NEUROIMAGING STRATIFICATION REVEALS A BRAIN PATHWAY LINKING ENVIRONMENTAL STRESSES TO PSYCHOTIC SYMPTOMS IN THE FIRST- DEGREE RELATIVES OF PATIENTS WITH SCHIZOPHRENIA

Abstract Background Schizophrenia is characterized by its complex gene-by-environment interactive etiology (Stilo and Murray, 2019, McCutcheon et al., 2020). The genetic risk of schizophrenia affected the development of key brain structures, such as the striatum with rich dopaminergic projections (Luo et al., 2019, Grama et al., 2020, Hibar et al., 2015). However, we do not know if such brain changes have a 'priming’ effect that confers vulnerability for negative environmental influences, such as negative life events (Sideli et al., 2020). Aims & Objectives To test this hypothesis that in UFR-SZ, the presence of a lower putamen volume may indicate a state of vulnerability for adverse life events to further affect the structural integrity of the brain, especially the striatum. Method We investigated the both associations of striatum volume with negative life events and psychotic symptoms in whole group or subgroup of 63 unaffected first-degree relatives of patients with schizophrenia (UFR-SZ). Mediation analysis was applied to test the causal pathway of striatum in above association and cellular mechanism behind the pathway was studied by transcriptomic analysis. Results Stratifying the UFR-SZ by the right putamen volume, the effect of negative life events on the left caudate became apparent in the smaller-putamen subgroup. Mediation analysis revealed the structural deficits in the caudate cluster, which occurred when suffering negative life events, influenced the burden of psychotic symptoms. Transcriptomic analysis revealed the brain regions mediating this causal relationship were enriched for the gene expression relevant for cellular response to oxidative stress. Discussion & Conclusion The current findings provided new evidence that the right putamen volume can be a neuroimaging marker representing the heterogeneity in schizophrenia. Greater striatum volume has been used as a marker for a neuroimaging subtype of schizophrenia (Chand et al., 2020). However, the striatum volume has also been associated with antipsychotic treatments (Gong et al., 2016). Therefore, we investigated the UFR-SZ carrying genetic risks for schizophrenia but free of antipsychotic and illness confounding. Stratifying by the right putamen volume revealed brain volumes that were associated with both the environmental stress and the psychotic symptoms in UFR-SZ, which could not be uncovered without the stratification. The current findings uncovered, for the first time, a caudate pathway for the two-hit theory of schizophrenia among the individuals with both high genetic risk and reduced right putamen volume. Environmental stress has long been hypothesized that the sensitized dopamine system, especially in the striatum, becomes more vulnerable to acute stress in schizophrenia (Birnbaum and Weinberger, 2017). Here, our findings of the caudate volume mediating the stress-symptom relationship and the association of such brain mediation effect with oxidative stress indicating a potential pathway from environmental stress via caudate volume to psychosis. These findings highlighted that the certain brain structural changes (putamen) associated with genetic risk for schizophrenia can render other regions (caudate) more vulnerable to environmental stresses and thereby increasing the propensity for a psychotic episode. The relevance of oxidative stress pathway in this chain of influence provides a lead to a potential therapeutic strategy. References BIRNBAUM, R. & WEINBERGER, D. R. 2017. Genetic insights into the neurodevelopmental origins of schizophrenia. Nature Reviews Neuroscience, 18, 727-740. CHAND, G. B., DWYER, D. B., ERUS, G., SOTIRAS, A., VAROL, E., SRINIVASAN, D., DOSHI, J., POMPONIO, R., PIGONI, A. & DAZZAN, P. 2020. Two distinct neuroanatomical subtypes of schizophrenia revealed using machine learning. Brain, 143, 1027- 1038. GONG, Q., LUI, S. &SWEENEY, J. A. 2016. A selective review of cerebral abnormalities in patients with first-episode schizophrenia before and after treatment. American Journal of Psychiatry, 173, 232- 243. GRAMA, S., WILLCOCKS, I., HUBERT, J. J., PARDIÑ AS, A. F., LEGGE, S. E., BRACHER-SMITH, M., MENZIES, G. E., HALL, L. S., POCKLINGTON, A. J. &ANNEY, R. J. 2020. Polygenic risk for schizophrenia and subcortical brain anatomy in the UK Biobank cohort. Translational psychiatry, 10, 309. HAIJMA, S. V., VAN HAREN, N., CAHN, W., KOOLSCHIJN, P. C. M., HULSHOFF POL, H. E. &KAHN, R. S. 2013. Brain volumes in schizophrenia: a meta-analysis in over 18 000 subjects. Schizophrenia bulletin, 39, 1129-1138. HIBAR, D. P., STEIN, J. L., RENTERIA, M. E., ARIAS-VASQUEZ, A., DESRIVIÈ RES, S., JAHANSHAD, N., TORO, R., WITTFELD, K., ABRAMOVIC, L. &ANDERSSON, M. 2015. Common genetic variants influence human subcortical brain structures. Nature, 520, 224-229. LUO, Q., CHEN, Q., WANG, W., DESRIVIÈ RES, S., QUINLAN, E. B., JIA, T., MACARE, C., ROBERT, G. H., CUI, J. &GUEDJ, M. 2019. Association of a schizophrenia-risk nonsynonymous variant with putamen volume in adolescents: a voxelwise and genome- wide association study. JAMA psychiatry, 76, 435-445. MCCUTCHEON, R. A., MARQUES, T. R. &HOWES, O. D. 2020. Schizophrenia— an overview. JAMA psychiatry, 77, 201-210. SIDELI, L., MURRAY, R. M., SCHIMMENTI, A., CORSO, M., LA BARBERA, D., TROTTA, A. &FISHER, H. L. 2020. Childhood adversity and psychosis: a systematic review of bio-psycho-social mediators and moderators. Psychological medicine, 50, 1761-1782.STILO, S. A. &MURRAY, R. M. 2019. Non-genetic factors in schizophrenia. Current psychiatry reports, 21, 1-10.