Searching for Imaging Biomarkers of Psychotic Dysconnectivity

Biol Psychiatry Cogn Neurosci Neuroimaging. 2021 Dec;6(12):1135-1144. doi: 10.1016/j.bpsc.2020.12.002. Epub 2020 Dec 16.


Background: Progress in precision psychiatry is predicated on identifying reliable individual-level diagnostic biomarkers. For psychosis, measures of structural and functional connectivity could be promising biomarkers given consistent reports of dysconnectivity across psychotic disorders using magnetic resonance imaging.

Methods: We leveraged data from four independent cohorts of patients with psychosis and control subjects with observations from approximately 800 individuals. We used group-level analyses and two supervised machine learning algorithms (support vector machines and ridge regression) to test within-, between-, and across-sample classification performance of white matter and resting-state connectivity metrics.

Results: Although we replicated group-level differences in brain connectivity, individual-level classification was suboptimal. Classification performance within samples was variable across folds (highest area under the curve [AUC] range = 0.30) and across datasets (average support vector machine AUC range = 0.50; average ridge regression AUC range = 0.18). Classification performance between samples was similarly variable or resulted in AUC values of approximately 0.65, indicating a lack of model generalizability. Furthermore, collapsing across samples (resting-state functional magnetic resonance imaging, N = 888; diffusion tensor imaging, N = 860) did not improve model performance (maximal AUC = 0.67). Ridge regression models generally outperformed support vector machine models, although classification performance was still suboptimal in terms of clinical relevance. Adjusting for demographic covariates did not greatly affect results.

Conclusions: Connectivity measures were not suitable as diagnostic biomarkers for psychosis as assessed in this study. Our results do not negate that other approaches may be more successful, although it is clear that a systematic approach to individual-level classification with large independent validation samples is necessary to properly vet neuroimaging features as diagnostic biomarkers.

Keywords: Biomarkers; Connectivity; MRI; Machine learning; Magnetic resonance imaging; Psychosis.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Biomarkers
  • Brain
  • Diffusion Tensor Imaging* / methods
  • Humans
  • Magnetic Resonance Imaging / methods
  • White Matter*


  • Biomarkers