Correspondence between morphological similarity of the left lateral orbitofrontal cortex and neurotransmitter systems in adolescent males with autism

BackgroundAutism spectrum disorder (ASD) is a neurodevelopmental condition marked by pronounced heterogeneity in brain structure, which limits the development of targeted interventions. Morphological brain networks (MBNs) enable mapping of coordinated structural features across brain regions at the individual level. However, the specific organization of such networks in ASD and their potential relationships with underlying neurotransmitter systems remain largely unexplored. AimsTo characterize alterations in cortical thickness-based MBNs among adolescent males with ASD and to test whether these network changes spatially correspond to normative PET-derived neurotransmitter receptor/transporter maps. MethodsIn this case-control study, T1-weighted MRI data from 424 adolescent males (207 ASD, 217 typically developing) in the Autism Brain Imaging Data Exchange were analyzed. MBNs were constructed using interregional cortical thickness similarity quantified by Jensen-Shannon divergence. Graph-theoretical metrics were computed and group differences were assessed with permutation tests controlling for age and IQ. Spatial correlations between the left lateral orbitofrontal morphological similarity and atlas-based neurotransmitter maps were investigated using the JuSpace toolbox. ResultsAdolescent males with ASD showed increased normalized clustering coefficient (t=2.40, p=0.020, FDR corrected) and reduced nodal measures in the left lateral orbitofrontal cortex (OFC) including degree centrality, PageRank centrality, and betweenness centrality (all p<0.001, FDR corrected). Morphological similarity analysis revealed decreased OFC-based similarity with 65 brain regions. Furthermore, the OFC-related morphological similarity was associated with the spatial distributions of neurotransmitter systems, with GABAa, 5-HT1a, and -opioid receptors remaining significant after FDR correction. ConclusionsThese findings highlight the left lateral OFC as a structural key hub in adolescent males with ASD, linking left lateral OFC-based morphological similarity to neurotransmitter systems and providing a potential neurobiological basis for targeted interventions in this population. 1. What is already known on this topicStructural brain alterations and heterogeneity in autism spectrum disorder (ASD) are well established, but little is known about how individual brain networks relate to neurochemical systems that may guide treatment targets. 2. What this study addsThis study adds to existing knowledge by identifying the left lateral orbitofrontal cortex (OFC) as a disrupted structural hub in adolescent males with ASD and demonstrating its morphological similarity alterations are linked to GABAa, 5-HT1a, and -opioid receptor systems. 3. How this study might affect research, practice or policyBy establishing spatial correspondence between left lateral OFC morphological similarity and GABAa, 5-HT1a, and -opioid receptor systems, this work may provide potential neurobiological markers and targets for circuit-based interventions in adolescent males with ASD.