Neurofunctional mechanisms of action of trigeminal nerve stimulation (TNS) in children and adolescents with Attention Deficit/Hyperactivity Disorder (ADHD)

Attention-Deficit/Hyperactivity Disorder (ADHD) is associated with brain differences predominantly in fronto-striatal systems. Multisession 4-week real versus sham Trigeminal Nerve Stimulation (TNS) has shown to increase right prefrontal activation using electroencephalography (EEG) in a pilot study in children with ADHD which was associated with clinical improvement. Our subsequent larger multicentre 4-week UK RCT, however, found no clinical improvement. In the present secondary mechanistic analysis of this RCT, we tested the effects of TNS on cortical and subcortical brain activation using the more spatially resolved technique of fMRI and using a more rigorous sham TNS control condition. Three ADHD-sensitive fMRI tasks of response inhibition, working memory and sustained attention were used to test the underlying task-related brain activation effects of real TNS compared to a rigorous sham TNS condition in 62 children and adolescents with ADHD. There was no significant effect of real versus sham TNS on brain activation, nor on task performance in any of the tasks. The lack of a neurofunctional effect, alongside its lack of clinical efficacy, raises doubts on the potential of TNS as a neurotherapy for ADHD.