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：生物标志物发现和验证，以及特定的挑战主题03-MH-101：精神疾病中的生物标志物。注意力缺陷/多动障碍（ADHD）是儿童期最普遍的行为障碍，影响着美国约600万学龄儿童和1000万成年人。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过于宽泛，过于主观，或者对发展不敏感。儿童双相情感障碍是一个更具争议的诊断，与专家之间的标准和患病率的广泛差异有关。这项挑战资助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志物。其中两个似乎是ADHD的标志物，在有限的样本中区分ADHD儿童和对照儿童具有完美的准确性。然而，这些研究仅包括9 - 12岁的男孩，他们符合联合亚型的标准，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复制，扩展到女孩，老年人和年轻人，所有ADHD亚型，以及既往没有精神病治疗史的ADHD受试者。第三个标志物似乎可以识别双相情感障碍儿童，在103名受试者的样本中，将双相情感障碍与ADHD和对照组区分开来的敏感性和特异性为94%。该样本中的双相情感障碍儿童符合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种潜在的生物标志物，以解决两个严重但重叠的挑战。一方面，确定正常结束的地方和ADHD开始的地方是一个挑战。另一方面，确定多动、破坏性、攻击性和情绪不稳定的儿童是否患有多动症、双相情感障碍，或者两者兼而有之，或者完全不同的东西，也是一个挑战。第一个生物标志物来自对头部运动和位置稳定性的最先进的非线性分析。最大李雅普诺夫指数区分62 ADHD儿童62匹配的控制与完美的准确性（ROC = 1.0）。第二个标记物是左壳核和右背外侧前额叶皮层的区域T2弛豫时间（T2 RT）的测量。第三个标志物是睡眠、白天多动和昼夜节律失调的活动记录仪测量的复合物。DSM-IV双相情感障碍的儿童在睡眠和昼夜节律方面比ADHD和共病情绪障碍的儿童有更大的损害。这些潜在标志物的有效性将在160名6-17岁儿童（80名ADHD，40名双相情感障碍，40名对照）的混合性别样本中进行测试（n=80神经成像）。识别区分ADHD与正常ADHD和ADHD与双相情感障碍的标志物可能会对该领域产生巨大影响。这些发现（如果进一步验证）可以导致临床标准的修改，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。这项挑战补助金旨在测试两种潜在生物标志物的有效性，这些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。还将研究第三种生物标志物，以94%的灵敏度和特异性将双相情感障碍儿童与ADHD受试者和健康正常对照区分开来。将在160名男女儿童（6-17岁）中评估这些标志物。80名受试者患有ADHD，40名患有双相情感障碍，40名为健康对照。

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.