Study design and setting

The SPIRIT Schedule of enrollment, interventions, and assessments appears in Fig 1. (The study SPIRIT Checklist, IRB Master Protocol, and CONSORT Diagram are in S1-S3 Files, respectively.) This is an open-label feasibility study of 28 days of nightly TNS treatment in 30 pediatric outpatients with PAE and ADHD. Each 8-hr treatment session is delivered overnight in sleep. Participants receive neuropsychological assessments and multimodal MR brain imaging before and after the treatment regimen. The trial is being conducted at the Division of Child & Adolescent Psychiatry Clinical Trials Hub, Semel Institute for Neuroscience, David Geffen School of Medicine at UCLA, Los Angeles. All multimodal MR scans are completed on the 3-T Siemens Prisma MRI scanner at the UCLA Staglin Center for Cognitive Neuroscience (CCN) at the Institute. Recruitment began on April 1, 2025, and is expected to continue until September 2026.

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Fig 1. SPIRIT Schedule of enrollment, interventions, and assessments.

SNAP-4, Swanson, Nolan and Pelham Rating Scale; PAE, prenatal alcohol exposure; HIW, Health Interview for Women; HIAFP, Health Interview for Foster and Adoptive Parents; MINI-KID, Mini International Neuropsychiatric Interview for Children and Adolescents; KBIT-2, Kaufman Brief Intelligence Test, Second Edition; PDS, Pubertal Development Scale; TNS; trigeminal nerve stimulation; CSHQ, Children’s Sleep Habits Questionnaire; ADHD-RS, ADHD Rating Scale; CGI-S/I, Clinician’s Global Impression Severity/Improvement; Conners 4, Conners 4 Parent Short Version; BRIEF II, Behavior Rating Inventory of Executive Function; CDI 2, Children’s Depression Inventory 2; RCAD, Revised Child Anxiety and Depression Scale Parent/Child Versions; ARI, Affective Reactivity Index Child/Parent.

https://doi.org/10.1371/journal.pone.0330986.g001

Participants

Children admitted to the study will be between 8 and 12 years of age with a history of ADHD with PAE. Primary caregivers will be referred to as “parents” with the understanding that they could be biological, foster, or adoptive parents. The study team will use a checklist of Inclusion/Exclusion criteria when making the enrollment decision for each participant. The team will also maintain a CONSORT-type diagram (S3 File) of participant screenings, exclusion, enrollment, retention, and dropout throughout the study. Data will specify reasons for study exclusion and dropout.

Trigeminal nerve stimulation (TNS) treatment

TNS instruction Instructions on the use of the TNS study device are provided to each family along with a chance to practice using the instrument before treatment begins.

Primary study device: Monarch® eTNS® System TNS is administered nightly for 4 weeks by the parent during sleep. Stimulation is performed using the Generation 1.0 Monarch® eTNS® System (NeuroSigma, Inc., Los Angeles), FDA-cleared for unmedicated pediatric ADHD. This device has been used safely and successfully in other prior and ongoing TNS trials at UCLA. The stimulator is worn on the child’s pajamas or T-shirt and is attached with thin wires to disposable, silver-gel, self-adhesive patch electrodes. Parents apply patches across their child’s forehead to provide bilateral stimulation of both V1 trigeminal branches for ~8 hr nightly. Patches are removed each morning. The active condition uses a 120-Hz repetition frequency, with 250-ms pulse width, and a duty cycle of 30 s on/30 s off. Current settings from 2–4 mA (range 0–10 mA) are established at baseline by titration, which identifies a stimulation level below the participant’s level of discomfort. Power is provided by 9-V Li rechargeable medical-grade batteries (iPower v.3), which are checked and replaced regularly. Families are informed at a scripted presentation that “pulses may come so fast or so slowly that the nerves in the forehead might or might not detect a sensation.” Each night parents turn on the device, press the “up” button until the device reaches the current level set for the patient at titration, pressing “down” to decrease by 0.2-mA steps in case of overshoot. Current to the patch is limited to a safe range (0–10 mA). Some patients may feel some sensation, which generally fades with time.

