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Abstract Cognitive dysfunction is a core feature of many brain disorders, including schizophrenia (SZ), and has been linked to aberrant brain activations. However, it is unclear how these activation abnormalities emerge. We propose that aberrant flow of brain activity across functional connectivity (FC) pathways leads to altered activations that produce cognitive dysfunction in SZ. We tested this hypothesis using activity flow mapping, an approach that models the movement of task-related activity between brain regions as a function of FC. Using functional magnetic resonance imaging data from SZ individuals and healthy controls during a working memory task, we found that activity flow models accurately predict aberrant cognitive activations across multiple brain networks. Within the same framework, we simulated a connectivity-based clinical intervention, predicting specific treatments that normalized brain activations and behavior in patients. Our results suggest that dysfunctional t

United statesLos angelesLos angeles countyNew jerseyYale universityUniversity of californiaConsortium for neuropsychiatric phenomicsSlovenian research agencyAustralian government national healthBlackthorn therapeutics incResearch council emerging leaderLos angeles county department of mental healthUniversity of new jerseyAhmanson lovelace brain mapping center siemensStaglin centerOffice of advanced research computing