Complex human behavior emerges from dynamic patterns of neural activity that transiently synchronize between distributed brain networks. This study aims to model the dynamics of neural activity in individuals with schizophrenia and to investigate whether the attributes of these dynamics associate with the disorder's behavioral and cognitive deficits. A hidden Markov model (HMM) was inferred from resting‐state functional magnetic resonance imaging (fMRI) data that was temporally concatenated across individuals with schizophrenia (n = 41) and healthy comparison individuals (n = 41). Under the HMM, fluctuations in fMRI activity within 14 canonical resting‐state networks were described using a repertoire of 12 brain states. The proportion of time spent in each state and the mean length of visits to each state were compared between groups, and canonical correlation analysis was used to test for associations between these state descriptors and symptom severity. Individuals with schizophrenia activated default mode and executive networks for a significantly shorter proportion of the 8‐min acquisition than healthy comparison individuals. While the default mode was activated less frequently in schizophrenia, the duration of each activation was on average 4–5 s longer than the comparison group. Severity of positive symptoms was associated with a longer proportion of time spent in states characterized by inactive default mode and executive networks, together with heightened activity in sensory networks. Furthermore, classifiers trained on the state descriptors predicted individual diagnostic status with an accuracy of 76–85%.

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The potential of normative modeling to make individualized predictions has led to structural neuroimaging results that go beyond the case-control approach. However, site effects, often confounded with variables of interest in a complex manner, induce a bias in estimates of normative models, which has impeded the application of normative models to large multi-site neuroimaging data sets. In this study, we suggest accommodating for these site effects by including them as random effects in a hierarchical Bayesian model. We compare the performance of a linear and a non-linear hierarchical Bayesian model in modeling the effect of age on cortical thickness. We used data of 570 healthy individuals from the ABIDE (autism brain imaging data exchange, http://preprocessed-connectomes-project.org/abide/) data set in our experiments. We compare the proposed method to several harmonization techniques commonly used to deal with additive and multiplicative site effects, including regressing out site and harmonizing for site with ComBat, both with and without explicitly preserving variance related to age and sex as biological variation of interest. In addition, we make predictions from raw data, in which site has not been accommodated for. The proposed hierarchical Bayesian method shows the best performance according to multiple metrics. Performance is particularly bad for the regression model and the ComBat model when age and sex are not explicitly modeled. In addition, the predictions of those models are noticeably poorly calibrated, suffering from a loss of more than 90 % of the original variance. From these results we conclude that harmonization techniques like regressing out site and ComBat do not sufficiently accommodate for multi-site effects in pooled neuroimaging data sets. Our results show that the complex interaction between site and variables of interest is likely to be underestimated by those tools. One consequence is that harmonization techniques removed too much variance, which is undesirable and may have unpredictable consequences for subsequent analysis. Our results also show that this can be mostly avoided by explicitly modeling site as part of a hierarchical Bayesian Model. We discuss the potential of z-scores derived from normative models to be used as site corrected variables and of our method as site correction tool.

Correlation in functional MRI activity between spatially separated brain regions can fluctuate dynamically when an individual is at rest. These dynamics are typically characterized temporally by measuring fluctuations in functional connectivity between brain regions that remain fixed in space over time. Here, dynamics in functional connectivity were characterized in both time and space. Temporal dynamics were mapped with sliding-window correlation, while spatial dynamics were characterized by enabling network regions to vary in size (shrink/grow) over time according to the functional connectivity profile of their constituent voxels. These temporal and spatial dynamics were evaluated as biomarkers to distinguish schizophrenia patients from controls, and compared to current biomarkers based on static measures of resting-state functional connectivity. Support vector machine classifiers were trained using: (a) static, (b) dynamic in time, (c) dynamic in space, and (d) dynamic in time and space characterizations of functional connectivity within canonical resting-state brain networks. Classifiers trained on functional connectivity dynamics mapped over both space and time predicted diagnostic status with accuracy exceeding 91%, whereas utilizing only spatial or temporal dynamics alone yielded lower classification accuracies. Static measures of functional connectivity yielded the lowest accuracy (79.5%). Compared to healthy comparison individuals, schizophrenia patients generally exhibited functional connectivity that was reduced in strength and more variable. Robustness was established with replication in an independent dataset. The utility of biomarkers based on temporal and spatial functional connectivity dynamics suggests that resting-state dynamics are not trivially attributable to sampling variability and head motion.