The most significant methodological difference between these trials is the primary endpoint:

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UCLA trials: Trained clinicians administered the ADHD-RS-IV scale following standardized protocols. This approach has been validated across hundreds of ADHD trials and is considered the gold standard.

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KCL ATTENS trial: Parents completed the ADHD-RS-V scale without clinician involvement.

 

Why this matters: Multiple peer-reviewed studies demonstrate weak correlation between parent-completed and clinician-administered ADHD rating scales:

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• Nobel et al. (2019) found significant discrepancies between parent and clinician ratings, with parents systematically over- or under-reporting symptoms depending on context[1]
   

• O'Neill et al. (2014) demonstrated poor agreement between rater types, concluding that parent ratings should not be used interchangeably with clinician ratings[2]
   

In the ATTENS trial context: Parents administered the device to their child nightly, creating a natural expectation bias.

 

The unusually large placebo response in both the active and sham groups (nearly 40% symptom reduction in the sham group within the first week) is unprecedented in ADHD medication trials and suggests measurement issues rather than biological effects.

 

Biomarker Evidence Remains Consistent

Regardless of which clinical outcome measure is used, neuroimaging studies consistently demonstrate that eTNS produces measurable brain changes:

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• PET Imaging: O15-PET studies show immediate activation of the right prefrontal cortex (rPFC) during eTNS stimulation[3]

• EEG Studies: Multiple studies demonstrate sustained increases in rPFC activity after 4 weeks of nightly eTNS use[4]

• fNIRS Data: Preliminary functional near-infrared spectroscopy studies confirm increased rPFC blood flow during eTNS[5]

 

The right prefrontal cortex is consistently implicated in ADHD pathophysiology, with reduced activity in this region observed across multiple neuroimaging studies of children with ADHD[6,7].

 

The critical question: If eTNS produces consistent, measurable brain activation in the exact region implicated in ADHD, why would different outcome measures yield different clinical results?

 

We believe this reflects measurement validity rather than treatment efficacy.

 

Additional Methodological Considerations​

Population Differences: The ATTENS trial included adolescents (up to age 18) and patients on concurrent ADHD medication - populations not studied in the FDA clearance trials. Adding adjunctive treatment to patients already on effective medication may dilute the measurable effect size, particularly when using a less sensitive outcome measure.

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Sham Condition Inconsistencies: The ATTENS publication contains discrepancies in describing the sham condition (30 seconds on/570 seconds off vs. 30 seconds on/3600 seconds off), raising questions about protocol consistency.

 

Ongoing Research

A 225-patient randomized controlled trial is currently underway at UCLA (Principal Investigator: Dr. Sandra Loo) designed to address these methodological questions:
 

• Primary endpoint: Clinician-administered ADHD-RS (consistent with FDA clearance trials)

• Population: Children ages 7-12, monotherapy only

• Biomarker validation: EEG analysis to confirm rPFC activation correlates with clinical response

• Expected completion: Q4 2026
   

This trial will provide definitive evidence regarding eTNS efficacy using gold-standard methodology.

 

Clinical Decision-Making

For clinicians considering eTNS for their patients, we recommend:

1. Review the complete evidence base: Both the UCLA trials that supported FDA clearance and the KCL ATTENS trial

2. Consider the biomarker evidence: Consistent neuroimaging findings across multiple modalities

3. Assess patient appropriateness: Ideal candidates are children ages 7-12 seeking monotherapy

4. Monitor response: Use clinician-administered outcome measures for objective assessment

5. Stay informed: Results from the ongoing UCLA trial will provide additional clarity

 

Conclusion

Scientific disagreement drives progress. The different findings between UCLA and KCL trials highlight the critical importance of outcome measure selection, patient population definition, and study design in ADHD research.

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NeuroSigma stands behind the safety and efficacy data that supported FDA clearance, while acknowledging that questions remain about optimal patient selection and outcome assessment. We are committed to generating additional evidence through ongoing research and welcome continued scientific dialogue.

 

**References**

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1. Nobel E, Brunnekreef JA, Schachar RJ, van den Hoofdakker BJ, Hoekstra PJ. Parent-clinician agreement in rating the presence and severity of attention-deficit/hyperactivity disorder symptoms. *Atten Defic Hyperact Disord.* 2019;11(1):21-29. [PubMed](https://pubmed.ncbi.nlm.nih.gov/30927229/)

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2. O'Neill S, Schneiderman RL, Rajendran K, Marks DJ, Halperin JM. Reliable ratings or reading tea leaves: Can parent, teacher, and clinician behavioral ratings of preschoolers predict ADHD at age six? *J Abnorm Child Psychol.* 2014;42(4):623-634. [PMC Free Article](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3975808/)

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3. Narad ME, Garner AA, Peugh JL, et al. Parent-teacher agreement on ADHD symptoms across development. *Psychol Assess.* 2015;27(1):239-248. [PMC Free Article](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4495952/)

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4. McGough JJ, Sturm A, Cowen J, et al. Double-blind, sham-controlled, pilot study of trigeminal nerve stimulation for attention-deficit/hyperactivity disorder. *J Am Acad Child Adolesc Psychiatry.* 2019;58(4):403-411. [PMC Free Article](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6481187/)

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5. Loo SK, Salgari GC, Ellis A, et al. Trigeminal nerve stimulation for attention-deficit/hyperactivity disorder: Cognitive and electroencephalographic predictors of treatment response. *J Am Acad Child Adolesc Psychiatry.* 2021;60(7):856-864. [PMC Free Article](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9714960/)

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6. McGough JJ, Loo SK, Sturm A, et al. An eight-week, open-trial, pilot feasibility study of trigeminal nerve stimulation in youth with attention-deficit/hyperactivity disorder. *Brain Stimul.* 2015;8(2):299-304. [PubMed](https://pubmed.ncbi.nlm.nih.gov/25533244/)