Stavros I Dimitriadis1, Thomas M Lancaster2, Gavin Perry3, Katherine E Tansey4, Derek K Jones3, Krish D Singh3, Stanley Zammit5, George Davey Smith6, Jeremy Hall7, Michael C O'Donovan7, Michael J Owen7, David E Linden8. 1. Neuroscience and Mental Health Research Institute, Cardiff University, Cardiff, United Kingdom; Cardiff University Brain Research Imaging Centre, School of Psychology, Cardiff University, Cardiff, United Kingdom; MRC Centre for Neuropsychiatric Genetics and Genomics, Institute of Psychological Medicine and Clinical Neurosciences, Cardiff School of Medicine, Cardiff University, Cardiff, United Kingdom; Neuroinformatics Group, School of Psychology, Cardiff University, Cardiff, United Kingdom. Electronic address: DimitriadisS@cardiff.ac. 2. Neuroscience and Mental Health Research Institute, Cardiff University, Cardiff, United Kingdom; Cardiff University Brain Research Imaging Centre, School of Psychology, Cardiff University, Cardiff, United Kingdom; School of Psychology, Bath University, Bath, United Kingdom. 3. Cardiff University Brain Research Imaging Centre, School of Psychology, Cardiff University, Cardiff, United Kingdom. 4. MRC Integrative Epidemiology Unit, University of Bristol, United Kingdom. 5. MRC Centre for Neuropsychiatric Genetics and Genomics, Institute of Psychological Medicine and Clinical Neurosciences, Cardiff School of Medicine, Cardiff University, Cardiff, United Kingdom; Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, United Kingdom. 6. MRC Integrative Epidemiology Unit, University of Bristol, United Kingdom; Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, United Kingdom. 7. Neuroscience and Mental Health Research Institute, Cardiff University, Cardiff, United Kingdom; MRC Centre for Neuropsychiatric Genetics and Genomics, Institute of Psychological Medicine and Clinical Neurosciences, Cardiff School of Medicine, Cardiff University, Cardiff, United Kingdom. 8. Neuroscience and Mental Health Research Institute, Cardiff University, Cardiff, United Kingdom; Cardiff University Brain Research Imaging Centre, School of Psychology, Cardiff University, Cardiff, United Kingdom; MRC Centre for Neuropsychiatric Genetics and Genomics, Institute of Psychological Medicine and Clinical Neurosciences, Cardiff School of Medicine, Cardiff University, Cardiff, United Kingdom; School for Mental Health and Neuroscience, Faculty of Health, Medicine and Life Sciences, Maastricht University, Maastricht, the Netherlands.
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.
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.
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Authors: R Matthew Hutchison; Thilo Womelsdorf; Elena A Allen; Peter A Bandettini; Vince D Calhoun; Maurizio Corbetta; Stefania Della Penna; Jeff H Duyn; Gary H Glover; Javier Gonzalez-Castillo; Daniel A Handwerker; Shella Keilholz; Vesa Kiviniemi; David A Leopold; Francesco de Pasquale; Olaf Sporns; Martin Walter; Catie Chang Journal: Neuroimage Date: 2013-05-24 Impact factor: 6.556
Authors: Stephan Ripke; Colm O'Dushlaine; Kimberly Chambert; Jennifer L Moran; Anna K Kähler; Susanne Akterin; Sarah E Bergen; Ann L Collins; James J Crowley; Menachem Fromer; Yunjung Kim; Sang Hong Lee; Patrik K E Magnusson; Nick Sanchez; Eli A Stahl; Stephanie Williams; Naomi R Wray; Kai Xia; Francesco Bettella; Anders D Borglum; Brendan K Bulik-Sullivan; Paul Cormican; Nick Craddock; Christiaan de Leeuw; Naser Durmishi; Michael Gill; Vera Golimbet; Marian L Hamshere; Peter Holmans; David M Hougaard; Kenneth S Kendler; Kuang Lin; Derek W Morris; Ole Mors; Preben B Mortensen; Benjamin M Neale; Francis A O'Neill; Michael J Owen; Milica Pejovic Milovancevic; Danielle Posthuma; John Powell; Alexander L Richards; Brien P Riley; Douglas Ruderfer; Dan Rujescu; Engilbert Sigurdsson; Teimuraz Silagadze; August B Smit; Hreinn Stefansson; Stacy Steinberg; Jaana Suvisaari; Sarah Tosato; Matthijs Verhage; James T Walters; Douglas F Levinson; Pablo V Gejman; Kenneth S Kendler; Claudine Laurent; Bryan J Mowry; Michael C O'Donovan; Michael J Owen; Ann E Pulver; Brien P Riley; Sibylle G Schwab; Dieter B Wildenauer; Frank Dudbridge; Peter Holmans; Jianxin Shi; Margot Albus; Madeline Alexander; Dominique Campion; David Cohen; Dimitris Dikeos; Jubao Duan; Peter Eichhammer; Stephanie Godard; Mark Hansen; F Bernard Lerer; Kung-Yee Liang; Wolfgang Maier; Jacques Mallet; Deborah A Nertney; Gerald Nestadt; Nadine Norton; Francis A O'Neill; George N Papadimitriou; Robert Ribble; Alan R Sanders; Jeremy M Silverman; Dermot Walsh; Nigel M Williams; Brandon Wormley; Maria J Arranz; Steven Bakker; Stephan Bender; Elvira Bramon; David Collier; Benedicto Crespo-Facorro; Jeremy Hall; Conrad Iyegbe; Assen Jablensky; Rene S Kahn; Luba Kalaydjieva; Stephen Lawrie; Cathryn M Lewis; Kuang Lin; Don H Linszen; Ignacio Mata; Andrew McIntosh; Robin M Murray; Roel A Ophoff; John Powell; Dan Rujescu; Jim Van Os; Muriel Walshe; Matthias Weisbrod; Durk Wiersma; Peter Donnelly; Ines Barroso; Jenefer M Blackwell; Elvira Bramon; Matthew A Brown; Juan P Casas; Aiden P Corvin; Panos Deloukas; Audrey Duncanson; Janusz Jankowski; Hugh S Markus; Christopher G Mathew; Colin N A Palmer; Robert Plomin; Anna Rautanen; Stephen J Sawcer; Richard C Trembath; Ananth C Viswanathan; Nicholas W Wood; Chris C A Spencer; Gavin Band; Céline Bellenguez; Colin Freeman; Garrett Hellenthal; Eleni Giannoulatou; Matti Pirinen; Richard D Pearson; Amy Strange; Zhan Su; Damjan Vukcevic; Peter Donnelly; Cordelia Langford; Sarah E Hunt; Sarah Edkins; Rhian Gwilliam; Hannah Blackburn; Suzannah J Bumpstead; Serge Dronov; Matthew Gillman; Emma Gray; Naomi Hammond; Alagurevathi Jayakumar; Owen T McCann; Jennifer Liddle; Simon C Potter; Radhi Ravindrarajah; Michelle Ricketts; Avazeh Tashakkori-Ghanbaria; Matthew J Waller; Paul Weston; Sara Widaa; Pamela Whittaker; Ines Barroso; Panos Deloukas; Christopher G Mathew; Jenefer M Blackwell; Matthew A Brown; Aiden P Corvin; Mark I McCarthy; Chris C A Spencer; Elvira Bramon; Aiden P Corvin; Michael C O'Donovan; Kari Stefansson; Edward Scolnick; Shaun Purcell; Steven A McCarroll; Pamela Sklar; Christina M Hultman; Patrick F Sullivan Journal: Nat Genet Date: 2013-08-25 Impact factor: 38.330