Trigeminal Nerve Stimulation for Attention-Deficit/Hyperactivity Disorder: Cognitive and Electroencephalographic Predictors of Treatment Response

Abstract

The current study applies a precision medicine approach to trigeminal nerve simulation (TNS), a Food and Drug Administration-approved neuromodulation treatment for attention-deficit/hyperactivity disorder (ADHD), by testing secondary outcomes of cognitive and electroencephalographic [EEG] predictors of treatment response among subjects from the original randomized controlled trial. Children aged 8 to 12 years with ADHD, were randomized to 4 weeks of active or sham TNS treatment, after which the sham group crossed over into 4 weeks of open-label treatment. TNS treatment responders (RESP) had an ADHD Rating Scale (ADHD-RS) Total score reduction of≥25%, whereas nonresponders (NR) had<25% reduction posttreatment. Assessments included weekly behavioral ratings and pre-/posttreatment cognitive EEG measures. The final sample was 25 RESP and 26 NR comprising 34 male and 17 female children, with a mean (SD) age of 10.3 (1.4) years. Baseline measures that significantly differentiated RESP from NR included: lower working memory, lower spelling and mathematics achievement, deficits on behavioral ratings of executive function (BRIEF), and lower resting state EEG power in the right frontal (F4) region (all p values<.05). Compared to NRs, responders showed significantly increased right frontal EEG power with TNS treatment, which was predictive of improved executive functions and ADHD symptomatology (β= 0.65, p< .001). When EEG findings and behavior were modeled together, the area under the curve (AUC) for BRIEF Working Memory scale was 0.83 (p= .003), indicating moderate prediction of treatment response. Children with ADHD who have executive dysfunction are more likely to be TNS responders and show modulation of right frontal brain activity, improved/normalized executive functions, and ADHD symptom reduction. Developmental Pilot Study of External Trigeminal Nerve Stimulation for ADHD; http://clinicaltrials.gov; NCT02155608.