Mapping Resting-State Brain Functional Specialization to Neurotransmitter Profiles in Autism Spectrum Disorder

Autism spectrum disorder (ASD) is a highly prevalent neurodevelopmental disorder. However, its diagnosis and effective treatment present challenges. Understanding neurotransmitter impairments may offer new perspectives into the mechanisms underlying ASD and the potential therapeutic targets for this condition. This study aimed to investigate the spatial associations of ASD-related brain activity patterns and multiple specific neurotransmitter distributions to identify abnormal neurotransmitter alterations in patients with ASD, and to assess how these spatial associations relate to clinical features.

We included 44 patients with ASD and 132 typically developing controls (TDCs) and compared the regional homogeneity (ReHo) differences between the two groups. Associations between the spatial patterns of ReHo alterations and specific neurotransmitter receptor/transporter densities in patients with ASD were evaluated, and the correlations of these associations with the clinical characteristics were analyzed.

In comparison with TDCs, patients with ASD exhibited specific brain activity abnormalities in the visuomotor network, cerebro-cerebellar circuits, angular gyrus, and limbic areas. These atypical brain activity patterns were significantly co-localized with the serotonergic, glutamatergic, GABAergic, dopaminergic, noradrenergic, cholinergic, and cannabinoid neurotransmitter systems in patients with ASD, and the results showed good reproducibility between different neurotransmitter maps. Additionally, the awareness score in the Social Responsiveness Scale (ρ = -0.475, p = 0.009) and the social score in the Autism Diagnostic Observation Schedule (ρ = -0.415, p = 0.049) exhibited negative correlations with the strength of ReHo co-localization of serotonin 5-hydroxytryptamine receptor subtype 2a.

This is the first systematic analysis of multiple neurotransmitter systems to show abnormalities in these systems in patients with ASD. These results will enhance the existing understanding of the mechanisms underlying ASD and may provide the foundation for identifying therapeutic targets.