Developmental Pilot Study of External Trigeminal Nerve Stimulation for ADHD

注意力缺陷/多动障碍（ADHD）估计影响高达9.5%的学龄儿童和4.4%的成年人。ADHD与增加的功能障碍、共病精神病理学和总体医疗保健费用相关。虽然采用了各种心理社会干预措施，但药物仍然是ADHD治疗的主要手段。据估计，在美国有超过280万儿童被处方精神兴奋剂，主要用于ADHD。尽管这些药物在急性治疗中通常是安全有效的，但仍存在相当大的副作用和缺乏已证明的长期益处。父母对使用ADHD药物的态度非常矛盾。虽然对多动症的非药物治疗方法有很大的需求，但大多数流行的替代方法与对大脑过程的任何机械理解无关，同样缺乏重要的科学证据来支持它们的使用。外部三叉神经刺激（eTNS）是一种非侵入性的脑调制方法，在治疗成人耐药性癫痫和抑郁症方面取得了成功。在eTNS中，三叉神经通过应用于前额并在睡眠期间佩戴的电极接收低电流电刺激。初步的成人研究显示，情绪、睡眠和注意力都有显著改善。PET成像显示，在涉及注意力和执行功能的大脑区域中存在急性eTNS相关激活。基于这项工作的初步儿科研究评估了eTNS治疗ADHD的可行性。结果表明，eTNS耐受性和接受性良好，并与ADHD症状和反应抑制和工作记忆的实验室测量的显着改善。该R34提出了一个为期三年的临床试验开发项目，以进一步标准化eTNS，为确定的ADHD疗效试验做准备，并阐明潜在的大脑机制，这些机制可能支持eTNS在ADHD以及其他行为，情绪和认知障碍中的使用。该项目是一项为期四周的双盲随机试验，比较活性与假eTNS，然后在治疗停止后进行为期四周的随访。参与者将通过脑电图（EEG）对行为评级、认知过程和皮层激活进行重复评估。本研究将评估eTNS治疗ADHD的首项随机对照试验中不同条件下的结局轨迹差异、假eTNS作为设盲对照的有效性和保真度、关于反应发生和抵消的时程效应以及与治疗结局相关的脑变化的潜在机制。该提案与NIMH的几个优先事项一致，包括开发创新干预措施和干预研究设计，开发对大脑疾病过程的综合理解，为理解精神疾病提供基础，并评估大脑有效干预措施的作用机制。

DESCRIPTION (provided by applicant): Attention-Deficit/Hyperactivity Disorder (ADHD) is estimated to affect up to 9.5% of school-aged children and 4.4% of adults. ADHD is associated with increased functional impairments, comorbid psychopathology, and overall health care costs. Although various psychosocial interventions are employed, medication remains the mainstay of ADHD treatment. It is estimated that over 2.8 million children in the United States are prescribed psychostimulants, mostly for ADHD. Although these are generally safe and effective in acute treatment, considerable concerns remain about side effects and the absence of demonstrated long-term benefit. Parents are highly ambivalent about using ADHD medications. While there is great demand for non- medication approaches to ADHD, most popular alternatives are not linked to any mechanistic understanding of brain processes and similarly lack significant scientific evidence to support their use. External trigeminal nerve stimulation (eTNS) is a non-invasive method of brain modulation with demonstrated success in treating adults with medication-resistant epilepsy and depression. In eTNS, the trigeminal nerve receives low current electrical stimulation via an electrode applied to the forehead and worn during sleep. Preliminary adult studies revealed significant improvements in mood, sleep, and attention. PET imaging demonstrated acute eTNS-related activation in brain areas involved in attention and executive functioning. A preliminary pediatric study based on this work assessed the feasibility of eTNS for ADHD. Results demonstrated that eTNS was well tolerated and accepted, and was associated with significant improvements in ADHD symptoms and laboratory measures of response inhibition and working memory. This R34 proposes a three-year clinical trial development project to further standardize eTNS in preparation for definitive ADHD efficacy trials and to elucidate underlying brain mechanisms that will potentially support use of eTNS in ADHD as well as other behavioral, emotional, and cognitive disorders. The project is a four-week double-blind randomized trial of active vs. sham eTNS followed by four weeks follow-up after treatment discontinuation. Participants will have repeated assessments on behavioral ratings, cognitive processes, and cortical activation via electroencephalography (EEG). This study will assess differences in outcome trajectories by condition in the first randomized controlled trial of eTNS for ADHD, validity and fidelity of sham eTNS as a blinded control, time course effects regarding onset and offset of response, and underlying mechanisms of brain change that are associated with treatment outcomes. The proposal is consistent with several NIMH priorities, including the development of innovative interventions and designs for intervention studies, development of an integrated understanding of brain disorder processes that provide the foundation for understanding mental disorders, and assessment of the mechanisms of action of efficacious interventions in the brain.