Clinical and cognitive effects of external trigeminal nerve stimulation (eTNS) in neurological and psychiatric disorders: a systematic review and meta-analysis

Abstract

This pre-registered (CRD42022322038) systematic review and meta-analysis investigated clinical and cognitive outcomes of external trigeminal nerve stimulation (eTNS) in neurological and psychiatric disorders. PubMed, OVID, Web of Science, Chinese National Knowledge Infrastructure, Wanfang, and VIP database for Chinese technical periodicals were searched (until 16/03/2022) to identify trials investigating cognitive and clinical outcomes of eTNS in neurological or psychiatric disorders. The Cochrane Risk of Bias 2.0 tool assessed randomized controlled trials (RCTs), while the Risk of Bias of Non-Randomized Studies (ROBINS-I) assessed single-arm trials. Fifty-five peer-reviewed articles based on 48 (27 RCTs; 21 single-arm) trials were included, of which 12 trials were meta-analyzed (N participants = 1048; of which ~3% ADHD, ~3% Epilepsy, ~94% Migraine; age range: 10–49 years). The meta-analyses showed that migraine pain intensity (K trials = 4, N = 485; SMD = 1.03, 95% CI[0.84–1.23]) and quality of life (K = 2, N = 304; SMD = 1.88, 95% CI[1.22–2.53]) significantly improved with eTNS combined with anti-migraine medication. Dimensional measures of depression improved with eTNS across 3 different disorders (K = 3, N = 111; SMD = 0.45, 95% CI[0.01–0.88]). eTNS was well-tolerated, with a good adverse event profile across disorders. eTNS is potentially clinically relevant in other disorders, but well-blinded, adequately powered RCTs must replicate findings and support optimal dosage guidance.

The efficacy of real versus sham external Trigeminal Nerve Stimulation (eTNS) in youth with Attention-Deficit/Hyperactivity Disorder (ADHD) over 4 weeks: a protocol for a multi-centre, double-blind, randomized, parallel-group, phase IIb study (ATTENS)

“…Other non-pharmacological treatments such as behavioural therapies, cognitive training (CT) [ 38 ], Electrophysiology-Neurofeedback [ 3 ], non-invasive brain stimulation, fMRI Neurofeedback [ 27 , 29 ] or dietary interventions show only small to moderate efficacy on improving ADHD symptoms or cognition [ 3 – 5 ]. eTNS is hence the non-pharmacological treatment that has shown the largest effect size so far in improving ADHD and is the only non-pharmacological medical device licensed as treatment for ADHD by the FDA.…”

“…Studies have shown improvements in pain, in neurological disorders such as epilepsy, migraine as well as in psychiatric disorders [ 38 ]. Our meta-analysis of TNS studies in neurological and psychiatric disorders showed improvement in migraine pain combined with medication and in depressive symptoms across three disorders [ 38 ].…”

“…There was no difference between groups on questions pertaining to belief in having active or sham device [ 9 ]. The blinding was also successful in similar studies with the device in depression [ 38 ]. To further enhance the blinding in this study, the first 30s of every hour of stimulation will be real stimulation but at a lower frequency in the sham eTNS and then be switched off.…”

“…There is little evidence of side or (serious) adverse effects of eTNS [ 38 ]. Hence, withdrawal from the treatment due to adverse effects is not expected.…”