¹Fudan University, National Clinical Research Center for Aging and Medicine at Huashan Hospital, Research Institute of Intelligent Complex Systems, Shanghai, China, ²The Second Xiangya Hospital of Central South University, Department of Psychiatry, National Clinical Research Center for Mental Disorders, and National Center for Mental Disorders, Changsha, China, ³The Third Xiangya Hospital of Central South University, Department of Clinical Psychology, National Clinical Research Center for Mental Disorders, Changsha, China, ⁴Fudan University, National Clinical Research Center for Aging and Medicine at Huashan Hospital, Research Institute of Intelligent Complex Systems, Institute of Science and Technology for Brain-Inspired Intelligence, Shanghai, China

Background: Stress is a key environmental risk factor for schizophrenia. However, the stress-schizophrenia mediating pathway remains undetermined mainly due to its heterogeneity.

Aims & Objectives: To account for the heterogeneity, a stratification algorithm was designed to elucidate the stress-psychosis mediating patterns of volumetric changes across multiple brain regions.

Method: This study analyzed the brain's grey-matter volume, polygenic schizophrenia risk, stressful life event, and psychotic-like experience in the IMAGEN cohort (N=975, age 19). A mediating-pathway stratification algorithm was used to identify subgroups in which individuals share the same pattern of volumetric changes that mediates the stress-schizophrenia relationship. We trained subgroup classifiers and applied them to validation datasets, including unaffected first-degree relatives of schizophrenia (UFR-SZ) and early-onset schizophrenia (EOS) patients.

Results: We identified four subgroups with distinct mediating patterns of grey-matter volumetric changes. One subgroup had a tri-network pattern of increased grey-matter volumes in the executive-control, auditory and default-mode regions, that was associated with both higher stress and more psychotic-like experience. The salience, dorsal-attention, and limbic regions were additionally involved in the other three subgroups, respectively. The tri-network subgroup had higher polygenic schizophrenia risk than the salience-augmented subgroup. Only the tri-network subgroup was generalized to UFR-SZ and EOS patients. Several key biological processes associated with stress responses, immune and inflammation regulation were enriched in the tri-network subgroup.

Discussion & Conclusions: These findings emphasized the importance of stratification in parsing the heterogeneity in stress-schizophrenia neural mediating pathways, highlighting a tri-network pathway.