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Evolutionary modifications in human brain connectivity associated with schizophrenia - PubMed

  • ️Tue Jan 01 2019

Evolutionary modifications in human brain connectivity associated with schizophrenia

Martijn P van den Heuvel et al. Brain. 2019.

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.

Keywords: brain evolution; connectome; neuroimaging; neuropathology; schizophrenia.

© The Author(s) (2019). Published by Oxford University Press on behalf of the Guarantors of Brain.

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Figures

Figure 1
Figure 1

Schizophrenia dysconnectivity. (A) The cortico-cortical fibre connections of the group average human connectome (group threshold 60%) with level of dysconnectivity (fractional anisotropy weighted) as measured between n = 48 schizophrenia patients and n = 43 matched healthy control subjects. Dysconnectivity levels are indicated from light blue (no patient-control difference) to dark blue (patients showing significantly lower fractional anisotropy than controls) NBS, P = 0.024. (B) Cortical regions involved in the NBS subnetwork showing significantly reduced white matter connectivity in patients.

Figure 2
Figure 2

Chimpanzee and human connectome. (A and B) Fibre reconstruction of an exemplary chimpanzee and human subject. Lower right images show the DK-114 parcellation for an exemplary chimpanzee and human brain subject. (C) The group averaged chimpanzee (n = 22, 60% group threshold) and human connectome (n = 58, 60% threshold group connectome). Coloured values show (normalized) fractional anisotropy values of the chimpanzee and human connectome from low (blue) to high (red). Non-coloured pixels represent no connection present. (D) Correlation between fractional anisotropy (FA) values of all shared connections of the two species (r = 0.93, P < 0.001).

Figure 3
Figure 3

Human-specific connections and association to disease. (A) Identified cortico-cortical connections of the human cerebral connectome. Red connections identify human-specific connections, orange connections show human-chimpanzee shared connections showing significant positive human enhancement (normalized fractional anisotropy, P < 0.05 FDR). Green connections indicate remaining human-chimpanzee shared connections showing no species difference and connections of the group average connectome. (B) Subset of cortical regions that displayed one or more human-specific cortico-cortical connections. (C) Schizophrenia effects (y-axis: t-statistic of fractional anisotropy values controls versus patients) across human-specific (red) and connections shared between humans and chimpanzees. Effects in shared connections were further decomposed into connections showing enhanced human development as compared to chimpanzees (chimpanzee-human difference FDR P < 0.05) and connections that showed no positive difference in normalized fractional anisotropy between chimpanzees and humans (P > 0.05). Human-specific connections showed the largest effect, with human enhanced connections in second place (Jonckheere-Terpstra P = 0.002). Boxes display the interval between 25th and 75th percentiles (q1 and q3); white lines indicate median values, white circles indicate mean values; whiskers indicate the interval between q1−1.5×(q3−q1) and q3+1.5×(q3−q1); violin plots show the distribution of values (smoothed for visualization with a 0.4 kernel).

Figure 4
Figure 4

Cross-disorder comparison. Schizophrenia effects were compared to other brain disorders to assess the level of specificity to schizophrenia. Figure shows the difference in overlap of disease dysconnectivity between human-specific versus species-shared connections (y-axis) for schizophrenia (three datasets combined) and seven other brain disorders (x-axis) associated with connectome alterations in the literature, together with effects in the schizophrenia COBRE dataset. *P < 0.05 human-specific versus human-shared connections, FDR corrected. SCZ = schizophrenia, combined effect of the principal and two validation schizophrenia sets (see Supplementary Fig. 4 for effects in all datasets separately); BP = bipolar disorder; ASD = autism spectrum disorder, combined effect of three ASD ABIDE-II datasets; MDD = major depressive disorder; OCD = obsessive-compulsive disorder; bvFTD = behavioural variant frontotemporal dementia; AD = Alzheimer’s disease; MCI = mild cognitive impairment; SCZcobre = shizophrenia COBRE dataset. Inset depicts the number of patient datasets included in each disorder dataset (Supplementary Tables 6 and 7). Boxes display the interval between 25th and 75th percentiles (q1 and q3); white lines indicate median values, white circles indicate mean values; whiskers indicate the interval between q1−1.5×(q3−q1) and q3+1.5×(q3−q1); violin plots show the distribution of values (smoothed for visualization with a 0.4 kernel).

Figure 5
Figure 5

Human-chimpanzee-macaque comparison. Violin plot of schizophrenia dysconnectivity levels for human-specific connections (H), human-chimpanzee-specific connections (HC, connections observed in humans and chimpanzees, not in macaques) and human-chimpanzee-macaque shared connections (HCM). Boxes display the interval between 25th and 75th percentiles (q1 and q3); white lines indicate median values, white circles indicate mean values; whiskers indicate the interval between q1−1.5×(q3−q1) and q3+1.5×(q3−q1); violin plots show the distribution of values (smoothed for visualization with a 0.4 kernel).

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References

    1. Alvarado-Alanis P, Leon-Ortiz P, Reyes-Madrigal F, Favila R, Rodriguez-Mayoral O, Nicolini H, et al.Abnormal white matter integrity in antipsychotic-naive first-episode psychosis patients assessed by a DTI principal component analysis. Schizophr Res 2015; 162: 14–21. - PMC - PubMed
    1. Andreasen NC, Olsen SA, Dennert JW, Smith MR. Ventricular enlargement in schizophrenia: relationship to positive and negative symptoms. Am J Psychiatry. 1982; 139: 297–302. - PubMed
    1. Ardesch DJ, Scholtens LH, Li L, Preuss TM, Rilling J, van den Heuvel MP. Evolutionary expansion of connectivity between multimodal association areas in the human brain compared to chimpanzees. Proc Natl Acad Sci U S A 2019; 116: 7101–6. - PMC - PubMed
    1. Baker ST, Yucel M, Fornito A, Allen NB, Lubman DI. A systematic review of diffusion weighted MRI studies of white matter microstructure in adolescent substance users. Neurosci Biobehav Rev 2013; 37: 1713–23. - PubMed
    1. Beaulieu C. The basis of anisotropic water diffusion in the nervous system-a technical review. NMR Biomed 2002; 15: 435–55. - PubMed

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