FDA-clearance for the Monarch eTNS device covers children with ADHD who are not currently taking ADHD medication. PAE does not exclude a child from this labelling but taking ADHD medication does. Our study does admit children who are taking ADHD medication. Our initial assessment found no evidence for additional risks of TNS due to PAE or to concurrent medication. While the initial trials of TNS for ADHD were performed on unmedicated children, the largest trial to date, the ATTENS trial in London [57], explicitly permits concurrent ADHD medication. For other major indications of TNS (depression, epilepsy, migraine) numerous clinical trials have allowed concurrent psychotropic medication without serious adverse events [58]. Therefore, we do not ask parents to take their children off medication. TNS has generally been well tolerated with infrequent and mild side effects across its indications. Nonetheless, we closely monitor for potential side effects and adverse events, including those associated with medication. The UCLA MIRB has classified use of TNS in medicated children and children with PAE in our study as “investigational use of a non-significant risk (NSR) device”. An NSR classification means, “risks no greater than those of everyday life”.

TNS treatment duration The treatment duration is set at 4 weeks as this was the optimal time for achieving positive changes in symptoms in the original studies of TNS in pediatric ADHD [36,37]. A follow-up period after 4 weeks is used to measure short-term maintenance of gains. Retention is encouraged by delaying participant compensation until after follow-up.

TNS Diary For each overnight session of TNS, the parent makes an entry into the TNS Diary. Items include start and end times for every day and week of treatment and current level. Purpose is to encourage adherence with the treatment program.

TNS Compliance Questionnaire This questionnaire measures daily compliance with treatment on a daily basis and includes: date, device not worn, stimulation level, time on device, time off device and explanation for any changes in usage not covered by the protocol.

Side Effects Rating Scale and Adverse Events Inventory [36]. These instruments assess potential side effects of TNS and adverse events (including serious adverse events) and were used in prior clinical trials of TNS for pediatric ADHD. (Side effects and adverse events were mild and few.) We slightly modified the Side Effects Rating Scale Parent Version to create an additional Side Effects Rating Scale Child Version worded in a way more easily understood by children. Both are completed during Pre-TNS Assessment and at the end of each week of treatment in the presence (telephone, Zoom, or in-person) of a study investigator. The Side Effects Rating Scale Parent is completed by the parent. The Side Effects Rating Scale Child is read to the child by a study investigator. Parents and children are generally advised to report serious emergent side effects or adverse events to the physician investigator as soon as possible for each occurrence.

Sleep quality: Children’s Sleep Habits Questionnaire (CSHQ; [59]). This is a validated, reliable parent-completed test of a child’s sleep quality and sleep behaviors. The CSHQ showed adequate internal consistency for a clinical sample (p = 0.78); alpha coefficients for the various subscales of the CSHQ ranged from 0.56 (Parasomnias) to 0.93 (Sleep-Disordered Breathing) for a sleep clinic group. Test-retest reliability was acceptable (0.79). CSHQ individual items, as well as the subscale and total scores consistently differentiated a community group from a sleep-disordered group, demonstrating validity. This measure revealed improvement in sleep with TNS in prior ADHD samples [36,37]. The CSHQ is administered weekly during treatment and at the Pre- and Post-TNS Assessments.

Pre- and Post-TNS treatment assessment measures

ADHD severity: ADHD-RS The ADHD Rating Scale (ADHD-RS; [60]) is a parent interview administered by a physician investigator that assesses severity of core symptoms (inattention, hyperactivity) of ADHD. Total Score on the ADHD-RS was the primary outcome in prior clinical trials of TNS for ADHD [36,37]. It is the primary efficacy measure in this trial. It is administered at Pre- and Post-TNS Assessments and at Follow-Up.

ADHD severity: CGI-S/I The Clinician’s Global Impression Severity (CGI-S) and Clinician’s Global Impression Improvement. (CGI-I; [61]) are secondary efficacy measures in this trial. These extremely widely used, multiply validated 7-point scales assess initial severity, respectively, improvement (or worsening) of core symptoms of a chosen mental disorder (here ADHD) based on a physician’s experience with typical patients. The CGI-S is administered at the Pre-TNS Assessment. The purpose is to serve as one metric of pretreatment severity of ADHD-like symptoms of PAE. The CGI-I is administered at the Post-TNS Assessment and at Follow-Up. The purpose is to serve as a metric of post-treatment change in severity of ADHD symptoms and maintenance of gains at follow-up.

