Abstract Brain functional networks identified from resting fMRI data have the potential to reveal biomarkers for brain disorders, but studies of complex mental illnesses such as schizophrenia (SZ) often yield mixed results across replication studies. This is likely due in part to the complexity of the disorder, the short data acquisition time, and the limited ability of the approaches for brain imaging data mining. Therefore, the use of analytic approaches which can both capture individual variability while offering comparability across analyses is highly preferred. Fully blind data-driven approaches such as independent component analysis (ICA) are hard to compare across studies, and approaches that use fixed atlas-based regions can have limited sensitivity to individual sensitivity. By contrast, spatially constrained ICA (scICA) provides a hybrid, fully automated solution that can incorporate spatial network priors while also adapting to new subjects. However, scICA has thus far only been used with a single spatial scale. In this work, we present an approach using scICA to extract subject-specific intrinsic connectivity networks (ICNs) from fMRI data at multiple spatial scales (ICA model orders), which also enables us to study interactions across spatial scales. We evaluate this approach using a large N (N&gt;1,600) study of schizophrenia divided into separate validation and replication sets. A multi-scale ICN template was estimated and labeled, then used as input into spatially constrained ICA which was computed on an individual subject level. We then performed a subsequent analysis of multiscale functional network connectivity (msFNC) to evaluate the patient data, including group differences and classification. Results showed highly consistent group differences in msFNC in regions including cerebellum, thalamus, and motor/auditory networks. Importantly, multiple msFNC pairs linking different spatial scales were implicated. We also used the msFNC features as input to a classification model in cross-validated hold-out data and also in an independent test data. Visualization of predictive features was performed by evaluating their feature weights. Finally, we evaluated the relationship of the identified patterns to positive symptoms and found consistent results across datasets. The results verified the robustness of our framework in evaluating brain functional connectivity of schizophrenia at multiple spatial scales, implicated consistent and replicable brain networks, and highlighted a promising approach for leveraging resting fMRI data for brain biomarker development.

Multi-model order spatially constrained ICA reveals highly replicable group differences and consistent predictive results from fMRI data