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

Abstract

Objective: 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.

Method: 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.

Results: 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.

Conclusion: 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.

Clinical trial registration information: Developmental Pilot Study of External Trigeminal Nerve Stimulation for ADHD; https://ichgcp.net/clinical-trials-registry/NCT02155608" title="See in ClinicalTrials.gov">NCT02155608.

Keywords: BRIEF; electroencephalography; executive functions; neuromodulation.

Conflict of interest statement

Disclosure: Dr. McGough has provided expert witness testimony for Eli Lilly and Co. and Tris Pharma and has received DSMB honoraria from Sunovion. Drs. Loo, Ellis, Cowen, Dillon and Ms. Salgari have reported no biomedical financial interests or potential conflicts of interest.

Copyright © 2020 American Academy of Child and Adolescent Psychiatry. Published by Elsevier Inc. All rights reserved.

Figures

Figure 1:. Attention-Deficit/Hyperactivity Disorder (ADHD) Symptom Scores by Study Phase

Note: Blinded treatment was discontinued between week 4 and 5 (indicated by dotted line). Sham crossover treatment began week 5. Black and blue arrows indicate pre- and post-treatment measurements for the Active Trial and Sham Crossover groups, respectively. BOCF=baseline observation carried forward; RS = rating scale.

Figure 2:. Treatment Change in Right Frontal Electroencephalogram Power and Executive Function Scores

Note: In panel A (left), responders exhibited increased power in right frontal theta (4–7 Hertz [Hz]) and alpha (8–12 Hz) power, whereas non-responders showed no change. In panel B (right), Responders generally had pre-treatment scores in the clinically impaired range (T-score ≥65) on the Behavioral Rating of Individual Executive Function (BRIEF) scales, which improved and normalized (T-score 60. Solid bars indicate pre-Trigeminal Nerve Stimulation (TNS) treatment. Diagonal bars indicate post-TNS treatment. dB=decibel; MC=Metacognition; Org=Organization; Plan=Planning; WM=Working Memory.