Neuroimaging and Behavioral Biomarkers for ADHD in Children

描述(由申请人提供)：本申请涉及广泛的挑战领域03：生物标记物的发现和验证，以及特定的挑战主题03-MH-101：精神疾病中的生物标记物。注意力缺陷/多动障碍(ADHD)是最常见的儿童行为障碍，在美国约有600万学龄儿童和1000万成年人受到影响。然而，ADHD是一种非常有争议的疾病。一些批评者质疑它的有效性，另一些人则认为标准太宽泛、太主观，或者对发展不敏感。儿童双相情感障碍是一种更具争议性的诊断，与专家在标准和患病率上的广泛差异有关。这项挑战拨款的目的是严格测试我们的初步发现，确定三个潜在的生物标记物。其中两个似乎是ADHD的标记，在有限样本中区分ADHD儿童和对照组方面具有完美的准确性。然而，这些研究只包括9-12岁的男孩，他们符合合并亚型的标准，并且以前曾接受过哌醋甲酯(MPH)治疗。关键是要确定这些发现是否可以在一个独立的样本中重复，扩展到女孩、年长和年轻的人，所有的ADHD亚型，以及以前没有精神药物治疗史的ADHD受试者。第三个标记物似乎可以识别双相情感障碍的儿童，在103名受试者中，双相情感障碍与ADHD和对照组的区分具有94%的敏感性和特异性。此样本中的双相儿童符合DSM-IV双相情感障碍的严格操作标准。因此，我们建议严格评估三个潜在的生物标记物，以应对两个严峻但重叠的挑战。一方面，存在着识别正常结束和ADHD开始的挑战。另一方面，还有一个挑战是确定过度活跃、捣乱、攻击性和情绪不稳定的儿童是否患有ADHD、双相情感障碍、两者都有，或者是完全不同的东西。第一个生物标记物来自对头部运动和位置稳定性的最先进的非线性分析。最大Lyapunov指数对62名ADHD儿童和62名匹配对照儿童的判别准确率非常高(ROC=1.0)。第二个标记是测量左侧壳核和右侧背外侧前额叶皮质的局部T2-松弛时间(T2RT)。第三个指标是睡眠、日间多动和昼夜节律失调的动图测量的组合。患有DSM-IV双相情感障碍的儿童在睡眠和昼夜节律性方面的障碍比患有ADHD和共病情绪障碍的儿童更严重。这些潜在标记物的有效性将在160名6-17岁儿童(n=80名神经影像)的混合性别样本中进行测试(80名ADHD，40名双相情感障碍儿童，40名对照儿童)。识别区分ADHD与正常、ADHD与躁郁症的标志物可能会对该领域产生巨大影响。这些发现(如果进一步证实)可能导致临床标准的修订，并迅速推进对ADHD和儿童双相情感障碍的遗传学、病因学、病理生理学和治疗的研究。这项挑战奖励旨在测试两个潜在生物标志物的有效性，这两个潜在的生物标志物在初步研究中完全准确地区分了患有注意力缺陷多动障碍(ADHD)的男孩和对照组。第三个生物标记物也将被研究，以94%的灵敏度和特异度区分双相情感障碍儿童与ADHD和健康的正常对照。这些标记物将在160名儿童(6-17岁)中进行评估，无论男女。80名受试者将患有ADHD，40名双相情感障碍患者，40名健康对照组。

DESCRIPTION (provided by applicant): This application addresses broad Challenge Area 03: Biomarker Discovery and Validation, and the specific Challenge Topic 03-MH-101: Biomarkers in Mental Disorders. Attention-deficit/hyperactivity disorder (ADHD) is the most prevalent behavioral disorder of childhood affecting about 6 million school children and perhaps 10 million adults in the US. ADHD is however a very controversial disorder. Some critics question its validity, others argue that the criteria are too broad, too subjective, or not developmentally sensitive. Pediatric bipolar disorder is an even more controversial diagnosis, associated with widespread disparity between experts in criteria and prevalence rates. The aim of this Challenge Grant is to rigorously test our preliminary findings identifying three potential biomarkers. Two of these appear to be markers for ADHD that had perfect accuracy in discriminating between children with ADHD and controls in limited samples. However, these studies only included boys aged 9 - 12 who met criteria for Combined Subtype, and had been previously treated with methylphenidate (MPH). It is critical to ascertain if these findings can be replicated in an independent sample, extended to girls, older and younger individuals, to all ADHD subtypes, and to ADHD subjects with no prior history of psychotropic treatment. The third marker appears to identify children with bipolar disorder, and in a sample of 103 subjects distinguished bipolar from ADHD and controls with 94% sensitivity and specificity. Bipolar children in this sample met strict operational criteria for DSM-IV bipolar disorder. Hence, we propose to rigorously evaluate three potential biomarkers that address two severe but overlapping challenges. On one hand, there is the challenge of identifying where normal ends and where ADHD begins. On the other hand, there is the challenge of determining whether hyperactive, disruptive, aggressive and emotionally labile children have ADHD, bipolar disorder, both, or something entirely different. The first biomarker emerged from a state-of-the-art non-linear analysis of head movements and positional stability. The maximum Lyapunov exponent discriminated 62 ADHD children from 62 matched controls with perfect accuracy (ROC = 1.0). The second marker is a measure of regional T2-relaxation time (T2RT) in left putamen and right dorsolateral prefrontal cortex. The third marker is a composite of actigraph measures of sleep, daytime hyperactivity and circadian dysregulation. Children with DSM-IV bipolar disorder had greater impairments in sleep and circadian rhythmicity than children with ADHD and comorbid mood disorders. The validity of these potential markers will be tested in a mixed gender sample of 160 children (80 ADHD, 40 bipolar, 40 control) between 6-17 years of age (n=80 neuroimaging). Identifying markers that distinguish ADHD from normal and ADHD from bipolar could have an enormous impact on the field. These findings (if further validated) can lead to a revamping of clinical criteria, and rapidly advance research into the genetics, etiology, pathophysiology and treatment of ADHD and pediatric bipolar disorder. This Challenge Grant is designed to test the validity of two potential biomarkers that in preliminary studies distinguished boys with Attention-Deficit Hyperactivity Disorder (ADHD) from controls with complete accuracy. A third biomarker will also be studied that distinguished children with bipolar disorder from subjects with ADHD and healthy normal controls with 94% sensitivity and specificity. These markers will be assessed in 160 children (6-17 years of age) from both genders. Eighty subjects will have ADHD, 40 bipolar disorder, and 40 will be healthy controls.