Characterizing Two Distinct ADHD Neurobiologies with fMRI

描述（由申请人提供）：本项目将使用功能磁共振成像（fMRI）来表征患有注意力缺陷/多动障碍（ADHD）的青少年的两个理论上可分离的神经认知通路的功能障碍。多动症是一种儿童期常见的疾病，通常会导致终身的教育、社会和职业障碍。几十年的研究大大改善了我们对这种疾病复杂性的认识。迄今为止，还没有一项研究成功地确定了一种有效的生物标记，一种单一的神经心理学测试，或一种特定的基因图谱，可以准确地识别多动症患者，部分原因是之前的研究得出了不一致的结果。许多研究人员得出结论，这是因为多动症的病因是多因素的，本质上可能是多基因的，涉及对大脑功能的许多微小影响。一致的证据表明，大脑额纹状体区域的低多巴胺能状态，假设导致至少两种形式的神经认知障碍，与冲动性多动症症状有关，在要求抑制反应的测试中，“执行”表现受损，以及在评估延迟强化不敏感的测试中，动机受损。尽管这一模型得到了神经心理学证据的支持，但功能性神经影像学研究尚未充分表征导致这些认知缺陷的生物学病理。以前的ADHD神经认知研究的不一致性很可能来自于检查具有异质病理的样本。了解神经生物学异质性的主要来源是未来ADHD研究中最重要的一步，最终将帮助临床医生更好地诊断和治疗这种疾病。本项目旨在通过检查神经心理学特征、中脑皮层和中脑边缘功能障碍以及候选基因易感性的关联，来表征这两种ADHD神经认知障碍的功能神经解剖学特征。参与者将是130名被诊断为合并亚型ADHD的青少年（DSM 314.01）和130名人口统计学匹配的健康对照。所有参与者都将接受严格的精神病学评估，几个不同认知领域的神经心理学评估，反应抑制和奖励系统大脑活动的fMRI测量，以及DAT1， DRD4和其他几个先前与ADHD相关的多巴胺相关遗传标记的基因分型。这些数据将使我们能够证实ADHD中存在两种独立的脑功能病理，并阐明脑功能紊乱、认知表现和基因型之间的关系。计划中的项目是功能性神经影像学、认知测试、临床评估和精神遗传学专家之间的高度合作。注意缺陷/多动障碍的神经生物学基础尚不清楚，因为尚未确定一种可靠的生物标志物或确定的疾病测试。对多动症青少年的认知研究表明，冲动行为可能源于两种明显不同类型的神经生物学功能障碍。该项目将使用功能性磁共振成像（fMRI）将ADHD青少年的这两种异常脑功能与特定类型的神经心理功能障碍和某些遗传标记联系起来，为临床使用这些工具更精确地诊断生物学上有意义的ADHD亚型提供支持。公共卫生相关性：注意力缺陷/多动障碍的神经生物学基础尚不清楚，因为尚未确定该障碍的单一可靠的生物标志物或明确的测试。对多动症青少年的认知研究表明，冲动行为可能源于两种明显不同类型的神经生物学功能障碍。该项目将使用功能性磁共振成像（fMRI）将ADHD青少年的这两种异常脑功能与特定类型的神经心理功能障碍和某些遗传标记联系起来，为临床使用这些工具更精确地诊断生物学上有意义的ADHD亚型提供支持。

DESCRIPTION (provided by applicant): This project will use functional magnetic resonance imaging (fMRI) to characterize dysfunction in two theoretically separable neurocognitive pathways in adolescents with Attention-Deficit/Hyperactivity Disorder (ADHD). ADHD is a common disorder arising in childhood that often results in lifelong educational, social, and occupational impairment. Decades of research has greatly refined our appreciation of the disorder's complexity. To date, no study has managed to identify an effective biological marker, a single neuropsychological test, or a specific genetic profile that accurately identifies persons with ADHD, in part because previous studies have produced inconsistent findings. Many researchers have concluded that this is because the etiology of ADHD is multi-factorial, probably polygenetic in nature, involving numerous small influences on brain function. Consistent evidence points to a hypodopaminergic state in frontostriatal brain regions, hypothesized to result in at least two forms of neurocognitive impairment linked to impulsive ADHD symptoms impaired `executive' performance on tests requiring inhibition of response, and impaired motivation measured by tests assessing insensitivity to delayed reinforcement. Although this model is supported by neuropsychological evidence, functional neuroimaging studies have not yet fully characterized the biological pathology giving rise to these cognitive deficits. It is likely that much of the inconsistency in previous ADHD neurocognitive research results from examining samples with heterogeneous pathologies. Understanding the major sources of neurobiological heterogeneity is the most significant step in future research of ADHD, and ultimately will help clinicians better diagnose and treat the disorder. This project seeks to characterize the functional neuroanatomy of these two ADHD neurocognitive impairments by examining the association of neuropsychological profile, mesocortical and mesolimbic brain dysfunction, and candidate gene susceptibilities. Participants will be 130 adolescents diagnosed with Combined-subtype ADHD (DSM 314.01) and 130 demographically-matched healthy controls. All participants will undergo rigorous psychiatric evaluation, neuropsychological assessment of several different cognitive domains, fMRI measurement of response inhibition and reward system brain activity, and genotyping DAT1, DRD4, plus several other dopamine-related genetic markers previously linked to ADHD. These data will allow us to validate the presence of two separate brain function pathologies in ADHD and to clarify relationships among disordered brain function, cognitive performance and genotype. The planned project is highly collaborative between experts in functional neuroimaging, cognitive testing, clinical assessment and psychiatric genetics. The neurobiological basis of Attention-Deficit/Hyperactivity Disorder is poorly understood because a single reliable biomarker or definitive test for the disorder has yet to be identified. There is evidence from cognitive studies of ADHD youth that impulsive behavior may arise from two markedly different types of neurobiological dysfunction. This project will use functional magnetic resonance imaging (fMRI) to link these two profiles of abnormal brain function in ADHD adolescents to specific types of neuropsychological dysfunction and to certain genetic markers, providing support for the clinical use of these tools to more precisely diagnose biologically-meaningful subtypes of ADHD. PUBLIC HEALTH RELEVANCE: The neurobiological basis of Attention-Deficit/Hyperactivity Disorder is poorly understood because a single reliable biomarker or definitive test for the disorder has yet to be identified. There is evidence from cognitive studies of ADHD youth that impulsive behavior may arise from two markedly different types of neurobiological dysfunction. This project will use functional magnetic resonance imaging (fMRI) to link these two profiles of abnormal brain function in ADHD adolescents to specific types of neuropsychological dysfunction and to certain genetic markers, providing support for the clinical use of these tools to more precisely diagnose biologically-meaningful subtypes of ADHD.