Correspondence between morphological similarity of the left lateral orbitofrontal cortex and neurotransmitter systems...

Autism 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 the mapping of coordinated structural features across brain regions at the individual level. However, the specific organisation of such networks in ASD and their potential relationships with underlying neurotransmitter systems remain largely unexplored.

To characterise alterations in cortical thickness-based MBNs among adolescent males with ASD and to test whether these network changes spatially correspond to normative positron emission tomography-derived neurotransmitter receptor/transporter maps.

In this cross-sectional study, T1-weighted magnetic resonance imaging (MRI) data from 424 adolescent males (207 with ASD, 217 typically developing) in the Autism Brain Imaging Data Exchange were analysed. 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 intelligence quotient (IQ). Spatial correlations between left lateral orbitofrontal morphological similarity and atlas-based neurotransmitter maps were investigated using the JuSpace toolbox.

The ASD group exhibited a significantly increased normalised clustering coefficient (t = 2.40, p = 0.020) and decreased nodal centrality in the left lateral orbitofrontal cortex (OFC). This region showed reduced morphological similarity with 65 other brain regions. Furthermore, the OFC-based similarity patterns were significantly associated with the spatial distributions of gamma-aminobutyric acid type A (GABAa), 5-hydroxytryptamine receptor 1A (5-HT1a) and μ-opioid receptor systems (r = 0.22, p = 0.017, spin-corrected). These alterations were robust to stringent cross-family correction.

These findings highlight the left lateral OFC as a structural key hub in adolescent males with ASD. The robustness of these OFC-centred network alterations under stringent cross-family correction, together with their associations with neurotransmitter systems, provides a potential neurobiological basis for targeted interventions in this population.