Effects of External Trigeminal Nerve Stimulation on Neurocognitive Functioning in Children and Adolescents With ADHD: A Phase 2b Multicenter Randomized Controlled Trial

OBJECTIVE: Attention deficit hyperactivity disorder (ADHD) is associated with atypical cognition and related autonomic nervous system regulation. Trigeminal nerve stimulation (TNS) received U.S. Food and Drug Administration clearance as neuromodulation treatment for ADHD based on findings of clinical improvements from a pilot trial that were not confirmed in the authors' larger multicenter UK trial. Effects of TNS on cognition in ADHD, however, are relatively unknown. The authors therefore tested secondary outcomes, that is, short- and longer-term effects of active versus sham TNS in youths with ADHD on a broad neurocognitive task battery, physiological indicators of autonomic nervous system regulation, and head motion. METHODS: In the first confirmatory, multicenter, double-blind, parallel-group, phase 2b randomized sham-controlled trial, 150 youths with ADHD (ages 8-18 years) were assigned to 4 weeks of nightly active (N=75) or sham (N=75) TNS. Cognitive performance was assessed using a comprehensive battery of executive function and attention tasks (inhibition, sustained attention, time estimation, processing speed, and intrasubject response variability) at baseline, posttreatment, and 6-month follow-up. Autonomic nervous system regulation (heart rate, heart rate variability, and electrodermal activity) was measured via a wristband device and head motion with an eye tracker during rest or cognitive testing. RESULTS: Intention-to-treat analysis showed no significant differential treatment effects between active and sham TNS on any cognitive or physiological outcomes after 4 weeks of treatment or on cognitive measures at 6-month follow-up. CONCLUSIONS: TNS does not appear to improve neurocognitive performance, autonomic regulation, or head motion in youths with ADHD, extending negative clinical findings. The findings do not provide evidence to support TNS as a viable treatment to improve cognitive or autonomic nervous system functioning in youths with ADHD.