Schizophrenia is a debilitating neuropsychiatric disorder whose underlying correlates remain unclear despite decades of neuroimaging investigation. One contentious topic concerns the role of global signal fluctuations and how they affect more focal functional changes. Moreover, it has been difficult to pinpoint causal mechanisms of circuit disruption. Here we analysed resting-state fMRI data from 47 schizophrenia patients and 118 age-matched healthy controls and used dynamical analyses to investigate how global fluctuations and other functional metastable states are affected by this disorder. We then used in-silico perturbation of a whole-brain model to identify critical areas involved in the disease. We found that brain dynamics in the schizophrenic group were characterised by an increased probability of globally coherent states and reduced recurrence of a substate dominated by coupled activity in the default mode and limbic networks. Perturbing a set of temporoparietal sensory and associative areas in a model of the healthy brain reproduced global pathological dynamics. Healthy brain dynamics were instead restored by perturbing a set of medial fronto-temporal and cingulate regions in the model of pathology. These results highlight the relevance of global signal alterations in schizophrenia and identify a set of vulnerable areas involved in determining a shift in brain state.

Schizophrenia is a debilitating neuropsychiatric disorder whose underlying correlates remain unclear despite decades of neuroimaging investigation. One contentious topic concerns the role of global signal (GS) fluctuations and how they affect more focal functional changes. Moreover, it has been difficult to pinpoint causal mechanisms of circuit disruption. Here, we analyzed resting-state fMRI data from 47 schizophrenia patients and 118 age-matched healthy controls and used dynamical analyses to investigate how global fluctuations and other functional metastable states are affected by this disorder. We found that brain dynamics in the schizophrenia group were characterized by an increased probability of globally coherent states and reduced recurrence of a substate dominated by coupled activity in the default mode and limbic networks. We then used the in silico perturbation of a whole-brain model to identify critical areas involved in the disease. Perturbing a set of temporo-parietal sensory and associative areas in a model of the healthy brain reproduced global pathological dynamics. Healthy brain dynamics were instead restored by perturbing a set of medial fronto-temporal and cingulate regions in the model of pathology. These results highlight the relevance of GS alterations in schizophrenia and identify a set of vulnerable areas involved in determining a shift in brain state.