Neuroimaging and Behavioral Biomarkers for ADHD in Children

儿童多动症的神经影像和行为生物标志物

• 批准号: 7836088
• 负责人: MARTIN H TEICHER
• 金额: $ 50万
• 依托单位: MCLEAN HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-30 至 2011-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7836088
• 关键词: 12 year old; 17 year old; Address; Adult; Affect; Age; Area; Arts; Attention deficit hyperactivity disorder; Behavior Disorders; Behavioral; Biological Markers; Bipolar Disorder; Child; Childhood; Circadian Dysregulation; Circadian Rhythms; Clinical; DSM-IV; Data; Diagnosis; Disease; Functional disorder; Gender; Genetic Predisposition to Disease; Grant; Grouping; Hand; Head Movements; Hyperactive behavior; Impairment; Individual; Lead; Left; Measures; Mental disorders; Methylphenidate; Mood Disorders; Periodicity; Prefrontal Cortex; Prevalence; Process; Recording of previous events; Relaxation; Research; Sampling; Schools; Sensitivity and Specificity; Sleep; Symptoms; Testing; Time; Validation; actigraphy; aged; boys; childhood bipolar disorder; design; disorder control; disorder subtype; girls; male; meetings; neuroimaging; putamen

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.

描述（由申请人提供）：本申请涉及广泛的挑战领域03：生物标志物的发现和验证，以及特定的挑战主题03- mh -101：精神障碍中的生物标志物。注意力缺陷/多动障碍（ADHD）是儿童时期最普遍的行为障碍，影响着美国约600万学童和1000万成年人。然而，多动症是一种非常有争议的疾病。一些批评人士质疑其有效性，另一些人则认为，这些标准过于宽泛、过于主观，或者对发展不敏感。儿童双相情感障碍是一个更有争议的诊断，与专家之间在标准和患病率方面的广泛差异有关。这项挑战基金的目的是严格测试我们的初步发现，确定三种潜在的生物标志物。其中两个似乎是ADHD的标记，在有限的样本中区分ADHD儿童和对照组具有完美的准确性。然而，这些研究仅包括符合联合亚型标准的9 - 12岁男孩，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独立样本中复制，扩展到女孩，老年人和年轻人，所有ADHD亚型，以及没有精神药物治疗史的ADHD受试者。第三种标记似乎可以识别患有双相情感障碍的儿童，在103个受试者的样本中，将双相情感障碍与多动症和对照组区分开来的灵敏度和特异性为94%。本样本中的双相儿童符合DSM-IV双相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志物，以解决两个严重但重叠的挑战。一方面，确定正常的结束和ADHD的开始是一个挑战。另一方面，确定多动、破坏性、攻击性和情绪不稳定的儿童是患有多动症、双相情感障碍，还是两者兼而有之，还是完全不同的疾病，这是一个挑战。第一个生物标记来自于对头部运动和位置稳定性的最先进的非线性分析。最大Lyapunov指数从62个匹配对照中区分出62名ADHD儿童，准确度为完美（ROC = 1.0）。第二个指标是测量左侧壳核和右侧背外侧前额叶皮层的区域t2松弛时间（T2RT）。第三个标志是由睡眠、白天多动和昼夜节律失调的活动记录仪测量的组合。患有DSM-IV双相情感障碍的儿童在睡眠和昼夜节律方面比患有ADHD和共病情绪障碍的儿童有更大的损害。这些潜在标记的有效性将在160名6-17岁儿童（n=80神经影像学）的混合性别样本中进行测试（80名ADHD儿童，40名躁郁症儿童，40名对照组）。识别ADHD与正常以及ADHD与双相障碍的区别标志可能会对该领域产生巨大影响。这些发现（如果得到进一步证实）可能会导致临床标准的修改，并迅速推进对多动症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。这项挑战基金旨在测试两种潜在生物标志物的有效性，在初步研究中，这两种生物标志物能够完全准确地区分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和健康正常对照区分开来。这些指标将在160名男女儿童（6-17岁）中进行评估。80名研究对象患有多动症，40名患有双相情感障碍，40名作为健康对照。