Latent Clinical-Anatomical Dimensions of Schizophrenia.

Widespread structural brain abnormalities have been consistently reported in schizophrenia, but their relation to the heterogeneous clinical manifestations remains unknown. In particular, it is unclear whether anatomical abnormalities in discrete regions give rise to discrete symptoms or whether distributed abnormalities give rise to the broad clinical profile associated with schizophrenia. Here, we apply a multivariate data-driven approach to investigate covariance patterns between multiple-symptom domains and distributed brain abnormalities in schizophrenia. Structural magnetic resonance imaging and clinical data were derived from one discovery sample (133 patients and 113 controls) and one independent validation sample (108 patients and 69 controls). Disease-related voxel-wise brain abnormalities were estimated using deformation-based morphometry. Partial least-squares analysis was used to comprehensively map clinical, neuropsychological, and demographic data onto distributed deformation in a single multivariate model. The analysis identified 3 latent clinical-anatomical dimensions that collectively accounted for 55% of the covariance between clinical data and brain deformation. The first latent clinical-anatomical dimension was replicated in an independent sample, encompassing cognitive impairments, negative symptom severity, and brain abnormalities within the default mode and visual networks. This cognitive-negative dimension was associated with low socioeconomic status and was represented across multiple races. Altogether, we identified a continuous cognitive-negative dimension of schizophrenia, centered on 2 intrinsic networks. By simultaneously taking into account both clinical manifestations and neuroanatomical abnormalities, the present results open new avenues for multi-omic stratification and biotyping of individuals with schizophrenia.

Spatial Patterning of Tissue Volume Loss in Schizophrenia Reflects Brain Network Architecture.

BACKGROUND: There is growing recognition that connectome architecture shapes cortical and subcortical gray matter atrophy across a spectrum of neurological and psychiatric diseases. Whether connectivity contributes to tissue volume loss in schizophrenia in the same manner remains unknown. METHODS: Here, we relate tissue volume loss in patients with schizophrenia to patterns of structural and functional connectivity. Gray matter deformation was estimated in a sample of 133 individuals with chronic schizophrenia (48 women, mean age 34.7 ± 12.9 years) and 113 control subjects (64 women, mean age 23.5 ± 8.4 years). Deformation-based morphometry was used to estimate cortical and subcortical gray matter deformation from T1-weighted magnetic resonance images. Structural and functional connectivity patterns were derived from an independent sample of 70 healthy participants using diffusion spectrum imaging and resting-state functional magnetic resonance imaging. RESULTS: We found that regional deformation is correlated with the deformation of structurally and functionally connected neighbors. Distributed deformation patterns are circumscribed by specific functional systems (the ventral attention network) and cytoarchitectonic classes (limbic class), with an epicenter in the anterior cingulate cortex. CONCLUSIONS: Altogether, the present study demonstrates that brain tissue volume loss in schizophrenia is conditioned by structural and functional connectivity, accounting for 25% to 35% of regional variance in deformation.

Identifying schizophrenia subgroups using clustering and supervised learning.

Schizophrenia has a 1% incidence rate world-wide and those diagnosed present with positive (e.g. hallucinations, delusions), negative (e.g. apathy, asociality), and cognitive symptoms. However, both symptom burden and associated brain alterations are highly heterogeneous and intimately linked to prognosis. In this study, we present a method to predict individual symptom profiles by first deriving clinical subgroups and then using machine learning methods to perform subject-level classification based on magnetic resonance imaging (MRI) derived neuroanatomical measures. Symptomatic and MRI data of 167 subjects were used. Subgroups were defined using hierarchical clustering of clinical data resulting in 3 stable clusters: 1) high symptom burden, 2) predominantly positive symptom burden, and 3) mild symptom burden. Cortical thickness estimates were obtained in 78 regions of interest and were input, along with demographic data, into three machine learning models (logistic regression, support vector machine, and random forest) to predict subgroups. Random forest performance metrics for predicting the group membership of the high and mild symptom burden groups exceeded those of the baseline comparison of the entire schizophrenia population versus normal controls (AUC: 0.81 and 0.78 vs. 0.75). Additionally, an analysis of the most important features in the random forest classification demonstrated consistencies with previous findings of regional impairments and symptoms of schizophrenia.