Double-Blind Randomized Clinical Trial of EEG Neurofeedback for ADHD

描述(由申请人提供)：目前已建立的针对注意力缺陷/多动障碍(ADHD)的循证治疗方法并不完全有效，也不是所有人都能接受，而且尽管有显著的立竿见影的效果，但随着时间的推移，效果似乎会逐渐减弱。例如，FDA批准的药物显示出巨大的急性益处，即使与行为治疗相结合，三分之一的儿童也只得到部分治疗，而且在两年后还没有被证明有效。需要其他有效的治疗，最好是与预测治疗反应的生物标志物相关的持久受益。一个很好的候选者是脑电(EEG)生物反馈，称为神经反馈(NF)。这是基于1)观察到ADHD患者经常有过多的theta频段(4-8赫兹)定量脑电功率，低的β频段(13-21赫兹)功率和过高的theta-beta比率(TBR)，以及2)操作性条件反射的理论应用来纠正这种脑电失衡。对6个随机临床试验的荟萃分析发现，对注意力不集中的症状有很大的益处，对多动-冲动症状有中等的益处。不幸的是，这些都不是盲目的。4项小规模盲法研究中有3项发现，与假手术相比，核因子没有优势，但使用了次优的核因子，使情况没有定论。由于NF所需的费用和时间，公共卫生需要确定它是否具有特定的影响，而不是每周与一名友好、鼓励的成年人一起进行几次有重点的活动的明显的非特定好处，该成年人加强了对任务的关注。神经营养、多动症、临床试验、统计学、广告数据管理方面的专家已经联合设计了一项双盲假对照随机临床试验，以一种对所有人都可信的方式回答几个紧迫的科学和临床问题。在2个地点(1所大学和1个神经营养不良诊所)的每个地点(1所大学和1所神经营养不良诊所)，70名7到10岁的儿童(总N=140)被严格诊断为中到重度ADHD和TBR&GT；5将以3：2的比例随机分配到由NF进行的主动TBR下训练与相同持续时间、强度和外观的假训练中。为了让参与者和研究人员都失明，假人将使用预先记录的脑电波，上面叠加了参与者的人工制品。这场骗局将由一名与参与者没有联系的非现场统计学家指导的人员通过互联网编程到设备中。治疗忠诚度将由2名公认的核因子领导人以保护失明的方式进行培训和监测。在基线、治疗中期、治疗结束和6个月、1年和2年的随访中进行的多领域评估将包括家长和教师对症状和损害的评级、神经心理测试、临床医生评级和定量脑电以及失明和虚假惰性测试。这些假设包括：与Sham相比，NF将更好地改善家长和教师评定的注意力不集中症状(主要结果)和其他结果，这种益处将在培训后持续两年，初始TBR将缓和治疗反应，以及TBR的变化将中介反应。研究领域的标准和脑电波的变化，包括脑干阻力与临床症状、执行功能受损和睡眠的关系。

DESCRIPTION (provided by applicant): 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. Meta- analysis 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, ad 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 tha 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.