Abstract Pathologic perturbations in schizophrenia have been suggested to propagate via the functional and structural connectome across the lifespan. Yet 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 that propagate through the functional and structural connectome. We compared 95 patients with antipsychotic-naïve first-episode EOS and 99 typically developing controls (7–17 years of age, 120 females). Whereas 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 situated in association regions linked to language, affective, and cognitive functions, while epicenters of increased thickness 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 and the association end was related to expression of excitatory/inhibitory neurons. More generally, we observed that the epicenter map was associated with neurodevelopmental disease gene dysregulation and human accelerated region genes, suggesting potential shared genetic determinants across various neurodevelopmental disorders. Taken together, our results underscore the developmentally rooted pathologic origins of schizophrenia and their transcriptomic overlap with other neurodevelopmental diseases.

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