Global Brain Flexibility During Working Memory Is Reduced in a High-Genetic-Risk Group for Schizophrenia

Stavros I. Dimitriadis, Thomas M. Lancaster, Gavin Perry, Katherine E. Tansey, Derek K. Jones, Krish D. Singh, Stanley Zammit, George Davey Smith, Jeremy Hall, Michael C. O'Donovan, Michael J. Owen, David E. Linden

Research output: Contribution to journalArticlepeer-review


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 dynamic functional connectivity analysis to functional magnetic resonance imaging data 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-PRSs]) and 98 individuals (52 female, 46 male) with high SCZ-PRSs from both tails of the SCZ-PRS distribution from a genotyped population cohort, the Avon Longitudinal Study of Parents and Children (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, 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 flexibility index and network modularity across n-back levels. The whole-brain flexibility index and that of the frontoparietal 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.

Original languageEnglish
Pages (from-to)1176-1184
Number of pages9
JournalBiological Psychiatry: Cognitive Neuroscience and Neuroimaging
Issue number12
Early online date29 Jan 2021
Publication statusPublished - 31 Dec 2021


  • Brain flexibility
  • Genetics
  • Imaging
  • Population study
  • Schizophrenia
  • Temporal modularity

ASJC Scopus subject areas

  • Radiology Nuclear Medicine and imaging
  • Clinical Neurology
  • Cognitive Neuroscience
  • Biological Psychiatry


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