Neurodevelopmentally rooted epicenters in schizophrenia: sensorimotor-association spatial axis of cortical thickness alterations.

Pathological disturbances in schizophrenia have been suggested to propagate via the functional and structural connectome across the lifespan. However, how the connectome guides early cortical reorganization of developing schizophrenia remains unknown. Here, we used early-onset schizophrenia (EOS) as a neurodevelopmental disease model to investigate putative early pathologic origins propagating through the functional and structural connectome. We compared 95 patients with antipsychotic-naïve first-episode EOS and 99 typically developing controls (total n = 194; 120 females; 7-17 years of age). While patients showed widespread cortical thickness reductions, thickness increases were observed in primary cortical areas. Using normative connectomics models, we found that epicenters of thickness reductions were located in association regions linked to language, affective, and cognitive functions, while epicenters of thickness increases in EOS were located in sensorimotor regions subserving visual, somatosensory, and motor functions. Using post-mortem transcriptomic data of six donors, we observed that the epicenter map differentiated oligodendrocyte-related transcriptional changes at its sensory apex, whereas the association end was related to the expression of excitatory/inhibitory neurons. More generally, the epicenter map was associated with dysregulation of neurodevelopmental disorder genes and human accelerated region genes, suggesting potential common genetic determinants across diverse neurodevelopmental conditions. Taken together, our results highlight the developmentally rooted pathological origins of schizophrenia and its transcriptomic overlap with other neurodevelopmental disorders.