Double-Blind 2-Site Randomized Clinical Trial of Neurofeedback for ADHD

Study Overview
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Brief Summary
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Additional treatments with long-term benefit for attention-deficit/hyperactivity disorder (ADHD) are needed; one of the more promising is neurofeedback (EEG biofeedback), which has several randomized controlled trials showing significant benefit, but which are inconclusive because they were not double-blinded; the benefit could have been nonspecific (placebo response). Because of neurofeedback's labor-intensive cost (1 treatment costing as much as a month's medication), It is important to know how much specific benefit it yields. This 2- site placebo-controlled double-blind randomized clinical trial is the first to test for a specific benefit of neurofeedback with adequate power, the first designed and implemented collaboratively by experts in neurofeedback, ADHD, and clinical trials, the first to rigorously monitor quality not only of treatment, but also of placebo and blinding, and the first to follow up for 2 years to examine enduring effect; the results, whether positive or negative, will provide evidence for clinical practice and public policy regarding ADHD.

Detailed Description
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Current established, evidence-based treatments for attention-deficit/hyperactivity disorder (ADHD) are incompletely effective and not universally acceptable, and appear to wane in effect over time despite significant immediate benefit. E.g., FDA-approved medication, which shows large acute benefit, leaves a third of children only partially treated even when combined with behavioral treatment, and has not been demonstrated effective beyond 2 years. Additional treatments are needed that are effective with persisting benefit, preferably related to a biomarker predicting treatment response. A good candidate is electroencephalographic (EEG) biofeedback, called neurofeedback (NF). It is based on 1) observations that patients with ADHD often have excessive theta band (4-8 Hz) quantitative EEG power, low beta band (13-21 Hz) power, and excessive theta beta ratio (TBR), and 2) theoretical application of operant conditioning to correct this EEG imbalance. Metaanalysis of 6 randomized clinical trials found a large benefit for inattentive symptoms and medium benefit for hyperactive-impulsive symptoms. Unfortunately, none of these were blinded. Three of 4 small blinded studies found no advantage for NF over sham, but used suboptimal NF, leaving the situation inconclusive. Because of the expense and time required by NF, there is a public health need to determine whether it has a specific effect beyond the obvious nonspecific benefit of doing a focused activity several times a week with a friendly,encouraging adult who reinforces for attending to the task. Experts in NF, ADHD, clinical trials, statistics, and data management have joined to design a double-blind sham-controlled randomized clinical trial to answer several pressing scientific and clinical questions in a way that will be credible to all. At each of 2 sites (1 university & 1 NF clinic) 70 children (total N=140) age 7 through 10 with rigorously diagnosed moderate to severe ADHD and TBR>5 will be randomized in a 3:2 ratio to active TBR downtraining by NF vs. a sham training of equal duration, intensity, and appearance. To keep both participants and study staff blind, the sham will utilize pre-recorded EEGs with the participant's artifacts superimposed. The sham will be programmed into the equipment via internet by an off-site statistician-guided person who has no contact with participants. Treatment fidelity will be trained and monitored by 2 acknowledged NF leaders in a manner that protects blinding. Multi-domain assessments at baseline, mid-treatment, treatment end, and follow-ups at 6 months, 1 year, and 2 years will include parent and teacher ratings of symptoms & impairment, neuropsychological tests,clinician ratings, and quantitative EEG as well as tests of blinding and of sham inertness. Hypotheses include that NF will improve parent- and teacher-rated inattentive symptoms (primary outcome) and other outcomes more than sham,that benefit will persist for 2 years after training, that initial TBR will moderate treatment response, and that change in TBR will mediate response. Research Domain Criteria and EEG brain changes will be explored, including relationship of TBR to clinical symptoms, executive-function impairment, and sleep.

Official Title
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Double-Blind 2-Site Randomized Clinical Trial of Neurofeedback for ADHD

Conditions
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Attention-Deficit/Hyperactivity Disorder

Intervention / Treatment
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* Device: Neurofeedback treatment


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Boys and girls age 7 to 10 IQ>80 diagnosed DSM-5 ADHD inattentive presentation or combined presentation an item mean ≥1.5 sd above norms on a 0-3 metric both on parent ratings of either DSM-IV inattentive symptoms or all 18 ADHD symptoms and on teacher ratings of either inattentive symptoms or all 18 ADHD symptoms an eyes-open QEEG with theta-beta power ratio >4.5 at Cz or Fz Exclusion Criteria: comorbid disorder requiring psychoactive medication other than FDA-approved ADHD medication a medical disorder requiring systemic chronic medication with confounding psychoactive effects sleep apnea restless legs syndrome IQ <80 plans to move requiring school change during the next 3 months plans to start other ADHD treatment in the next 3 months antipsychotic agent in the 6 months prior to baseline assessment fluoxetine in the 4 weeks prior to baseline other psychiatric medication in the two weeks prior to baseline ->5 previous NF treatments Vitamin D deficiency will be a temporary exclusion

Ages Eligible for Study
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Minimum Age: 7 Years
Maximum Age: 10 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Neurofeedback treatment<br>The intended treatment is downtraining of theta power and uptraining of beta power for 38 treatments of active NF. | Device: Neurofeedback treatment<br>* Each session, the child participates in 5 training tasks. Each task lasts 5 minutes at the beginning and gradually increases to 9 minutes per task over the course of the neurofeedback as the child's attention span improves. We record four results for each of the 5 tasks: The number of half-second periods that they met the reward parameters (i.e. theta mV below threshold; beta mV above threshold) Average voltage of theta waves Average voltage of beta Average ratio of theta to beta power (TBR)<br>|
| Placebo Comparator: Sham neurofeedback treatment<br>Participants assigned to sham and their trainers will be fed EEG data from pre-recorded files (recorded during live clinical NF) rather than from the participant's live signal. In order to prevent unblinding of experienced NF trainers/technicians, artifacts from the participant's EMG and EOG are blended into the pre-recorded EEG so that the trainer controlling the feedback cannot differentiate between live and simulated data. To insure trainer/technician blindness, the pre-recorded EEG will be 38 consecutive EEGs from the same age-matched clinical case so that EEGs of the sham group will also show training progress over successive sessions, like real NF. | Device: Neurofeedback treatment<br>* Each session, the child participates in 5 training tasks. Each task lasts 5 minutes at the beginning and gradually increases to 9 minutes per task over the course of the neurofeedback as the child's attention span improves. We record four results for each of the 5 tasks: The number of half-second periods that they met the reward parameters (i.e. theta mV below threshold; beta mV above threshold) Average voltage of theta waves Average voltage of beta Average ratio of theta to beta power (TBR)<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Scores of Teacher and Parent Rated Inattentive Symptoms | The primary outcome measure is the composite scores of teacher and parent-rated inattentive symptoms on the Conners-3, rated on a scale of 0-3. Lower scores represent a better outcome, with a maximum score of 3 and a minimum score of 0. | Assessed at Baseline, Mid-treatment (2 months), End-treatment (4 months), at 6 month follow up, at 13 month follow up | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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EEG, ADHD, Attention-Deficit/Hyperactivity Disorder, neurofeedback