Segura Patricia, Pagani Marco, Bishop Somer L, Thomson Phoebe, Colcombe Stan, Xu Ting, Factor Zekiel Z, Hector Emily C, Kim So Hyun, Lombardo Michael V, Gozzi Alessandro, Castellanos Xavier F, Lord Catherine, Milham Michael P, Di Martino Adriana
Child Mind Institute, New York, NY, USA.
Department of Medical Physiology and Biophysics, University of Seville, Seville, Spain.
Mol Psychiatry. 2026 Jan;31(1):282-295. doi: 10.1038/s41380-025-03205-8. Epub 2025 Oct 23.
Clinical, neuroimaging and genomics evidence have increasingly underscored a degree of overlap between autism and attention-deficit/hyperactivity disorder (ADHD). This study explores the specific contribution of their core symptoms to shared biology in N = 166 verbal children (6-12 years) with rigorously-established primary diagnoses of either autism or ADHD (without autism). We investigated the associations between inter-individual differences in low motion whole-brain intrinsic functional connectivity (iFC) and dimensional measures of autism and ADHD symptoms indexed by clinician-based observation and parent interview, respectively. Additionally, we explored their linked gene expression patterns in silico. Whole-brain multivariate distance matrix regression revealed a transdiagnostic association between autism severity and iFC of two nodes primarily on the left hemisphere: the middle frontal gyrus of the frontoparietal network and the posterior cingulate cortex of the default mode network. Across children, the greater the iFC between these nodes, the more severe the autism symptoms, even after controlling for ADHD ratings. Results from secondary segregation analyses were consistent with primary findings, underscoring the significance of internetwork iFC for autism symptom severity across diagnoses. No statistically significant brain-behavior relationships were observed for ADHD symptoms. Genetic enrichment analyses of the iFC maps associated with autism symptoms implicated genes known to: (i) have greater rate of variance in autism and ADHD, and (ii) be involved in neuron projections, suggesting shared genetic mechanisms for this specific brain-clinical phenotype. These findings underscore the relevance of transdiagnostic dimensional approaches in linking clinically-defined and observation-based phenomena to shared presentations at the macroscale circuit- and genomic-levels across diagnoses.
临床、神经影像学和基因组学证据越来越多地强调了自闭症与注意力缺陷多动障碍（ADHD）之间存在一定程度的重叠。本研究探讨了N = 166名6至12岁有明确原发性自闭症或ADHD（无自闭症）诊断的儿童中，其核心症状对共同生物学特征的具体贡献。我们分别研究了基于临床医生观察和家长访谈得出的自闭症和ADHD症状维度测量值与低运动全脑内在功能连接（iFC）个体间差异之间的关联。此外，我们还在计算机上探索了它们相关的基因表达模式。全脑多变量距离矩阵回归显示，自闭症严重程度与主要位于左半球的两个节点的iFC之间存在跨诊断关联：额顶叶网络的额中回和默认模式网络的后扣带回皮质。在所有儿童中，即使在控制了ADHD评分后，这些节点之间的iFC越强，自闭症症状就越严重。二次分离分析的结果与主要发现一致，强调了网络间iFC对跨诊断自闭症症状严重程度的重要性。未观察到ADHD症状与脑行为之间有统计学意义的关系。对与自闭症症状相关的iFC图谱进行基因富集分析，发现涉及以下基因：（i）在自闭症和ADHD中有更大的变异率，以及（ii）参与神经元投射，这表明这种特定的脑-临床表型存在共同的遗传机制。这些发现强调了跨诊断维度方法在将临床定义和基于观察的现象与跨诊断的宏观尺度回路和基因组水平上的共同表现联系起来方面的相关性。
