754. Developmental Reorganization of Network Functional Connectivity Abnormalities and Molecular Signatures in Attention-Deficit/Hyperactivity Disorder

Abstract

Abstract Background Attention-deficit/hyperactivity disorder (ADHD) manifests differently across the lifespan, yet the neurobiological mechanisms driving these changes remain inadequately understood. Aims & Objectives This meta-analysis aims to explore age-related alterations in FC in ADHD and examine the associations with transcriptomic and neurotransmitter signatures. We aim to characterize how these alterations are influenced by developmental stages and their relationship with neurochemical and molecular factors. Method Following PRISMA guidelines, we conducted a seed-based meta-analysis comparing ADHD patients (n = 4,316) and healthy controls (n = 8,709) across 43 studies. Age-stratified analyses (children, adolescents, adults) were performed to examine FC alterations within major cortical and subcortical networks. Meta-regressions were used to investigate age-related effects. Molecular associations were assessed through transcriptomic data and neurotransmitter receptor/transporter maps from publicly available databases. Results A developmentally differentiated pattern of FC alterations was observed, with the most pronounced abnormalities in childhood, partially reversing in adulthood. Within the default mode network (DMN), connectivity with the insula reversed with age, from hypoconnectivity in children to hyperconnectivity in adults. Subgroup analyses of stimulant-naïve datasets confirmed the robustness of these findings. At the molecular level, FC alterations in the sbocortical network (SCN) and DMN were spatially associated with transcriptomic pathways related to synaptic signaling, while children exhibited specific enrichment of neurodevelopmental pathways, and SCN connectivity was linked to stimulus-response-related pathways. Neurotransmitter associations were network- and age-dependent, with dopaminergic and serotonergic markers linked to cortical network changes, and noradrenergic transporter density associated with SCN dysconnectivity in children. Discussion & Conclusions We demonstrates that ADHD is characterized by developmentally FC alterations. We identify a key reversal in DMN-VAN connectivity between child and adult patients, supporting models of delayed maturation and compensatory reorganization. Crucially, the medication-naïve subgroup exhibited more extensive DMN dysconnectivity, suggesting that pharmacological treatment may partially mask intrinsic network deficits. By integrating FC with transcriptomic and neurochemical evidence, we further reveal that these network-level abnormalities are associated with distinct molecular and neuromodulatory mechanisms that vary across networks and developmental stages. Together, these findings advance a multi-system framework for understanding ADHD from childhood to adulthood, bridging macro-scale network dysfunction with meso-scale biological substrates, and offering novel insights for intervention targets.