Evolutionary modifications in human brain connectivity associated with schizophrenia

Martijn P. van den Heuvel, Lianne H. Scholtens, Siemon C. de Lange, Rory Pijnenburg, Wiepke Cahn, Neeltje E.M. van Haren, Iris E. Sommer, Marco Bozzali, Kathrin Koch, Marco P. Boks, Jonathan Repple, Michela Pievani, Longchuan Li, Todd M. Preuss, James K. Rilling

Research output: Contribution to JournalArticleAcademicpeer-review

Abstract

The genetic basis and human-specific character of schizophrenia has led to the hypothesis that human brain evolution may have played a role in the development of the disorder. We examined schizophrenia-related changes in brain connectivity in the context of evolutionary changes in human brain wiring by comparing in vivo neuroimaging data from humans and chimpanzees, one of our closest living evolutionary relatives and a species with which we share a very recent common ancestor. We contrasted the connectome layout between the chimpanzee and human brain and compared differences with the pattern of schizophrenia-related changes in brain connectivity as observed in patients. We show evidence of evolutionary modifications of human brain connectivity to significantly overlap with the cortical pattern of schizophrenia-related dysconnectivity (P < 0.001, permutation testing). We validated these effects in three additional, independent schizophrenia datasets. We further assessed the specificity of effects by examining brain dysconnectivity patterns in seven other psychiatric and neurological brain disorders (including, among others, major depressive disorder and obsessive-compulsive disorder, arguably characterized by behavioural symptoms that are less specific to humans), which showed no such associations with modifications of human brain connectivity. Comparisons of brain connectivity across humans, chimpanzee and macaques further suggest that features of connectivity that evolved in the human lineage showed the strongest association to the disorder, that is, brain circuits potentially related to human evolutionary specializations. Taken together, our findings suggest that human-specific features of connectome organization may be enriched for changes in brain connectivity related to schizophrenia. Modifications in human brain connectivity in service of higher order brain functions may have potentially also rendered the brain vulnerable to brain dysfunction.

Original languageEnglish
Pages (from-to)3991-4002
Number of pages12
JournalBrain : a journal of neurology
Volume142
Issue number12
DOIs
Publication statusPublished - 1 Dec 2019

Funding

Data collection was performed at the Mind Research Network, and funded by a Center of Biomedical Research Excellence (COBRE) grant 5P20RR021938/P20GM103472 from the NIH to V.C. M.v.d.H. was supported by VIDI Grant 452-16-015 and Aard-en levenswetenschappen (ALW) Grant ALWOP.179 from the Netherlands Organization for Scientific Research and by a Mental Health and Quality of Life fellowship. This work was supported by National Institutes of Health Grants P01AG026423 and National Center for Research Resources P51RR165 (superseded by the Office of Research Infrastructure Programs/OD P51OD11132) to the Yerkes National Primate Research Center, and by the National Chimpanzee Brain Resource, R24NS092988. L.L. was supported by National Institutes of Health Grants P50MH100029, R01MH118534, R01MH118285. The Bipolar disorder imaging dataset BP-1 was supported by the National Institute of Mental Health (Grant number: R01MH 090 553). Human MRI data were partly provided by the Human Connectome Project, WU-Minn Consortium (Principal Investigators: David Van Essen and Kamil Ugurbil; 1U54MH091657) funded by the 16 NIH Institutes and Centers that support the NIH Blueprint for Neuroscience Research; and by the McDonnell Center for Systems Neuroscience at Washington University. M.P. was supported by the Italian Ministry of Health (GR2011-02349787 and Ricerca Corrente). The schizophrenia replication dataset 2 was funded by VIDI-grant 452-11-014 from the Dutch Organization for Scientific Research to NEM van Haren.

FundersFunder number
Center of Biomedical Research Excellence5P20RR021938/P20GM103472
Dutch Organization for Scientific Research
Italian Ministry of HealthGR2011-02349787, 452-11-014
National Chimpanzee Brain ResourceR01MH118285, P50MH100029, R01MH118534, R24NS092988
Netherlands Organization for Scientific Research
VIDIALWOP.179, 452-16-015
National Institutes of HealthP01AG026423
National Institute of Mental HealthR01MH 090 553, 1U54MH091657
NIH Office of the DirectorP51OD011132
National Center for Research ResourcesP51RR165
NIH Blueprint for Neuroscience Research
McDonnell Center for Systems Neuroscience
Yerkes National Primate Research Center, Emory University

    Keywords

    • brain evolution
    • connectome
    • neuroimaging
    • neuropathology
    • schizophrenia

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