Parietal prefrontal feedforward connectivity in association with schizophrenia genetic risk and delusions

BackgroundConceptualizations of delusion formation implicate, in part, deficits at feed-forward information transfer across posterior to prefrontal cortices, resulting in dysfunctional integration of new information in favor of over-familiar prior beliefs. Here, we used functional MRI and machine learning models to examine feedforward parietal-prefrontal information transfer in schizophrenia patients in relation to delusional thinking, and polygenic risk for schizophrenia.\n\nMethodsWe studied 66 schizophrenia patients and 143 healthy controls as they performed context updating during working memory (WM). Dynamic causal models of effective connectivity were focused on prefrontal and parietal cortex, where we examined parietal-prefrontal connectivity in relation to delusions in patients. We further tested for an effect of polygenic risk for schizophrenia on connectivity in healthy individuals. We then leveraged support vector regression models to define optimal normalized target connectivity tailored for each patient, and tested the extent to which deviation from this target predicted individual variation in delusion severity.\n\nResultsIn schizophrenia patients, updating and manipulating context information was disproportionately less accurate than was WM maintenance, with a task accuracy-by-diagnosis interaction. Also, patients with delusions tended to have relatively reduced feedforward effective connectivity during context updating in WM manipulation. The same parietal-prefrontal feedforward prefrontal effective connectivity was adversely influenced by polygenic risk for schizophrenia in healthy subjects. Individual patients deviation from predicted normal feedforward connectivity based on the support vector models correlated with delusional severity.\n\nConclusionsThese computationally-derived observations support a role for feed-forward parietal-prefrontal information processing deficits in delusional psychopathology, and in genetic risk for schizophrenia.