Autism and Cortical Thickness Deviation From Neurotypical Controls: Evidence for a Spatial Association With Serotonin Receptors

ABSTRACT Cortical thickness (CT) differences between autistic individuals (AI) and neurotypical controls have been consistently reported, yet the neurochemical mechanisms underlying these differences remain insufficiently understood. Neurotransmitter receptor systems exhibit distinct spatial distributions across the cortex and influence synaptic maturation, plasticity, and cortical organization. Consequently, mapping CT deviations onto these receptor density gradients provides a biologically informed framework for investigating the potential underlying neurochemical architectures of observed structural patterns in autism. A total of 1035 structural MRIs (AI n = 505, neurotypical controls n = 530) were included from Autism Brain Imaging Data Exchange (ABIDE). Group contrasts and individual‐level deviations from age‐predicted CT patterns were computed. These spatial patterns were correlated with neurotransmitter receptors cortical density distributions (D1, D2, 5HT1a, 5HT2a, 5HT4, 5HT6, mGluR5) from previous PET studies. Widespread vertex‐wise deviations in CT were observed in AI in comparison to neurotypical controls. At the group level, CT differences were spatially aligned with the cortical density of serotonin receptors (5HT1a: r = 0.22, FDR‐ p = 0.032; 5HT4: r = 0.21, FDR‐ p = 0.032). At the individual level, greater deviations from predicted CT, if mapped onto specific neurotransmitter receptor density gradients, correlated with greater difficulties in the social and communication domains. The findings provide novel evidence that serotonin receptors may play a role in shaping cortical structural brain differences between AI and neurotypical controls. The link between CT differences and spatial distributions of the serotoninergic system offers a translational perspective for future targeted support strategies focused on serotonergic pathways.