Global Brain Flexibility During Working Memory is reduced in a High Genetic Risk Group for Schizophrenia

Abstract Background Altered functional brain connectivity has been proposed as an intermediate phenotype between genetic risk loci and clinical expression of schizophrenia. Genetic high-risk groups of healthy subjects are particularly suited for the investigation of this proposition because they can be tested in the absence of medication or other secondary effects of schizophrenia. Methods Here we applied dFC analysis to functional MRI data in order to reveal the reconfiguration of brain networks during a cognitive task. We recruited healthy carriers of common risk variants using the recall-by-genotype design. We assessed 197 individuals: 99 individuals (52 female, 47 male) with low polygenic risk scores (Schizophrenia risk profile scores, SCZ-PRS) and 98 individuals (52 female, 46 male) with high SCZ-PRS from both tails of the SCZ-PRS distribution from a genotyped population cohort, the Avon Longitudinal Study of Parents And Children (ALSPAC) (N=8169). We compared groups both on conventional brain activation profiles, using the general linear model of the experiment, and on the neural Flexibility Index (FI) which quantifies how frequent a brain region’s community affiliation changes over experimental time. Results Behavioral performance and standard brain activation profiles did not differ significantly between groups. High SCZ-PRS was associated with reduced FI and network modularity across n-back levels. The whole-brain FI and that of the fronto-parietal working memory network was associated with n-back performance. We identified a dynamic network phenotype related to high SCZ-PRS. Conclusions Such neurophysiological markers can become important for the elucidation of biological mechanisms of schizophrenia and particularly the associated cognitive deficit.