Pan Nanfang, Long Yajing, Qin Kun, Pope Isaac, Chen Qiuxing, Zhu Ziyu, Cao Ying, Li Lei, Singh Manpreet K, McNamara Robert K, DelBello Melissa P, Chen Ying, Fornito Alex, Gong Qiyong
Huaxi MR Research Center (HMRRC), Department of Radiology, West China Hospital of Sichuan University; Research Unit of Psychoradiology, Chinese Academy of Medical Sciences; Functional & Molecular Imaging Key Laboratory of Sichuan Province, West China Hospital of Sichuan University, Chengdu, China.
The Turner Institute for Brain and Mental Health, School of Psychological Sciences and Monash Biomedical Imaging, Monash University, Clayton, Australia.
medRxiv. 2025 Mar 28:2025.03.27.25324802. doi: 10.1101/2025.03.27.25324802.
Attention-deficit/hyperactivity disorder (ADHD) is characterized by considerable clinical heterogeneity. This study investigates whether normative modelling of topological properties derived from brain morphometry similarity networks can provide robust stratification markers for ADHD children. Leveraging multisite neurodevelopmental datasets (discovery: 446 ADHD, 708 controls; validation: 554 ADHD, 123 controls), we constructed morphometric similarity networks and developed normative models for three topological metrics: degree centrality, nodal efficiency, and participation coefficient. Through semi-supervised clustering, we delineated putative biotypes and examined their clinical profiles. We further contextualized brain profiles of these biotypes in terms of their neurochemical and functional correlates using large-scale databases, and assessed model generalizability in an independent cohort. ADHD exhibited atypical hub organization across all three topological metrics, with significant case-control differences primarily localized to a covarying multi-metric component in the orbitofrontal cortex. Three biotypes emerged: one characterized by severe overall symptoms and longitudinally persistent emotional dysregulation, accompanied by pronounced topological alterations in the medial prefrontal cortex and pallidum; a second by predominant hyperactivity/impulsivity accompanied by changes in the anterior cingulate cortex and pallidum; and a third by marked inattention with alterations in the superior frontal gyrus. These neural profiles of each biotype showed distinct neurochemical and functional correlates. Critically, the core findings were replicated in an independent validation cohort. Our comprehensive approach reveals three distinct ADHD biotypes with unique clinical-neural patterns, advancing our understanding of ADHD's neurobiological heterogeneity and laying the groundwork for personalized treatment.
注意力缺陷多动障碍（ADHD）具有显著的临床异质性。本研究调查从脑形态测量相似性网络得出的拓扑属性的规范建模是否能够为ADHD儿童提供可靠的分层标记。利用多中心神经发育数据集（发现队列：446例ADHD患者，708例对照；验证队列：554例ADHD患者，123例对照），我们构建了形态测量相似性网络，并针对三个拓扑指标开发了规范模型：度中心性、节点效率和参与系数。通过半监督聚类，我们划分出假定的生物型并检查了它们的临床特征。我们使用大规模数据库，根据这些生物型的神经化学和功能相关性，进一步将其脑特征置于情境中，并在一个独立队列中评估模型的可推广性。ADHD在所有三个拓扑指标上均表现出非典型的枢纽组织，病例对照之间的显著差异主要集中在眶额皮质中一个共同变化的多指标成分上。出现了三种生物型：一种以严重的整体症状和纵向持续的情绪调节障碍为特征，伴有内侧前额叶皮质和苍白球明显的拓扑改变；第二种以主要的多动/冲动为特征，伴有前扣带回皮质和苍白球的变化；第三种以明显的注意力不集中为特征，伴有额上回的改变。每种生物型的这些神经特征显示出不同的神经化学和功能相关性。至关重要的是，核心发现在一个独立的验证队列中得到了重复。我们的综合方法揭示了三种具有独特临床-神经模式的不同ADHD生物型，增进了我们对ADHD神经生物学异质性的理解，并为个性化治疗奠定了基础。