ADHD severity: Conners 4 Parent Short Version (Conners 4 P; [62]. The Conners 4 is a standardized measure that provides a comprehensive assessment of symptoms and impairments associated with ADHD and common co-occurring problems and disorders in children and youth aged 6–18 years. Now fully digital, it provides online scoring for better data visualization, easy inventory management, a digital manual, and printable forms. It also provides a more comprehensive picture of how a rater approaches completing the measure, using updated validity scales, the number of omitted items, and the average number of items completed per minute. The Conners 4 has excellent internal consistency (median omega coefficient = 0.94), strong test-retest reliability (median r = 0.89), and convergent validity (median r = 0.73). The Conners 4 is administered during the Eligibility, Pre-TNS and Post-TNS Assessments.

Vitals The participant’s vitals (heart rate and blood pressure) are measured at the Pre- and Post-TNS Assessments.

Executive function: Behavior Rating Inventory of Executive Function (BRIEF II; [63]). The BRIEF II is a standardized validated assessment of executive functions for children and adolescents that is widely used in research. Executive function measures include inhibit, self-monitor, emotional control, initiate behavior, working memory, organization skill, task monitoring, and organization of materials. Summary scores include Behavioral Regulation, Cognitive Regulation, and Global Executive Control. We use the BRIEF II to assess severity of executive dysfunction. Children with ADHD and PAE have been found to have significant problems in executive function on parent ratings of the BRIEF II compared to typically developing controls [64]. The BRIEF II is administered at the Pre- and Post-TNS Assessments.

Executive function: NIH Toolbox Cognition Domain [65]. The NIH Toolbox is a multidimensional set of measures to assess neurological and behavioral function. It is a valid, reliable, brief, and state-of-the-art instrument. We administer the Cognition Domain to our child participants. The Cognition Domain measures basic cognitive and executive functions. The Cognition Domain yields a Cognitive Function Composite, Fluid Cognition Composite (Dimensional Change Card Sort, Flanker Inhibitory Control and Attention, Picture Sequence Memory, List Sorting, and Pattern Comparison measures), and Crystallized Cognition Composite (includes Picture Vocabulary and Reading Recognition measures) Scores. The NIH Toolbox is administered at the Pre- and Post-TNS Assessments.

Emotion regulation: NIH Toolbox Emotion Domain [65]. We administer the Emotion Domain to our child participants. We administer only the Emotion Control Domain to the parents. The Emotion Domain assesses aspects of the PAE behavioral phenotype described in DSM-5. The Emotion Domain for the child surveys Positive Affect, Emotional Support, Friendship, Loneliness, Perceived Rejection, Perceived Hostility, Self-Efficacy, Sadness, Perceived Stress, Fear, and Anger. The parent version of the Emotion Domain surveys parent impression of the child along the same features. Again, the Toolbox is given at the Pre- and Post-TNS Assessments

Mood: Children’s Depression Inventory 2 (CDI 2; [66]). The Children’s Depression Inventory 2 contains 28 items, each of which consists of three statements. For each item, the child is asked to select the statement that best describes his or her feelings. The assessment is designed for multiple settings, including schools, child clinics, pediatric practices, and child psychiatric settings. The CDI 2 assesses self-reported key symptoms of depression, such as feelings of worthlessness and loss of interest in activities, and supports early identification and diagnosis of depressive disorders. Importantly, suicidality as a potential study exclusion criterion is included in the assessment. The CDI 2 is administered at the Pre- and Post-TNS Assessments.

Mood: Revised Child Anxiety and Depression Scale Parent and Child Versions (RCADS; [67]). The RCADS assesses both the child report and parent report of youth’s symptoms of anxiety and depression across six subscales: social phobia, panic disorder, major depression, separation anxiety, generalized anxiety, and obsessive compulsive disorder. It also yields a Total Anxiety Scale (sum of the 5 anxiety subscales) and a Total Internalizing Scale (sum of all 6 subscales). One-week test-retest coefficients were good [68] with good concurrent validity compared to the Children’s Depression Inventory and with the Revised Children’s Manifest Anxiety Scale [67]. The RCADS is administered at the Pre- and Post-TNS Assessments.

Mood: Affective Reactivity Index Child and Parent (ARI; [69]). The ARI was developed to measure irritability in children from birth to 12 years. The ARI was specifically designed to obtain comparable information from youth and their parents. Using US- and UK-based samples, the parent- and self-report forms of the ARI showed excellent reliability and formed a single factor. In terms of validity, the parent- and self-reported ARI Total Score successfully differentiated cases from controls in clinical and community samples. The parent-rated ARI Total Score also differentiated between youth with severe mood dysregulation and youth with bipolar disorder. In the US sample, Cronbach’s alpha was 0.92 and 0.88, for the parent- and self-report scales, respectively. Regarding construct validity, the ARI showed a gradation with irritability significantly increasing from healthy volunteers through to severe mood dysregulation (SMD). The ARI is administered at the Pre- and Post-TNS Assessments.

