Increased whole-brain functional heterogeneity in psychosis during rest and task

Past work has shown that people with schizophrenia exhibit more cross-subject heterogeneity in their functional connectivity patterns. However, it remains unclear whether specific brain networks are implicated, whether common confounds could explain the results, or whether task activations might also be more heterogeneous. Unambiguously establishing the existence and extent of functional heterogeneity constitutes a first step toward understanding why it emerges and what it means clinically.

We first leveraged data from the HCP Early Psychosis project. Functional connectivity (FC) was extracted from 718 parcels via principal components regression. Networks were defined via a brain network partition (Ji et al., 2019). We also examined an independent data set with controls, later-stage schizophrenia patients, and ADHD patients during rest and during a working memory task. We quantified heterogeneity by averaging the Pearson correlation distance of each subject's FC or task activity pattern to that of every other subject of the same cohort.

Affective and non-affective early psychosis patients exhibited more cross-subject whole-brain heterogeneity than healthy controls (ps < 0.001, Hedges' g > 0.74). Increased heterogeneity could be found in up to seven networks. In-scanner motion, medication, nicotine, and comorbidities could not explain the results. Later-stage schizophrenia patients exhibited heterogeneous connectivity patterns and task activations compared to ADHD and control subjects. Interestingly, individual connection weights, parcel-wise task activations, and network averages thereof were not more variable in patients, suggesting that heterogeneity becomes most obvious over large-scale patterns.

Whole-brain cross-subject functional heterogeneity characterizes psychosis during rest and task. Developmental and pathophysiological consequences are discussed.