Assessing Development Trajectories of the Brain Biochemistry in ADHD at 4 Tesla

注意力缺陷多动障碍（ADHD）是一个严重的公共卫生问题，影响3%至9%的儿童，占转介到精神卫生服务的儿童的30%至40%。虽然这种疾病的发病机制仍然知之甚少，但ADHD越来越被视为一种神经发育障碍，涉及抑制性调节，执行功能，动机过程，感知和运动控制。我们的长期目标是增加我们对儿童ADHD神经发育偏差的理解。本更新申请的目的是测试早期发育的纹状体的改变是否先于发育较慢的前额叶区域（如背外侧前额叶皮层（DLPFC））中发生的改变。 从童年到青春期，大脑经历了实质性的结构和功能变化，具有不同的时间，这与认知和行为的成熟平行。这种“微调”或成熟认知表现的过程包括消除过度产生的神经元连接或突触，这可以使用非侵入性神经成像方法，体内磷（31 P）光谱法进行评估。从我们的第一个资助周期，在1.5特斯拉下获得的横截面体内31 P光谱结果显示基底神经节缺陷，表明树突分支和突触形成发育不足，以及前额叶皮质缺陷，但仅在相对较大的ADHD儿童中，表明微调的成熟过程未达到。然而，为了明确评估随时间的发展变化，需要纵向测量。因此，本研究的目的是在患有和不患有ADHD的儿童和青少年中获得纵向全脑3D多体素31 P光谱和4特斯拉的超高分辨率解剖MRI测量值;即基线加间隔12个月的两次随访。使用高场磁共振系统显著提高了区域特异性和生化分辨率。将评估皮质表面地形图的偏差，并在每个时间点收集针对不同认知/行为领域的神经心理学指标。这项纵向研究的总体假设是，ADHD儿童的神经发育轨迹相对于健康对照组（包括发育较慢的DLPFC）会表现出区域性偏差，但直到童年后期DLPFC发生微调过程。重要性：如果得到证实，这些研究将提供更直接的证据，证明纹状体自下而上的功能障碍可能损害ADHD儿童前额叶皮层控制过程或执行功能的微调。此外，这些观察结果将建立与健康对照相比的儿科ADHD生化轨迹的基础，这可能导致改善ADHD的评估和治疗。

DESCRIPTION (provided by applicant): Attention Deficit Hyperactivity Disorder (ADHD) is a serious public health problem that affects between 3 to 9% of children and accounts for between 30 to 40% of child referrals to mental health services. While the pathogenesis of this illness remains poorly understood, ADHD is increasingly seen as a neurodevelopmental disorder implicating inhibitory regulation, executive function, motivational processes, perception and motor control. Our long-term goal is to increase our understanding of neurodevelopmental deviations in pediatric ADHD. The objective of this renewal application is to test whether alterations of the earlier developing striatum precede alterations that occur later in the slower developing prefrontal areas such as the dorsolateral prefrontal cortex (DLPFC). From childhood to adolescence, the brain undergoes substantive structural and functional changes with differential timing, which parallel the maturation of cognition and behavior. This process of "fine-tuning" or maturing cognitive performance includes the elimination of overproduced neuronal connections or synapses, which can be assessed using the noninvasive neuroimaging method, in vivo phosphorous (31P) spectroscopy. From our first-cycle of funding, the cross-sectional in vivo 31P spectroscopy results acquired at 1.5 Tesla show basal ganglia deficits suggesting an underdevelopment of dendritic branching and synaptic formations, and prefrontal cortex deficits but only in the relatively older ADHD children suggesting an underachieved maturational process of fine-tuning. However, to definitively assess developmental changes over time requires longitudinal measurements. Therefore, the aims of this study are to acquire longitudinal whole-brain 3D multi- voxel 31P spectroscopy and ultra-high resolution anatomical MRI measurements at 4 Tesla in children and adolescent with and without ADHD; that is baseline plus two follow-up visits 12-months apart. Using a high- field MR system dramatically improves the regional specificity and biochemical resolution. Deviations in cortical surface topography will be assessed as well as neuropsychological measures targeting different cognitive/behavioral domains will be collected at each time point. The overall hypothesis of this longitudinal study is that children with ADHD will demonstrate regional deviations in neurodevelopmental trajectories relative to healthy controls including in the slower developing DLPFC, but not until the onset of the fine-tuning processes in the DLPFC that occurs late in childhood. Significance: If confirmed, these studies will provide more direct evidence of a developmental mechanism targeting a bottom-up dysfunction in the striatum potentially impairing the fine-tuning of control processes or executive functions in the prefrontal cortex of children with ADHD. Additionally, these observations will establish a foundation of biochemical trajectories in pediatric ADHD contrasted against healthy controls, which may lead toward improved assessment and treatment of ADHD.