Trigeminal Nerve Stimulation for ADHD (TNS for ADHD)

The purpose of this study is to develop external Trigeminal Nerve Stimulation (eTNS) as a potential nonmedication treatment for attention-deficit/hyperactivity disorder (ADHD). Study hypothesis address potential differences over 4 weeks of active vs. sham eTNS treatment on ADHD symptoms, measures of executive function, electroencephalography (EEG) profiles, other dimensional measures of height, weight, mood, anxiety, and sleep, and side effect profiles.

This three-year developmental study is a double-blind randomized trial of active vs. inactive sham eTNS for ADHD, with four weeks acute treatment followed by an additional one week of clinical observation and testing after treatment cessation. The study will enroll 85-90 participants aged 8-12 years to achieve a completion target of N=36 for each study condition (total final N = 72). Participants will meet Diagnostic and Statistical Manual-5 (DSM-5) criteria for ADHD, any current presentation, as established by the Behavior Disorders Module of the Kiddie Schedule for Affective Disorders and Schizophrenia (KSADS-PL) and clinical interview. Other screening procedures include measures of ADHD symptom severity, other behavioral ratings, and cognitive assessments. Once inclusion/exclusion criteria have been reviewed and verified, participants in Phase 1A will have a pre-treatment visit to establish behavioral and cognitive baseline ratings and to obtain an EEG. Participants and parents will be instructed in the use of eTNS, and participants will begin use of the eTNS as directed during sleep each night. Participants will be randomized 1:1 to active or inactive sham eTNS. Participants, families, and most of the study team will remain blind to treatment assignment. Participants will have weekly assessments over the five-week study to assess behavioral, cognitive, and brain activation change and to monitor safety, tolerability, and compliance. Weekly ratings will be obtained from a parent, teacher, and clinician investigator. EEG will occur at baseline, end of treatment (week 4). In Phase 1B, all participants remain blinded for one week after cessation of the intervention and return for a final visit to assess residual effects of eTNS therapy vs. sham.

Following screening and determination of eligibility, participants at baseline are randomized to receive 4 weeks nightly treatment with active or sham eTNS, followed by one week ongoing blinded assessment following treatment discontinuation. Positive responders will be invited to participate in a 12-month open extension.

Following screening and determination of eligibility, participants at baseline are randomized to receive 4 weeks nightly treatment with active or sham eTNS, followed by one week ongoing blinded assessment following treatment discontinuation. Following double-blind phase, interested participants randomized to sham have an option for a 4-week open TNS trial. Positive responders will be invited to participate in a 12-month open extension.

Participants will receive active trigeminal nerve stimulation (TNS) administered by the Monarch eTNS System nightly during sleep for 4 weeks, followed by one week of observation and followup while remaining blinded following treatment discontinuation. Participant deemed to be positive responders to blinded active treatment will be invited to continue open eTNS in a 12 month extension period.

Participants will receive sham trigeminal nerve stimulation (TNS) administered by the Monarch eTNS System nightly during sleep for 4 weeks, followed by one week of observation and followup while remaining blinded following treatment discontinuation. At the conclusion of the blinded trial, participants randomized to the sham group will be offered 4 weeks of open eTNS treatment. Participants deemed to be positive responders to open treatment will be invited to continue open nightly eTNS in a 12 month extension period.

A dimensional rating of ADHD symptoms, with scores ranging from 0 - 54, and higher scores indicating greater symptom severity.

Categorical measure indicating degree improved or not improved compared with baseline for each treatment group. Minimum score = 1 (very much improved); Maximum score = 7 (very much worse). Results reflect number of participants stratified as "Improved" (CGI-I <=2) or "Not Improved" (CGI-I > 2).

Parent completed dimensional measure of ADHD symptoms, with score range from 0- 30, and higher scores indicating more severe symptoms.

A child completed dimensional measure of emotional reactivity, with scores ranging from 0-12, and higher scores indicating greater severity.

A parent completed dimensional measure of emotional reactivity, with scores ranging from 0-12, and higher scores indicating greater severity.

A child completed rating of child anxiety, with scores ranging from 0-300, and higher scores indicating greater severity.

A parent completed rating of child anxiety, with scores ranging from 0-300, and higher scores indicating greater severity.

A child completed self-report dimensional measure of depressive symptoms, with range of scores from 0 to 54. Higher scores reflect increasing depression. Cutoff scores < 17 to 20 are generally considered to be in the normative range. A score of 36 or higher reflects a relatively severe depression.

Teacher completed dimensional measure of ADHD symptoms, with scores ranging from 0-30, and higher scores indicating more severe symptoms.

A parent completed rating of child executive function. Comprises 5 sub scales that measure various measures of behavior and cognition. Raw scores on each measure are converted to T scores ranging from 28 to 103, with higher scores indicating greater difficulties.

A parent completed 33-item scale to assess sleep related problems. Total scores range from 33 to 99 divided among 8 sub scales , with higher scores indicating more severe difficulties.

Inclusion Criteria: male and female children ages 8 to 12 years with DSM-5 ADHD, any current presentation, as determined by KSADS and clinical interview minimum scores of 12 on both the inattentive and hyperactive/impulsive subscales of the baseline ADHD-RS CGI-S score at baseline ≥ 4 no current medication with CNS effects parents able and willing to monitor proper use of the stimulation device and complete all required rating scales estimated Full Scale IQ ≥ 85 based on WASI subtests parent and participant able to complete rating scales and other measures in English able to cooperate during EEG Exclusion Criteria: impaired functioning to a degree that requires immediate initiation of ADHD medication in the opinion of the parents and/or investigator current diagnosis of autism spectrum disorder or major depression history of lifetime psychosis, mania, seizure disorder or head injury with loss of consciousness baseline suicidality

McGough JJ, Sturm A, Cowen J, Tung K, Salgari GC, Leuchter AF, Cook IA, Sugar CA, Loo SK. Double-Blind, Sham-Controlled, Pilot Study of Trigeminal Nerve Stimulation for Attention-Deficit/Hyperactivity Disorder. J Am Acad Child Adolesc Psychiatry. 2019 Apr;58(4):403-411.e3. doi: 10.1016/j.jaac.2018.11.013. Epub 2019 Jan 28.

Loo SK, Salgari GC, Ellis A, Cowen J, Dillon A, McGough JJ. Trigeminal Nerve Stimulation for Attention-Deficit/Hyperactivity Disorder: Cognitive and Electroencephalographic Predictors of Treatment Response. J Am Acad Child Adolesc Psychiatry. 2021 Jul;60(7):856-864.e1. doi: 10.1016/j.jaac.2020.09.021. Epub 2020 Oct 15.