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Multicenter Study
. 2020 Mar 1;143(3):1027-1038.
doi: 10.1093/brain/awaa025.

Two distinct neuroanatomical subtypes of schizophrenia revealed using machine learning

Ganesh B Chand  1   2 , Dominic B Dwyer  3 , Guray Erus  1   2 , Aristeidis Sotiras  1   2   4 , Erdem Varol  1   2   5 , Dhivya Srinivasan  1   2 , Jimit Doshi  1   2 , Raymond Pomponio  1   2 , Alessandro Pigoni  3   6 , Paola Dazzan  7 , Rene S Kahn  8 , Hugo G Schnack  9 , Marcus V Zanetti  10   11 , Eva Meisenzahl  12 , Geraldo F Busatto  10 , Benedicto Crespo-Facorro  13   14 , Christos Pantelis  15 , Stephen J Wood  16   17   18 , Chuanjun Zhuo  19   20 , Russell T Shinohara  2   21 , Haochang Shou  2   21 , Yong Fan  1   2 , Ruben C Gur  1   22 , Raquel E Gur  1   22 , Theodore D Satterthwaite  2   22 , Nikolaos Koutsouleris  3 , Daniel H Wolf  2   22 , Christos Davatzikos  1   2
Affiliations
Multicenter Study

Two distinct neuroanatomical subtypes of schizophrenia revealed using machine learning

Ganesh B Chand et al. Brain. .

Abstract

Neurobiological heterogeneity in schizophrenia is poorly understood and confounds current analyses. We investigated neuroanatomical subtypes in a multi-institutional multi-ethnic cohort, using novel semi-supervised machine learning methods designed to discover patterns associated with disease rather than normal anatomical variation. Structural MRI and clinical measures in established schizophrenia (n = 307) and healthy controls (n = 364) were analysed across three sites of PHENOM (Psychosis Heterogeneity Evaluated via Dimensional Neuroimaging) consortium. Regional volumetric measures of grey matter, white matter, and CSF were used to identify distinct and reproducible neuroanatomical subtypes of schizophrenia. Two distinct neuroanatomical subtypes were found. Subtype 1 showed widespread lower grey matter volumes, most prominent in thalamus, nucleus accumbens, medial temporal, medial prefrontal/frontal and insular cortices. Subtype 2 showed increased volume in the basal ganglia and internal capsule, and otherwise normal brain volumes. Grey matter volume correlated negatively with illness duration in Subtype 1 (r = -0.201, P = 0.016) but not in Subtype 2 (r = -0.045, P = 0.652), potentially indicating different underlying neuropathological processes. The subtypes did not differ in age (t = -1.603, df = 305, P = 0.109), sex (chi-square = 0.013, df = 1, P = 0.910), illness duration (t = -0.167, df = 277, P = 0.868), antipsychotic dose (t = -0.439, df = 210, P = 0.521), age of illness onset (t = -1.355, df = 277, P = 0.177), positive symptoms (t = 0.249, df = 289, P = 0.803), negative symptoms (t = 0.151, df = 289, P = 0.879), or antipsychotic type (chi-square = 6.670, df = 3, P = 0.083). Subtype 1 had lower educational attainment than Subtype 2 (chi-square = 6.389, df = 2, P = 0.041). In conclusion, we discovered two distinct and highly reproducible neuroanatomical subtypes. Subtype 1 displayed widespread volume reduction correlating with illness duration, and worse premorbid functioning. Subtype 2 had normal and stable anatomy, except for larger basal ganglia and internal capsule, not explained by antipsychotic dose. These subtypes challenge the notion that brain volume loss is a general feature of schizophrenia and suggest differential aetiologies. They can facilitate strategies for clinical trial enrichment and stratification, and precision diagnostics.

Keywords: neuroanatomical heterogeneity; schizophrenia; semi-supervised machine learning; structural MRI; voxel-wise analysis.

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Figures

Figure 1
Figure 1
Statistical significance of ARI obtained for different subtypes (K) via comparison with the null distribution obtained from random permutations. *FDR-corrected P < 10−3 for comparison between Null and schizophrenia (SCZ). n.s. = not significant.
Figure 2
Figure 2
Patterns of grey and white matter volumes identifying the two subtypes. Compared to healthy controls (HC), (A) schizophrenia Subtype 1 (SCZ1) exhibits widespread patterns of smaller grey matter volumes especially in the thalamus, nucleus accumbens, medial temporal, medial prefrontal/frontal and insular cortices, (B) schizophrenia Subtype 2 (SCZ2) exhibits larger grey matter volumes in the basal ganglia (pallidum, putamen, and parts of caudate), (C) schizophrenia Subtype 1 shows smaller white matter volumes, and (D) schizophrenia Subtype 2 shows larger white matter volumes, especially in the internal capsule. Effect size (Cohen’s d) maps were generated from regional volumetric maps masked by the set of regions that showed statistically significant differences (PFDR < 0.05) in the MIDAS analysis.
Figure 3
Figure 3
Reproducibility analysis. Patterns of grey matter volumes in the two subtypes using the leave-one-site-out validation: Compared to healthy control (HC), (A) schizophrenia Subtype 1 (SCZ1) shows widespread smaller volumes prominently in the thalamus, nucleus accumbens, medial temporal, medial prefrontal/frontal and insular cortices, and (B) Subtype 2 (SCZ2) shows larger volume in the basal ganglia. Effect size maps were generated from regional volumetric maps masked by the set of regions that showed statistically significant differences (PFDR < 0.05) in the MIDAS analysis.
Figure 4
Figure 4
Associations between total grey matter volume and illness duration in the two subtypes. (A) Grey matter volume is correlated negatively with illness duration in schizophrenia Subtype 1 (SCZ1; r = −0.201 and PFDR = 0.016), but (B) grey matter volume is not significantly correlated with illness duration in schizophrenia Subtype 2 (SCZ2; r = −0.045 and P = 0.652).
Figure 5
Figure 5
Summary of schizophrenia Subtypes 1 (SCZ1) and 2 (SCZ2).
See this image and copyright information in PMC

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