Characterizing Two Distinct ADHD Neurobiologies with fMRI

描述(申请人提供)：这个项目将使用功能磁共振成像(FMRI)来描述患有注意力缺陷/多动障碍(ADHD)的青少年在两条理论上可分离的神经认知通路中的功能障碍。ADHD是一种在儿童时期出现的常见疾病，通常会导致终身教育、社会和职业损害。几十年的研究大大提高了我们对这种疾病的复杂性的认识。到目前为止，还没有研究设法确定一个有效的生物标记物、单一的神经心理测试或特定的基因图谱来准确识别ADHD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ADHD的病因是多因素的，可能是多基因的，涉及到许多对大脑功能的微小影响。一致的证据表明，额纹状体脑区处于低多巴胺状态，假设导致至少两种形式的神经认知障碍，与冲动性ADHD症状有关，损害了在需要抑制反应的测试中的执行表现，以及通过评估对延迟强化不敏感的测试衡量的动机受损。尽管这一模型得到了神经心理学证据的支持，但功能神经成像研究尚未完全表征导致这些认知缺陷的生物病理。以前的ADHD神经认知研究中的许多不一致之处很可能是因为检查了具有不同病理特征的样本。了解神经生物学异质性的主要来源是ADHD未来研究中最重要的一步，最终将有助于临床医生更好地诊断和治疗该疾病。本项目旨在通过研究神经心理特征、中皮质和中边缘脑功能障碍以及候选基因易感性之间的关系来描述这两种ADHD神经认知障碍的功能神经解剖学特征。参与者包括130名被诊断患有混合型多动症(需求侧管理314.01)的青少年和130名人口统计学上匹配的健康对照。所有参与者都将接受严格的精神评估、对几个不同认知领域的神经心理评估、反应抑制和奖励系统大脑活动的fMRI测量，以及对DAT1、DRD4和其他几个以前与ADHD有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验证ADHD中存在两种不同的大脑功能病理，并澄清大脑功能紊乱、认知表现和基因之间的关系。计划中的项目是功能神经成像、认知测试、临床评估和精神遗传学方面的专家高度合作的项目。注意力缺陷/多动障碍的神经生物学基础尚不清楚，因为目前还没有一个可靠的生物标记物或明确的测试来诊断这种疾病。有证据表明，对ADHD青少年的认知研究表明，冲动行为可能源于两种截然不同的神经生物学功能障碍。该项目将使用功能磁共振成像(FMRI)将ADHD青少年脑功能异常的这两个方面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准确地诊断具有生物学意义的ADHD亚型提供支持。与公共卫生相关：注意力缺陷/多动障碍的神经生物学基础尚不清楚，因为该疾病的单一可靠生物标记物或决定性测试尚未确定。有证据表明，对ADHD青少年的认知研究表明，冲动行为可能源于两种截然不同的神经生物学功能障碍。该项目将使用功能磁共振成像(FMRI)将ADHD青少年脑功能异常的这两个方面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准确地诊断具有生物学意义的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.