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

8 Citations (SciVal)

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 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
Volume6
Issue number12
Early online date29 Jan 2021
DOIs
Publication statusPublished - 31 Dec 2021

Bibliographical note

Funding Information:
This work was supported by the Medical Research Council, United Kingdom (Grant No. MR/K004360/1 [to DEL]; Behavioural and Neurophysiological Effects of Schizophrenia Risk Genes: A Multi-locus, Pathway Based Approach), the MRC/Engineering and Physical Sciences Research Council?funded UK MEG Partnership Grant (Grant No. MR/K005464/1 [to KDS]), the MRC Centre for Neuropsychiatric Genetics and Genomics, United Kingdom (Grant No. MR/L010305/1 [to KDS]), a Marie Curie COFUND EU-UK Research Fellowship (to SID), a Wellcome Trust New Investigator Award and Wellcome Trust Strategic Award (Grant No. 104943/Z/14/Z [to DKJ]), and the National Institute for Health Research Biomedical Research Centre at University Hospitals Bristol NHS Foundation Trust and the University of Bristol (to SZ and GDS). GDS works in the Medical Research Council Integrative Epidemiology Unit at the University of Bristol, which is supported by the Medical Research Council (Grant No. MC_UU_00011/1 [to GDS]). The UK Medical Research Council and Wellcome (Grant No. 102215/2/13/2) and the University of Bristol provided core support for Avon Longitudinal Study of Parents and Children. Genome-wide association studies data were generated by Sample Logistics and Genotyping Facilities at Wellcome Sanger Institute and LabCorp (Laboratory Corporation of America) using support from 23andMe. DEL, KDS, DKJ, SZ, GDS, MJO, MCO, and JH designed research; GP and SID performed experiments; SID designed analysis pipeline and analyzed data; TML and KET contributed to data analysis; SID wrote the paper; and all of the authors discussed the results and made critical revisions to the manuscript. We are grateful to Professor Peter Holmans for comments on the manuscript. We are extremely grateful to all the families who took part in this study; the midwives for their help in recruiting them; and the whole Avon Longitudinal Study of Parents and Children team, which includes interviewers, computer and laboratory technicians, clerical workers, research scientists, volunteers, managers, receptionists, and nurses. The authors report no biomedical financial interests or potential conflicts of interest.

Funding Information:
This work was supported by the Medical Research Council, United Kingdom (Grant No. MR/K004360/1 [to DEL] ; Behavioural and Neurophysiological Effects of Schizophrenia Risk Genes: A Multi-locus, Pathway Based Approach), the MRC/Engineering and Physical Sciences Research Council–funded UK MEG Partnership Grant (Grant No. MR/K005464/1 [to KDS]), the MRC Centre for Neuropsychiatric Genetics and Genomics, United Kingdom (Grant No. MR/L010305/1 [to KDS] ), a Marie Curie COFUND EU-UK Research Fellowship (to SID), a Wellcome Trust New Investigator Award and Wellcome Trust Strategic Award (Grant No. 104943/Z/14/Z [to DKJ]), and the National Institute for Health Research Biomedical Research Centre at University Hospitals Bristol NHS Foundation Trust and the University of Bristol (to SZ and GDS). GDS works in the Medical Research Council Integrative Epidemiology Unit at the University of Bristol, which is supported by the Medical Research Council (Grant No. MC_UU_00011/1 [to GDS] ). The UK Medical Research Council and Wellcome (Grant No. 102215/2/13/2) and the University of Bristol provided core support for Avon Longitudinal Study of Parents and Children. Genome-wide association studies data were generated by Sample Logistics and Genotyping Facilities at Wellcome Sanger Institute and LabCorp (Laboratory Corporation of America) using support from 23andMe.

Publisher Copyright:
© 2021

Copyright:
Copyright 2021 Elsevier B.V., All rights reserved.

Keywords

  • 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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