Magnetic Resonance (MR) examinations of the brain This study explores possible brain bases of TNS therapy and predictors of clinical response. For these purposes, children undergo an ~ 75-min examination in a conventional clinical MRI scanner (3 T, 32-channel headcoil). Children are safety screened for MRI contraindications including metal in or on the body or clothing. Children’s heads are firmly and comfortably positioned in the scanner with ample head padding. An MRI-opaque Vitamin E capsule is taped to the right scalp to ensure proper left-right lateralization of images in post-processing. Ear plugs are provided to protect against loud scanner noise. Patient and scanner operator are in audio contact over a loudspeaker and microphone at all times. The patient also has an emergency squeeze bulb to sound an alarm in case of distress. Multiple whole-brain scans are acquired, each in a different MR modality. They include rapid scout structural scans, eyes-open resting-state fMRI (rsfMRI), high-resolution structural MRI, echo-planar spectroscopic imaging (EPSI), and diffusion tensor imaging (DTI). All of these scans are equivalent from a human subjects and safety point-of-view.

Parent and Child Satisfaction Parent and child satisfaction questionnaires are administered at Post-TNS Assessment to measure estimation of the difficulty in administering the treatment, its usefulness for helping the child, overall satisfaction with the outcome, and if parents would recommend the treatment to others.

Concurrent medication

Given frequent prescription of psychotropic medication in this population, recruiting exclusively unmedicated children would be impractical. Therefore, medications are allowed in this trial. Their use is included as covariates in statistical analyses. In particular, we control for atomoxetine and guanfacine use in the past two weeks prior to enrollment, as these affect the arousal system thought to be impacted by TNS [57,70]. Patients currently on stimulant medication are asked to withhold medication on assessment days. Otherwise medication continues throughout treatment.

Safety monitoring, adherence, compliance monitoring

Contraindications to TNS include metallic implants, e.g., cardiac and neurostimulation systems, and dermatitis or sensitive skin. The Monarch device should not be used in patients with body-worn devices (e.g., insulin pumps or transcutaneous vagal nerve stimulators). There are also hazards with improper use of the device or attaching the patches other than on the forehead. Concurrent use of cellular telephones can interfere with TNS. These TNS risks are mitigated by preselection of patients, by thorough instruction in proper use of the device, and by persistent monitoring for adverse events. For the MRI portion of the study, hazards and safety management are well known and not repeated here.

TNS side effects and adverse events TNS is generally well-tolerated. Side effects are relatively mild and include: bronchitis, headache, itching, light-headedness, nausea, poor appetite, skin rash, stomach ache, tooth pain, vomiting, trouble sleeping, nightmares, drowsiness, fatigue, tingling sensation, rapid heartbeat, constipation, frequent urination, increased appetite, and teeth clenching. These effects are typically transient. The study device has significant safety data and serious adverse events are not expected, although we do monitor for them. If any unanticipated problems related to the research involving risks to participants or others happen (including serious adverse events) these are reported to the IRB. Adverse events that are not serious but that are notable and could involve risks to participants are summarized in narrative form and submitted to the IRB at the time of continuing review.

During treatment, the parent monitors for side effects and adverse events and completes weekly interim assessments of side effects (Side Effects Rating Scale), adverse-events (Adverse Events Inquiry), and sleep quality (CSHQ). Parents are in regular contact with the study team and are encouraged to report side effects and adverse events promptly. The physician investigator treats or refers such conditions for treatment as needed and decides whether or not discontinuing TNS is called for. These measures mitigate the risk of adverse events which overall are reported as minimal and of low likely impact. The investigators discontinue TNS for any participant who, in the judgement of the study physician, experiences excessive risk (e.g., serious side-effects) or who requires prompt care (e.g., discovery of a serious incidental finding) that is incompatible with continued participation.

