This study is a large multisite randomized clinical trial to asses the efficacy of external trigeminal nerve stimulation (TNS), a novel, minimal risk, non-invasive neuromodulation treatment, for ADHD in children ages 7-12 years old (N=180).

Study hypotheses address potential differences in ADHD symptoms over 4 weeks treatment with active vs. sham TNS in an expanded multi-site investigation; whether resting state fronto-parietal connectivity mediates TNS impact on ADHD symptoms; if changes in fronto-parietal activation, as measured by electroencephalography (EEG), predict TNS-related treatment outcomes; and whether a baseline cognitive profile similarly predicts response to TNS therapy.

Trigeminal Nerve Stimulation (TNS), an FDA-approved, non-invasive minimal risk intervention approved for treatment of Attention-Deficit/Hyperactivity Disorder (ADHD), administers a low amount of electrical stimulus to the forehead during sleep and is shown to increase activity in brain regions associated with attention and impulse control.

The current study seeks to replicate previous efficacy and safety findings of TNS in a larger, multisite group of ADHD-diagnosed youth, ages 7-12. The study will be conducted at UCLA and Seattle Children's Hospital.

The study comprises 3 phases, with subsequent 12-month follow-up for participants who demonstrate positive response to active therapy. We will screen up to 280 participants to yield an overall study N=225 completers meeting Diagnostic and Statistical Manual-5 (DSM-5) ADHD criteria across the two sites.

Phase 1 is a 4-week double-blind, controlled trial of active vs. sham TNS. Once inclusion/exclusion criteria are assessed, eligible participants have an initial baseline assessment comprised of behavioral ratings, cognitive assessments, and electroencephalography (EEG), and are subsequently randomized 2:1 to active vs. sham treatment. Participants will begin use of TNS as directed each night during sleep for 4 weeks. Participants, families, and most of the study team will remain blind to treatment assignment. Weekly behavioral rating will be obtained from parents, teacher, and clinical investigators. EEG, along with other cognitive measures, will be repeated at week 4.

In Phase 2, participants initially randomized to sham will receive active TNS for an additional 4 weeks, with continued weekly assessments. Phase 3 entails brief naturalistic follow-ups via phone or Zoom at months 3 and 6 post-treatment.

Inclusion Criteria:

1. male and female children ages 7 to 12 years with DSM-5 ADHD, any current presentation, as determined by diagnostic interview, Kiddie Schedule for Affective Disorders and Schizophrenia (KSADS), and clinical interview;
2. total score >= 24 on baseline ADHD-RS;
3. CGI-S score at baseline >= 4;
4. no current medication with CNS effects (Participants previously on psychostimulant medication will be required to be not optimally treated and off medication for one week or 5 half-lives for all other medications); stable use of supplements will be permitted;
5. parents able and willing to monitor proper use of the stimulation device and complete all required rating scales;
6. estimated Full Scale IQ >= 80 based on WASI subtests;
7. parent and participant able to complete rating scales and other measures in English;
8. able to cooperate during EEG

Exclusion Criteria:

1. impaired functioning to a degree that requires immediate initiation of ADHD medication in the opinion of the parents and/or investigator;
2. current diagnosis of autism spectrum disorder or major depression;
3. history of lifetime psychosis, mania, or seizure disorder;
4. baseline suicidality;
5. history of seizure disorder or head injury with loss of consciousness

The study will be registered on clinicaltrials.gov and all data will be uploaded to the National Database for Clinical Trials (NDCT) related to Mental Illness. Final de-identified data will be uploaded to NDCT databases by the PIs and trained research personnel at the completion of the study. All research data will be redacted to prevent the disclosure of personal identifiers.

All individual participant data collected during the trial will be shared, following de-identification.

Beginning 3 months and ending 5 years after study publication.

External investigators will be able to apply for access via an online query system by submitting their affiliations and details of their proposed research.

Double-blind, sham-controlled