Generative network models of altered structural brain connectivity in schizophrenia
Xiaolong Zhang,
Urs Braun,
Anais Harneit,
Zhenxiang Zang,
Lena S. Geiger,
Richard F. Betzel,
Junfang Chen,
Janina I. Schweiger,
Kristina Schwarz,
Jonathan Rochus Reinwald,
Stefan Fritze,
Stephanie Witt,
Marcella Rietschel,
Markus M. Nöthen,
Franziska Degenhardt,
Emanuel Schwarz,
Dusan Hirjak,
Andreas Meyer-Lindenberg,
Danielle S. Bassett,
Heike Tost
Affiliations
Xiaolong Zhang
Department of Psychiatry and Psychotherapy, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, J5 68159 Mannheim, Germany
Urs Braun
Department of Psychiatry and Psychotherapy, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, J5 68159 Mannheim, Germany; Department of Bioengineering, University of Pennsylvania, Philadelphia, PA, USA; Corresponding author at Department of Psychiatry and Psychotherapy, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, J5 68159 Mannheim, Germany.
Anais Harneit
Department of Psychiatry and Psychotherapy, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, J5 68159 Mannheim, Germany
Zhenxiang Zang
Department of Psychiatry and Psychotherapy, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, J5 68159 Mannheim, Germany
Lena S. Geiger
Department of Psychiatry and Psychotherapy, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, J5 68159 Mannheim, Germany
Richard F. Betzel
Department of Psychological and Brain Sciences, Indiana University, Bloomington, IN, USA
Junfang Chen
Department of Psychiatry and Psychotherapy, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, J5 68159 Mannheim, Germany
Janina I. Schweiger
Department of Psychiatry and Psychotherapy, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, J5 68159 Mannheim, Germany
Kristina Schwarz
Department of Psychiatry and Psychotherapy, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, J5 68159 Mannheim, Germany
Jonathan Rochus Reinwald
Department of Psychiatry and Psychotherapy, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, J5 68159 Mannheim, Germany
Stefan Fritze
Department of Psychiatry and Psychotherapy, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, J5 68159 Mannheim, Germany
Stephanie Witt
Department of Genetic Epidemiology in Psychiatry, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany
Marcella Rietschel
Department of Genetic Epidemiology in Psychiatry, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany
Markus M. Nöthen
Institute of Human Genetics, University of Bonn, School of Medicine & University Hospital Bonn, Bonn, Germany
Franziska Degenhardt
Institute of Human Genetics, University of Bonn, School of Medicine & University Hospital Bonn, Bonn, Germany
Emanuel Schwarz
Department of Psychiatry and Psychotherapy, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, J5 68159 Mannheim, Germany
Dusan Hirjak
Department of Psychiatry and Psychotherapy, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, J5 68159 Mannheim, Germany
Andreas Meyer-Lindenberg
Department of Psychiatry and Psychotherapy, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, J5 68159 Mannheim, Germany
Danielle S. Bassett
Department of Bioengineering, University of Pennsylvania, Philadelphia, PA, USA; Department of Psychiatry, Department of Electrical & Systems Engineering, Department of Neurology, and Department of Physics & Astronomy, University of Pennsylvania, Philadelphia, PA, USA; Santa Fe Institute, Santa Fe, NM USA
Heike Tost
Department of Psychiatry and Psychotherapy, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, J5 68159 Mannheim, Germany
Alterations in the structural connectome of schizophrenia patients have been widely characterized, but the mechanisms remain largely unknown. Generative network models have recently been introduced as a tool to test the biological underpinnings of altered brain network formation. We evaluated different generative network models in healthy controls (n=152), schizophrenia patients (n=66), and their unaffected first-degree relatives (n=32), and we identified spatial and topological factors contributing to network formation. We further investigated how these factors relate to cognition and to polygenic risk for schizophrenia. Our data show that among the four tested classes of generative network models, structural brain networks were optimally accounted for by a two-factor model combining spatial constraints and topological neighborhood structure. The same wiring model explained brain network formation across study groups. However, relatives and schizophrenia patients exhibited significantly lower spatial constraints and lower topological facilitation compared to healthy controls. Further exploratory analyses point to potential associations of the model parameter reflecting spatial constraints with the polygenic risk for schizophrenia and cognitive performance. Our results identify spatial constraints and local topological structure as two interrelated mechanisms contributing to regular brain network formation as well as altered connectomes in schizophrenia and healthy individuals at familial risk for schizophrenia. On an exploratory level, our data further point to the potential relevance of spatial constraints for the genetic risk for schizophrenia and general cognitive functioning, thereby encouraging future studies in following up on these observations to gain further insights into the biological basis and behavioral relevance of model parameters.
