was reduced i) immediately after 60 min of eTNS and again 60 min later  or ii) 1  or 3 months of eTNS [91, 93], but two trials found no effect on pain intensity [88, 92]. Finally, one trial found that migraine duration was reduced after 3 months of eTNS . In addition to these 11 trials, a further four found – but did not statistically analyze – reductions from baseline in migraine pain, migraine symptoms, vertigo, or headache severity immediately after 20 min  and again 24 h later in  or 1 month of eTNS ; migraine frequency over 4 months of eTNS ; and anti-migraine medication intake after 20 min and again 24 h later  or over 4 months of eTNS .
In summary, there is evidence, consistent across studies, of reduced migraine frequency and/or symptoms (namely pain) with continued use of eTNS versus sham. There is some evidence that these improvements persist after stimulation or that eTNS can also improve the impact of migraine on quality of life. There was a lack, however, of well-blinded control arms with a few exceptions that showed clinical improvements [39,40,41, 85].
An open-label pilot study (N = 13 adults with insomnia) showed significantly improved self-reported sleep quality, insomnia severity, sleepiness in daily life, but not polysomnographic measures of sleep, immediately after 4 weeks of eTNS relative to baseline .
Tolerability, adverse events
Overall, eTNS was well-tolerated with no severe adverse events reported across any of the studies. The most commonly reported mild adverse events included mild and transitory itching, skin redness, pain, or paresthesia, usually reported in a minority of participants in any given trial. Several studies reported participants dropping out due to discomfort, but these were equivalent across eTNS or comparator arms (see Tables 3 and 4; Supplementary Fig. 3).
Twelve RCTs were included in our meta-analyses, making a total of 1,048 participants [26, 40,41,42, 63, 64, 74, 76, 78,79,80, 87]. These studies applied eTNS alone [26, 40, 41, 76, 78, 87], or eTNS plus TAU  or eTNS plus another medication that was part of the trial, such as anti-migraine medication [42, 74, 79] or breathing exercises . These interventions (eTNS alone or plus another intervention) were compared to sham eTNS [26, 40, 41], or another form of stimulation [64, 76], TAU , or a medication treatment [42, 74, 78]. We were unable to include several outcomes from six RCTs in our meta-analyses (see Supplements for excluded outcomes, with reasons). Unfortunately, there were insufficient trials to analyze other outcomes measuring neuropsychological processes or neurophysiology (e.g., heart rate variability).
Migraine pain intensity
We found no significant improvement in favor of eTNS applied alone versus a comparator (i.e., sham, medication control, or active control) when all trials were analyzed (K = 6, SMD = 0.63, 95% CI[−0.26–1.51]), nor in sensitivity analyses limited to trials with sham control, medication control, or with blinded outcome assessors. Between effect size heterogeneity was high and statistically significant (see Table 5, Fig. 1; all I2 roughly 95, and significant Qs all p < 0.001). However, a post hoc analysis showed a significant, large improvement in favor of eTNS when combined with an anti-migraine medication versus medication alone, which was associated with low and non-significant heterogeneity (K = 4, SMD = 1.03, 95% CI[0.84–1.23]; I2 = 0, Q p = 0.78). Jacknife sensitivity analysis (i.e., repeating the analysis with a different trial excluded each time) showed that the significant improvement in pain intensity with all trials included was robust, with no change in effect direction or significance level, with effect size ranging from moderate to large, while heterogeneity remained low and non-significant (see Table 6).
Quality of Life
We found a significant, large improvement in quality of life that was in favor of eTNS plus anti-migraine compared to medication alone (K = 2, SMD = 1.88, 95% CI[1.22.5–2.53]). However, heterogeneity was high and statistically significant (see Table 5, Fig. 2).
We found a significant, moderate improvement in dimensional measures of depression symptoms in patients with epilepsy with (K = 1) and without depression (K = 2) or with ADHD (K = 1) that favored eTNS relative to sham (ADHD), TAU (epilepsy without depression) or 20 Hz eTNS (epilepsy with depression) (K = 3, SMD = 0.45, 95% CI[0.01–0.88]), which was no longer significant when limited to trials with only adult samples (K = 2). Heterogeneity was low and statistically non-significant (see Table 5, Fig. 3). Jacknife sensitivity analysis revealed that this effect was no longer significant when we removed three studies [26, 63, 64]. Heterogeneity remained low and statistically non-significant (see Table 6).
Other outcome measures
We found no significant effect on monthly anti-migraine drug use, monthly migraine attacks, and migraine days. With the exception of the latter, all analyses were associated with high and statistically significant heterogeneity (see Table 5, Figs. 4–6).
Only the analysis of migraine pain intensity outcomes had the required number of trials (i.e., 10 or more per predictor) to conduct a meta-regression analysis. The overall effect size estimates were not significantly predicted by follow-up length, duration of treatment, or mean age (see Supplementary Table 2).
Egger’s regression test was non-significant for the analysis of dimensional measures of depression (p = 0.13). Egger’s regression test could not be conducted for the analyses on migraine pain intensity, migraine days, and quality of life because the significant heterogeneity would have confounded any interpretation of funnel plot asymmetry.