Strategies to improve adherence to treatment A key question regarding adherence is whether children will remove the TNS device overnight unbeknownst to their parents. Studies of TNS treatment of pediatric ADHD at UCLA to date are encouraging in that there have not been issues with children removing the device in these studies [36,37]. In principle, however, it could be different for children with ADHD and PAE. In addition to in-person training on the device, parents of each child are given a TNS Instructions and FAQ document at the beginning of treatment. Among several troubleshooting tips, parents are advised what to do if their child removes the device. If they catch it in the course of the night, they are advised to replace the device with fresh electrodes. If they do not become aware until the next morning, they are advised to note the incident in the TNS Diary and to contact the study team. When reapplying the device the next evening, parents are advised that putting a headband over the electrodes may help, especially if the child is a restless sleeper. Additionally, the parents are advised to ensure that no lotions or creams, that may facilitate slippage, are applied to the skin under or around the electrode.

Compliance monitoring TNS “compliance” is defined as the child wearing the device for 21 of 28 nights of treatment. The parent maintains a TNS Diary to ensure compliance, reinforced by daily telephone contact with investigative staff. Non-compliance is failure to wear the device for 7 hours or more on 8 or more nights during the treatment regimen. In such cases, we contemplate investigator-withdrawal of the child from the study. In the TNS Instructions and FAQ document and on the ICF, parents are informed that their child may be withdrawn from the study if he or she repeatedly removes the device overnight or otherwise fails to comply with study procedures. For participants who are withdrawn, all within-compliance data collected up to the time of withdrawal are retained and no further data are collected after withdarwal.

Statistical analysis

Primary objective The main objective of this study is to evaluate whether TNS treatment of ADHD in PAE is feasible under the conditions described. “Feasible” for this purpose means “safe, well tolerated, and promising efficacy”. The corresponding criteria are Safety: 1) No meaningful (i.e., serious morbidity or mortality) TNS-related adverse events; 2) Side effects requiring extensive remediation or interfering with study procedures in ≤3 patients (10%); Tolerability: 3) ≤3 patients (10%) withdrawing from the study based on side effects or poor tolerance of TNS; 4) TNS compliance ≥21/28 sessions (75%) in ≥24/30 patients (80%) (based on TNS diaries); Promise of Efficacy: 5) ≥25% reduction in ADHD-RS and/or CGI-I of 2 or 1 in ≥10 patients (33.3%). If these criteria are met, genuine efficacy can then be tested more rigorously in a future double-blind, sham-controlled RCT.

Secondary objectives: Behavioral Ancillary objectives include determining whether TNS treatment improves executive function, mood, and/or sleep. These will be tested by comparing Post-TNS to Pre-TNS scores on endpoints from the BRIEF II, NIH Toolbox, CDI 2, RCAD, ARI and CSHQ and looking for significant differences.

Secondary objectives: MR neuroimaging A final set of objectives is pursued by way of multimodal MRI measurements, including structural MRI, MRS, DTI, and rsfMRI. Briefly, we will test hypotheses regarding MR endpoints in anterior cingulate cortex, middle frontal cortex and inferior frontal cortex. These are brain regions which both show abnormalities in PAE and appear to be affected by TNS. The endpoints include local gyrification index (LGI; cortical curvature) and cortical myelin content measured by MRI, glutamate (Glu) concentration measured by MRS, mean diffusivity measured by DTI, and functional connectivity measured by rsfMRI. We hypothesize that group-mean Glu will increase and functional connectivity will decrease in these regions following TNS. We further hypothesize that low pre-TNS Glu, LGI and myelin and high MD and functional connectivity predict favorable post-TNS clinical response.

Data management Data are entered into an electronic database managed by the UCLA Semel Institute Biostatistics Core. Procedures include scanning for duplicate entries and range checks for variable values. Personal health information on participants is not shared outside the study. All members of the study team are certified in participant confidentiality. Paper records are kept in a locked filing cabinet; electronic records are stored on password-protected media.

General statistical procedures Mean differences and predictive associations are tested using the Linear Mixed Model in R with covariates and with last observation carried forward (LOCF) for early withdrawal patients. Covariates include demographics (sex, age, ethnicity), IQ Composite on the KBIT-2, maternal education (an established proxy for socioeconomic status), other teratogen exposures (tobacco, marijuana, illegal and prescription medications, caffeine), and clinical variables (DSM-5 comorbidities, child current medications). Possible covariates that are associated with outcomes at p < 0.10 will be included in final models. No correction for multiple comparisons is made for comparisons with a priori hypotheses. For other tests, FDR is applied. Efficacy is computed twice. Efficacy is computed once including all patients, both those who complete the study and those who were withdrawn using LOCF; efficacy is computed again including only completers. Both computations are useful and relevant. The former mitigates against bias in rejecting non-responders. The latter tells what efficacy is if compliance is achieved, a reasonable goal in most cases.